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Showing 1 - 200 of 3030 Journals sorted alphabetically
AASRI Procedia     Open Access   (Followers: 15)
Academic Pediatrics     Hybrid Journal   (Followers: 20, SJR: 1.402, h-index: 51)
Academic Radiology     Hybrid Journal   (Followers: 16, SJR: 1.008, h-index: 75)
Accident Analysis & Prevention     Partially Free   (Followers: 79, SJR: 1.109, h-index: 94)
Accounting Forum     Hybrid Journal   (Followers: 22, SJR: 0.612, h-index: 27)
Accounting, Organizations and Society     Hybrid Journal   (Followers: 27, SJR: 2.515, h-index: 90)
Achievements in the Life Sciences     Open Access   (Followers: 4)
Acta Anaesthesiologica Taiwanica     Open Access   (Followers: 5, SJR: 0.338, h-index: 19)
Acta Astronautica     Hybrid Journal   (Followers: 303, SJR: 0.726, h-index: 43)
Acta Automatica Sinica     Full-text available via subscription   (Followers: 3)
Acta Biomaterialia     Hybrid Journal   (Followers: 25, SJR: 2.02, h-index: 104)
Acta Colombiana de Cuidado Intensivo     Full-text available via subscription  
Acta de Investigación Psicológica     Open Access   (Followers: 2)
Acta Ecologica Sinica     Open Access   (Followers: 8, SJR: 0.172, h-index: 29)
Acta Haematologica Polonica     Free   (SJR: 0.123, h-index: 8)
Acta Histochemica     Hybrid Journal   (Followers: 3, SJR: 0.604, h-index: 38)
Acta Materialia     Hybrid Journal   (Followers: 196, SJR: 3.683, h-index: 202)
Acta Mathematica Scientia     Full-text available via subscription   (Followers: 5, SJR: 0.615, h-index: 21)
Acta Mechanica Solida Sinica     Full-text available via subscription   (Followers: 9, SJR: 0.442, h-index: 21)
Acta Oecologica     Hybrid Journal   (Followers: 9, SJR: 0.915, h-index: 53)
Acta Otorrinolaringologica (English Edition)     Full-text available via subscription   (Followers: 1)
Acta Otorrinolaringológica Española     Full-text available via subscription   (Followers: 3, SJR: 0.311, h-index: 16)
Acta Pharmaceutica Sinica B     Open Access   (Followers: 2)
Acta Poética     Open Access   (Followers: 4)
Acta Psychologica     Hybrid Journal   (Followers: 21, SJR: 1.365, h-index: 73)
Acta Sociológica     Open Access  
Acta Tropica     Hybrid Journal   (Followers: 5, SJR: 1.059, h-index: 77)
Acta Urológica Portuguesa     Open Access  
Actas Dermo-Sifiliograficas     Full-text available via subscription   (Followers: 4)
Actas Dermo-Sifiliográficas (English Edition)     Full-text available via subscription   (Followers: 3)
Actas Urológicas Españolas     Full-text available via subscription   (Followers: 3, SJR: 0.383, h-index: 19)
Actas Urológicas Españolas (English Edition)     Full-text available via subscription   (Followers: 2)
Actualites Pharmaceutiques     Full-text available via subscription   (Followers: 5, SJR: 0.141, h-index: 3)
Actualites Pharmaceutiques Hospitalieres     Full-text available via subscription   (Followers: 4, SJR: 0.112, h-index: 2)
Acupuncture and Related Therapies     Hybrid Journal   (Followers: 4)
Ad Hoc Networks     Hybrid Journal   (Followers: 11, SJR: 0.967, h-index: 57)
Addictive Behaviors     Hybrid Journal   (Followers: 15, SJR: 1.514, h-index: 92)
Addictive Behaviors Reports     Open Access   (Followers: 5)
Additive Manufacturing     Hybrid Journal   (Followers: 7, SJR: 1.039, h-index: 5)
Additives for Polymers     Full-text available via subscription   (Followers: 20)
Advanced Drug Delivery Reviews     Hybrid Journal   (Followers: 120, SJR: 5.2, h-index: 222)
Advanced Engineering Informatics     Hybrid Journal   (Followers: 11, SJR: 1.265, h-index: 53)
Advanced Powder Technology     Hybrid Journal   (Followers: 16, SJR: 0.739, h-index: 33)
Advances in Accounting     Hybrid Journal   (Followers: 8, SJR: 0.299, h-index: 15)
Advances in Agronomy     Full-text available via subscription   (Followers: 15, SJR: 2.071, h-index: 82)
Advances in Anesthesia     Full-text available via subscription   (Followers: 24, SJR: 0.169, h-index: 4)
Advances in Antiviral Drug Design     Full-text available via subscription   (Followers: 3)
Advances in Applied Mathematics     Full-text available via subscription   (Followers: 6, SJR: 1.054, h-index: 35)
Advances in Applied Mechanics     Full-text available via subscription   (Followers: 10, SJR: 0.801, h-index: 26)
Advances in Applied Microbiology     Full-text available via subscription   (Followers: 21, SJR: 1.286, h-index: 49)
Advances In Atomic, Molecular, and Optical Physics     Full-text available via subscription   (Followers: 16, SJR: 3.31, h-index: 42)
Advances in Biological Regulation     Hybrid Journal   (Followers: 4, SJR: 2.277, h-index: 43)
Advances in Botanical Research     Full-text available via subscription   (Followers: 3, SJR: 0.619, h-index: 48)
Advances in Cancer Research     Full-text available via subscription   (Followers: 26, SJR: 2.215, h-index: 78)
Advances in Carbohydrate Chemistry and Biochemistry     Full-text available via subscription   (Followers: 9, SJR: 0.9, h-index: 30)
Advances in Catalysis     Full-text available via subscription   (Followers: 5, SJR: 2.139, h-index: 42)
Advances in Cellular and Molecular Biology of Membranes and Organelles     Full-text available via subscription   (Followers: 12)
Advances in Chemical Engineering     Full-text available via subscription   (Followers: 24, SJR: 0.183, h-index: 23)
Advances in Child Development and Behavior     Full-text available via subscription   (Followers: 10, SJR: 0.665, h-index: 29)
Advances in Chronic Kidney Disease     Full-text available via subscription   (Followers: 8, SJR: 1.268, h-index: 45)
Advances in Clinical Chemistry     Full-text available via subscription   (Followers: 28, SJR: 0.938, h-index: 33)
Advances in Colloid and Interface Science     Full-text available via subscription   (Followers: 18, SJR: 2.314, h-index: 130)
Advances in Computers     Full-text available via subscription   (Followers: 16, SJR: 0.223, h-index: 22)
Advances in Developmental Biology     Full-text available via subscription   (Followers: 11)
Advances in Digestive Medicine     Open Access   (Followers: 4)
Advances in DNA Sequence-Specific Agents     Full-text available via subscription   (Followers: 5)
Advances in Drug Research     Full-text available via subscription   (Followers: 22)
Advances in Ecological Research     Full-text available via subscription   (Followers: 39, SJR: 3.25, h-index: 43)
Advances in Engineering Software     Hybrid Journal   (Followers: 25, SJR: 0.486, h-index: 10)
Advances in Experimental Biology     Full-text available via subscription   (Followers: 7)
Advances in Experimental Social Psychology     Full-text available via subscription   (Followers: 38, SJR: 5.465, h-index: 64)
Advances in Exploration Geophysics     Full-text available via subscription   (Followers: 3)
Advances in Fluorine Science     Full-text available via subscription   (Followers: 8)
Advances in Food and Nutrition Research     Full-text available via subscription   (Followers: 41, SJR: 0.674, h-index: 38)
Advances in Fuel Cells     Full-text available via subscription   (Followers: 14)
Advances in Genetics     Full-text available via subscription   (Followers: 15, SJR: 2.558, h-index: 54)
Advances in Genome Biology     Full-text available via subscription   (Followers: 11)
Advances in Geophysics     Full-text available via subscription   (Followers: 6, SJR: 2.325, h-index: 20)
Advances in Heat Transfer     Full-text available via subscription   (Followers: 18, SJR: 0.906, h-index: 24)
Advances in Heterocyclic Chemistry     Full-text available via subscription   (Followers: 8, SJR: 0.497, h-index: 31)
Advances in Human Factors/Ergonomics     Full-text available via subscription   (Followers: 22)
Advances in Imaging and Electron Physics     Full-text available via subscription   (Followers: 2, SJR: 0.396, h-index: 27)
Advances in Immunology     Full-text available via subscription   (Followers: 33, SJR: 4.152, h-index: 85)
Advances in Inorganic Chemistry     Full-text available via subscription   (Followers: 9, SJR: 1.132, h-index: 42)
Advances in Insect Physiology     Full-text available via subscription   (Followers: 3, SJR: 1.274, h-index: 27)
Advances in Integrative Medicine     Hybrid Journal   (Followers: 4)
Advances in Intl. Accounting     Full-text available via subscription   (Followers: 4)
Advances in Life Course Research     Hybrid Journal   (Followers: 7, SJR: 0.764, h-index: 15)
Advances in Lipobiology     Full-text available via subscription   (Followers: 1)
Advances in Magnetic and Optical Resonance     Full-text available via subscription   (Followers: 8)
Advances in Marine Biology     Full-text available via subscription   (Followers: 16, SJR: 1.645, h-index: 45)
Advances in Mathematics     Full-text available via subscription   (Followers: 10, SJR: 3.261, h-index: 65)
Advances in Medical Sciences     Hybrid Journal   (Followers: 5, SJR: 0.489, h-index: 25)
Advances in Medicinal Chemistry     Full-text available via subscription   (Followers: 5)
Advances in Microbial Physiology     Full-text available via subscription   (Followers: 4, SJR: 1.44, h-index: 51)
Advances in Molecular and Cell Biology     Full-text available via subscription   (Followers: 21)
Advances in Molecular and Cellular Endocrinology     Full-text available via subscription   (Followers: 10)
Advances in Molecular Toxicology     Full-text available via subscription   (Followers: 6, SJR: 0.324, h-index: 8)
Advances in Nanoporous Materials     Full-text available via subscription   (Followers: 3)
Advances in Oncobiology     Full-text available via subscription   (Followers: 3)
Advances in Organometallic Chemistry     Full-text available via subscription   (Followers: 15, SJR: 2.885, h-index: 45)
Advances in Parallel Computing     Full-text available via subscription   (Followers: 7, SJR: 0.148, h-index: 11)
Advances in Parasitology     Full-text available via subscription   (Followers: 7, SJR: 2.37, h-index: 73)
Advances in Pediatrics     Full-text available via subscription   (Followers: 20, SJR: 0.4, h-index: 28)
Advances in Pharmaceutical Sciences     Full-text available via subscription   (Followers: 14)
Advances in Pharmacology     Full-text available via subscription   (Followers: 13, SJR: 1.718, h-index: 58)
Advances in Physical Organic Chemistry     Full-text available via subscription   (Followers: 7, SJR: 0.384, h-index: 26)
Advances in Phytomedicine     Full-text available via subscription  
Advances in Planar Lipid Bilayers and Liposomes     Full-text available via subscription   (Followers: 3, SJR: 0.248, h-index: 11)
Advances in Plant Biochemistry and Molecular Biology     Full-text available via subscription   (Followers: 8)
Advances in Plant Pathology     Full-text available via subscription   (Followers: 5)
Advances in Porous Media     Full-text available via subscription   (Followers: 4)
Advances in Protein Chemistry     Full-text available via subscription   (Followers: 18)
Advances in Protein Chemistry and Structural Biology     Full-text available via subscription   (Followers: 17, SJR: 1.5, h-index: 62)
Advances in Psychology     Full-text available via subscription   (Followers: 56)
Advances in Quantum Chemistry     Full-text available via subscription   (Followers: 5, SJR: 0.478, h-index: 32)
Advances in Radiation Oncology     Open Access  
Advances in Small Animal Medicine and Surgery     Hybrid Journal   (Followers: 1, SJR: 0.1, h-index: 2)
Advances in Space Research     Full-text available via subscription   (Followers: 332, SJR: 0.606, h-index: 65)
Advances in Structural Biology     Full-text available via subscription   (Followers: 7)
Advances in Surgery     Full-text available via subscription   (Followers: 6, SJR: 0.823, h-index: 27)
Advances in the Study of Behavior     Full-text available via subscription   (Followers: 28, SJR: 1.321, h-index: 56)
Advances in Veterinary Medicine     Full-text available via subscription   (Followers: 14)
Advances in Veterinary Science and Comparative Medicine     Full-text available via subscription   (Followers: 12)
Advances in Virus Research     Full-text available via subscription   (Followers: 5, SJR: 1.878, h-index: 68)
Advances in Water Resources     Hybrid Journal   (Followers: 42, SJR: 2.408, h-index: 94)
Aeolian Research     Hybrid Journal   (Followers: 5, SJR: 0.973, h-index: 22)
Aerospace Science and Technology     Hybrid Journal   (Followers: 304, SJR: 0.816, h-index: 49)
AEU - Intl. J. of Electronics and Communications     Hybrid Journal   (Followers: 8, SJR: 0.318, h-index: 36)
African J. of Emergency Medicine     Open Access   (Followers: 4, SJR: 0.344, h-index: 6)
Ageing Research Reviews     Hybrid Journal   (Followers: 7, SJR: 3.289, h-index: 78)
Aggression and Violent Behavior     Hybrid Journal   (Followers: 390, SJR: 1.385, h-index: 72)
Agri Gene     Hybrid Journal  
Agricultural and Forest Meteorology     Hybrid Journal   (Followers: 15, SJR: 2.18, h-index: 116)
Agricultural Systems     Hybrid Journal   (Followers: 29, SJR: 1.275, h-index: 74)
Agricultural Water Management     Hybrid Journal   (Followers: 36, SJR: 1.546, h-index: 79)
Agriculture and Agricultural Science Procedia     Open Access  
Agriculture and Natural Resources     Open Access   (Followers: 1)
Agriculture, Ecosystems & Environment     Hybrid Journal   (Followers: 48, SJR: 1.879, h-index: 120)
Ain Shams Engineering J.     Open Access   (Followers: 5, SJR: 0.434, h-index: 14)
Air Medical J.     Hybrid Journal   (Followers: 3, SJR: 0.234, h-index: 18)
AKCE Intl. J. of Graphs and Combinatorics     Open Access   (SJR: 0.285, h-index: 3)
Alcohol     Hybrid Journal   (Followers: 9, SJR: 0.922, h-index: 66)
Alcoholism and Drug Addiction     Open Access   (Followers: 5)
Alergologia Polska : Polish J. of Allergology     Full-text available via subscription   (Followers: 1)
Alexandria Engineering J.     Open Access   (Followers: 1, SJR: 0.436, h-index: 12)
Alexandria J. of Medicine     Open Access  
Algal Research     Partially Free   (Followers: 7, SJR: 2.05, h-index: 20)
Alkaloids: Chemical and Biological Perspectives     Full-text available via subscription   (Followers: 3)
Allergologia et Immunopathologia     Full-text available via subscription   (Followers: 1, SJR: 0.46, h-index: 29)
Allergology Intl.     Open Access   (Followers: 5, SJR: 0.776, h-index: 35)
ALTER - European J. of Disability Research / Revue Européenne de Recherche sur le Handicap     Full-text available via subscription   (Followers: 6, SJR: 0.158, h-index: 9)
Alzheimer's & Dementia     Hybrid Journal   (Followers: 45, SJR: 4.289, h-index: 64)
Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring     Open Access   (Followers: 5)
Alzheimer's & Dementia: Translational Research & Clinical Interventions     Open Access   (Followers: 3)
American Heart J.     Hybrid Journal   (Followers: 45, SJR: 3.157, h-index: 153)
American J. of Cardiology     Hybrid Journal   (Followers: 47, SJR: 2.063, h-index: 186)
American J. of Emergency Medicine     Hybrid Journal   (Followers: 34, SJR: 0.574, h-index: 65)
American J. of Geriatric Pharmacotherapy     Full-text available via subscription   (Followers: 6, SJR: 1.091, h-index: 45)
American J. of Geriatric Psychiatry     Hybrid Journal   (Followers: 14, SJR: 1.653, h-index: 93)
American J. of Human Genetics     Hybrid Journal   (Followers: 32, SJR: 8.769, h-index: 256)
American J. of Infection Control     Hybrid Journal   (Followers: 25, SJR: 1.259, h-index: 81)
American J. of Kidney Diseases     Hybrid Journal   (Followers: 31, SJR: 2.313, h-index: 172)
American J. of Medicine     Hybrid Journal   (Followers: 48, SJR: 2.023, h-index: 189)
American J. of Medicine Supplements     Full-text available via subscription   (Followers: 3)
American J. of Obstetrics and Gynecology     Hybrid Journal   (Followers: 174, SJR: 2.255, h-index: 171)
American J. of Ophthalmology     Hybrid Journal   (Followers: 51, SJR: 2.803, h-index: 148)
American J. of Ophthalmology Case Reports     Open Access   (Followers: 2)
American J. of Orthodontics and Dentofacial Orthopedics     Full-text available via subscription   (Followers: 6, SJR: 1.249, h-index: 88)
American J. of Otolaryngology     Hybrid Journal   (Followers: 22, SJR: 0.59, h-index: 45)
American J. of Pathology     Hybrid Journal   (Followers: 23, SJR: 2.653, h-index: 228)
American J. of Preventive Medicine     Hybrid Journal   (Followers: 21, SJR: 2.764, h-index: 154)
American J. of Surgery     Hybrid Journal   (Followers: 32, SJR: 1.286, h-index: 125)
American J. of the Medical Sciences     Hybrid Journal   (Followers: 13, SJR: 0.653, h-index: 70)
Ampersand : An Intl. J. of General and Applied Linguistics     Open Access   (Followers: 5)
Anaerobe     Hybrid Journal   (Followers: 4, SJR: 1.066, h-index: 51)
Anaesthesia & Intensive Care Medicine     Full-text available via subscription   (Followers: 52, SJR: 0.124, h-index: 9)
Anaesthesia Critical Care & Pain Medicine     Full-text available via subscription   (Followers: 3)
Anales de Cirugia Vascular     Full-text available via subscription  
Anales de Pediatría     Full-text available via subscription   (Followers: 2, SJR: 0.209, h-index: 27)
Anales de Pediatría (English Edition)     Full-text available via subscription  
Anales de Pediatría Continuada     Full-text available via subscription   (SJR: 0.104, h-index: 3)
Analytic Methods in Accident Research     Hybrid Journal   (Followers: 2, SJR: 2.577, h-index: 7)
Analytica Chimica Acta     Hybrid Journal   (Followers: 38, SJR: 1.548, h-index: 152)
Analytical Biochemistry     Hybrid Journal   (Followers: 154, SJR: 0.725, h-index: 154)
Analytical Chemistry Research     Open Access   (Followers: 7, SJR: 0.18, h-index: 2)
Analytical Spectroscopy Library     Full-text available via subscription   (Followers: 10)
Anesthésie & Réanimation     Full-text available via subscription  
Anesthesiology Clinics     Full-text available via subscription   (Followers: 21, SJR: 0.421, h-index: 40)
Angiología     Full-text available via subscription   (SJR: 0.124, h-index: 9)
Angiologia e Cirurgia Vascular     Open Access  
Animal Behaviour     Hybrid Journal   (Followers: 143, SJR: 1.907, h-index: 126)
Animal Feed Science and Technology     Hybrid Journal   (Followers: 5, SJR: 1.151, h-index: 83)
Animal Reproduction Science     Hybrid Journal   (Followers: 5, SJR: 0.711, h-index: 78)
Annales d'Endocrinologie     Full-text available via subscription   (SJR: 0.394, h-index: 30)
Annales d'Urologie     Full-text available via subscription  
Annales de Cardiologie et d'Angéiologie     Full-text available via subscription   (SJR: 0.177, h-index: 13)
Annales de Chirurgie de la Main et du Membre Supérieur     Full-text available via subscription  
Annales de Chirurgie Plastique Esthétique     Full-text available via subscription   (Followers: 2, SJR: 0.354, h-index: 22)
Annales de Chirurgie Vasculaire     Full-text available via subscription   (Followers: 1)

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Journal Cover Advanced Drug Delivery Reviews
  [SJR: 5.2]   [H-I: 222]   [120 followers]  Follow
   Hybrid Journal Hybrid journal (It can contain Open Access articles)
   ISSN (Print) 0169-409X
   Published by Elsevier Homepage  [3030 journals]
  • Radiotherapy for Cancer: Present and Future
    • Authors: Christine Allen; Sohyoung Her; David A. Jaffray
      Pages: 1 - 2
      Abstract: Publication date: 15 January 2017
      Source:Advanced Drug Delivery Reviews, Volume 109
      Author(s): Christine Allen, Sohyoung Her, David A. Jaffray

      PubDate: 2017-02-10T10:38:49Z
      DOI: 10.1016/j.addr.2017.01.004
      Issue No: Vol. 109 (2017)
  • Advancements in brachytherapy
    • Authors: Kari Tanderup; Cynthia Ménard; Csaba Polgar; Jacob Christian Lindegaard; Christian Kirisits; Richard Pötter
      Pages: 15 - 25
      Abstract: Publication date: 15 January 2017
      Source:Advanced Drug Delivery Reviews, Volume 109
      Author(s): Kari Tanderup, Cynthia Ménard, Csaba Polgar, Jacob Christian Lindegaard, Christian Kirisits, Richard Pötter
      Brachytherapy is a radiotherapy modality associated with a highly focal dose distribution. Brachytherapy treats the cancer tissue from the inside, and the radiation does not travel through healthy tissue to reach the target as with external beam radiotherapy techniques. The nature of brachytherapy makes it attractive for boosting limited size target volumes to very high doses while sparing normal tissues. Significant developments over the last decades have increased the use of 3D image guided procedures with the utilization of CT, MRI, US and PET. This has taken brachytherapy to a new level in terms of controlling dose and demonstrating excellent clinical outcome. Interests in focal, hypofractionated and adaptive treatments are increasing, and brachytherapy has significant potential to develop further in these directions with current and new treatment indications.
      Graphical abstract image

      PubDate: 2017-02-10T10:38:49Z
      DOI: 10.1016/j.addr.2016.09.002
      Issue No: Vol. 109 (2017)
  • Molecular targeting of hypoxia in radiotherapy
    • Authors: Sergio Rey; Luana Schito; Marianne Koritzinsky; Bradly G. Wouters
      Pages: 45 - 62
      Abstract: Publication date: 15 January 2017
      Source:Advanced Drug Delivery Reviews, Volume 109
      Author(s): Sergio Rey, Luana Schito, Marianne Koritzinsky, Bradly G. Wouters
      Hypoxia (low O2) is an essential microenvironmental driver of phenotypic diversity in human solid cancers. Hypoxic cancer cells hijack evolutionarily conserved, O2- sensitive pathways eliciting molecular adaptations that impact responses to radiotherapy, tumor recurrence and patient survival. In this review, we summarize the radiobiological, genetic, epigenetic and metabolic mechanisms orchestrating oncogenic responses to hypoxia. In addition, we outline emerging hypoxia- targeting strategies that hold promise for individualized cancer therapy in the context of radiotherapy and drug delivery.
      Graphical abstract image

      PubDate: 2017-02-10T10:38:49Z
      DOI: 10.1016/j.addr.2016.10.002
      Issue No: Vol. 109 (2017)
  • Cancer stem cells: Radioresistance, prediction of radiotherapy outcome and
           specific targets for combined treatments
    • Authors: Mechthild Krause; Anna Dubrovska; Annett Linge; Michael Baumann
      Pages: 63 - 73
      Abstract: Publication date: 15 January 2017
      Source:Advanced Drug Delivery Reviews, Volume 109
      Author(s): Mechthild Krause, Anna Dubrovska, Annett Linge, Michael Baumann
      Inactivation of cancer stem cells (CSCs) is of utmost importance for tumor cure after radiotherapy. An increasing body of evidence complies with a higher radioresistance of CSCs compared to the mass of tumor cells, supporting the use of CSC related biomarkers for prediction of radiotherapy outcome. Treatment individualization strategies for patient groups with vastly different risk of recurrence will most likely require application of more than one biomarker. Specifically, inclusion of established biomarkers like tumor size for primary radio(chemo)therapy or human papilloma virus (HPV) infection status in head and neck squamous cell carcinoma seems to be of very high relevance. The high heterogeneity of CSC subclones along with changes of the functional behavior of individual tumors under treatment underlines the importance of the selection of the optimal timepoint(s) of biomarker evaluation, but also provides a potential therapeutic target for combined treatment approaches with irradiation.
      Graphical abstract image

      PubDate: 2017-02-10T10:38:49Z
      DOI: 10.1016/j.addr.2016.02.002
      Issue No: Vol. 109 (2017)
  • Integrating chemoradiation and molecularly targeted therapy
    • Authors: Daniel R. Wahl; Theodore S. Lawrence
      Pages: 74 - 83
      Abstract: Publication date: 15 January 2017
      Source:Advanced Drug Delivery Reviews, Volume 109
      Author(s): Daniel R. Wahl, Theodore S. Lawrence
      While the advent of combined chemoradiation has improved outcomes for innumerable patients with locally advanced cancers, further improvements are urgently needed. Escalation of either chemotherapy or radiotherapy is associated with unacceptable toxicity. An alternative strategy is the integration of chemoradiation and molecularly targeted therapies, which exploits biological differences between cancer and normal tissue and should therefore increase efficacy while maintaining tolerable toxicity. Combining chemoradiation with agents that modulate tumor-specific pathways such as cell cycle checkpoints, PARP signaling, EGFR signaling, the PI3K/AKT/mTOR axis and androgen signaling has shown immense promise in preclinical and clinical studies, as have combinations with environmentally-targeted agents against the immune system and angiogenesis. The optimal application of these strategies will likely require consideration of molecular heterogeneity between patients and within individual tumors.
      Graphical abstract image

      PubDate: 2017-02-10T10:38:49Z
      DOI: 10.1016/j.addr.2015.11.007
      Issue No: Vol. 109 (2017)
  • Gold nanoparticles for applications in cancer radiotherapy: Mechanisms and
           recent advancements
    • Authors: Sohyoung Her; David A. Jaffray; Christine Allen
      Pages: 84 - 101
      Abstract: Publication date: 15 January 2017
      Source:Advanced Drug Delivery Reviews, Volume 109
      Author(s): Sohyoung Her, David A. Jaffray, Christine Allen
      Gold nanoparticles (AuNPs) have emerged as novel radiosensitizers owing to their high X-ray absorption, synthetic versatility, and unique chemical, electronic and optical properties. Multi-disciplinary research performed over the past decade has demonstrated the potential of AuNP-based radiosensitizers, and identified possible mechanisms underlying the observed radiation enhancement effects of AuNPs. Despite promising findings from pre-clinical studies, the benefits of AuNP radiosensitization have yet to successfully translate into clinical practice. In this review, we present an overview of the current state of AuNP-based radiosensitization in the context of the physical, chemical and biological modes of radiosensitization. As well, recent advancements that focus on formulation design and enable multi-modality treatment and clinical utilization are discussed, concluding with design considerations to guide the development of next generation AuNPs for clinical applications.
      Graphical abstract image

      PubDate: 2017-02-10T10:38:49Z
      DOI: 10.1016/j.addr.2015.12.012
      Issue No: Vol. 109 (2017)
  • Radioimmunotherapy of cancer with high linear energy transfer (LET)
           radiation delivered by radionuclides emitting α-particles or Auger
    • Authors: Sadaf Aghevlian; Amanda J. Boyle; Raymond M. Reilly
      Pages: 102 - 118
      Abstract: Publication date: 15 January 2017
      Source:Advanced Drug Delivery Reviews, Volume 109
      Author(s): Sadaf Aghevlian, Amanda J. Boyle, Raymond M. Reilly
      Radioimmunotherapy (RIT) aims to selectively deliver radionuclides emitting α-particles, β-particles or Auger electrons to tumors by conjugation to monoclonal antibodies (mAbs) that recognize tumor-associated antigens/receptors. The approach has been most successful for treatment of non-Hodgkin's B-cell lymphoma but challenges have been encountered in extending these promising results to the treatment of solid malignancies. These challenges include the low potency of β-particle emitters such as 131I, 177Lu or 90Y which have been commonly conjugated to the mAbs, due to their low linear energy transfer (LET=0.1–1.0keV/μm). Furthermore, since the β-particles have a 2–10mm range, there has been dose-limiting non-specific toxicity to hematopoietic stem cells in the bone marrow (BM) due to the cross-fire effect. Conjugation of mAbs to α-particle-emitters (e.g. 225Ac, 213Bi, 212Pb or 211At) or Auger electron-emitters (e.g. 111In, 67Ga, 123I or 125I) would increase the potency of RIT due to their high LET (50–230keV/μm and 4 to 26keV/μm, respectively). In addition, α-particles have a range in tissues of 28–100μm and Auger electrons are nanometer in range which greatly reduces or eliminates the cross-fire effect compared to β-particles, potentially reducing their non-specific toxicity to the BM. In this review, we describe the results of preclinical and clinical studies of RIT of cancer using radioimmunoconjugates emitting α-particles or Auger electrons, and discuss the potential of these high LET forms of radiation to improve the outcome of cancer patients.
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      PubDate: 2017-02-10T10:38:49Z
      DOI: 10.1016/j.addr.2015.12.003
      Issue No: Vol. 109 (2017)
  • Radiation effects on the tumor microenvironment: Implications for
           nanomedicine delivery
    • Authors: Shawn Stapleton; David Jaffray; Michael Milosevic
      Pages: 119 - 130
      Abstract: Publication date: 15 January 2017
      Source:Advanced Drug Delivery Reviews, Volume 109
      Author(s): Shawn Stapleton, David Jaffray, Michael Milosevic
      The tumor microenvironment has an important influence on cancer biological and clinical behavior and radiation treatment (RT) response. However, RT also influences the tumor microenvironment in a complex and dynamic manner that can either reinforce or inhibit this response and the likelihood of long-term disease control in patients. It is increasingly evident that the interplay between RT and the tumor microenvironment can be exploited to enhance the accumulation and intra-tumoral distribution of nanoparticles, mediated by changes to the vasculature and stroma with secondary effects on hypoxia, interstitial fluid pressure (IFP), solid tissue pressure (STP), and the recruitment and activation of bone marrow-derived myeloid cells (BMDCs). The use of RT to modulate nanoparticle drug delivery offers an exciting opportunity to improve antitumor efficacy. This review explores the interplay between RT and the tumor microenvironment, and the integrated effects on nanoparticle drug delivery and efficacy.
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      PubDate: 2017-02-10T10:38:49Z
      DOI: 10.1016/j.addr.2016.05.021
      Issue No: Vol. 109 (2017)
  • Decision support systems for personalized and participative radiation
    • Authors: Philippe Lambin; Jaap Zindler; Ben G.L. Vanneste; Lien Van De Voorde; Daniëlle Eekers; Inge Compter; Kranthi Marella Panth; Jurgen Peerlings; Ruben T.H.M. Larue; Timo M. Deist; Arthur Jochems; Tim Lustberg; Johan van Soest; Evelyn E.C. de Jong; Aniek J.G. Even; Bart Reymen; Nicolle Rekers; Marike van Gisbergen; Erik Roelofs; Sara Carvalho; Ralph T.H. Leijenaar; Catharina M.L. Zegers; Maria Jacobs; Janita van Timmeren; Patricia Brouwers; Jonathan A. Lal; Ludwig Dubois; Ala Yaromina; Evert Jan Van Limbergen; Maaike Berbee; Wouter van Elmpt; Cary Oberije; Bram Ramaekers; Andre Dekker; Liesbeth J. Boersma; Frank Hoebers; Kim M. Smits; Adriana J. Berlanga; Sean Walsh
      Pages: 131 - 153
      Abstract: Publication date: 15 January 2017
      Source:Advanced Drug Delivery Reviews, Volume 109
      Author(s): Philippe Lambin, Jaap Zindler, Ben G.L. Vanneste, Lien Van De Voorde, Daniëlle Eekers, Inge Compter, Kranthi Marella Panth, Jurgen Peerlings, Ruben T.H.M. Larue, Timo M. Deist, Arthur Jochems, Tim Lustberg, Johan van Soest, Evelyn E.C. de Jong, Aniek J.G. Even, Bart Reymen, Nicolle Rekers, Marike van Gisbergen, Erik Roelofs, Sara Carvalho, Ralph T.H. Leijenaar, Catharina M.L. Zegers, Maria Jacobs, Janita van Timmeren, Patricia Brouwers, Jonathan A. Lal, Ludwig Dubois, Ala Yaromina, Evert Jan Van Limbergen, Maaike Berbee, Wouter van Elmpt, Cary Oberije, Bram Ramaekers, Andre Dekker, Liesbeth J. Boersma, Frank Hoebers, Kim M. Smits, Adriana J. Berlanga, Sean Walsh
      A paradigm shift from current population based medicine to personalized and participative medicine is underway. This transition is being supported by the development of clinical decision support systems based on prediction models of treatment outcome. In radiation oncology, these models ‘learn’ using advanced and innovative information technologies (ideally in a distributed fashion — please watch the animation: from all available/appropriate medical data (clinical, treatment, imaging, biological/genetic, etc.) to achieve the highest possible accuracy with respect to prediction of tumor response and normal tissue toxicity. In this position paper, we deliver an overview of the factors that are associated with outcome in radiation oncology and discuss the methodology behind the development of accurate prediction models, which is a multi-faceted process. Subsequent to initial development/validation and clinical introduction, decision support systems should be constantly re-evaluated (through quality assurance procedures) in different patient datasets in order to refine and re-optimize the models, ensuring the continuous utility of the models. In the reasonably near future, decision support systems will be fully integrated within the clinic, with data and knowledge being shared in a standardized, dynamic, and potentially global manner enabling truly personalized and participative medicine.
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      PubDate: 2017-02-10T10:38:49Z
      DOI: 10.1016/j.addr.2016.01.006
      Issue No: Vol. 109 (2017)
  • Editorial: Editors’ Collection 2016
    • Authors: Hamidreza Ghandehari
      First page: 1
      Abstract: Publication date: 1 January 2017
      Source:Advanced Drug Delivery Reviews, Volume 108
      Author(s): Hamidreza Ghandehari

      PubDate: 2017-01-29T07:42:20Z
      DOI: 10.1016/j.addr.2017.01.002
      Issue No: Vol. 108 (2017)
  • Advances in nano-based inner ear delivery systems for the treatment of
           sensorineural hearing loss
    • Authors: Lilun Li; Tiffany Chao; Jason Brant; Bert O'Malley; Andrew Tsourkas; Daqing Li
      Pages: 2 - 12
      Abstract: Publication date: 1 January 2017
      Source:Advanced Drug Delivery Reviews, Volume 108
      Author(s): Lilun Li, Tiffany Chao, Jason Brant, Bert O'Malley, Andrew Tsourkas, Daqing Li
      Sensorineural hearing loss (SNHL) is one of the most common diseases, accounting for about 90% of all hearing loss. Leading causes of SNHL include advanced age, ototoxic medications, noise exposure, inherited and autoimmune disorders. Most of SNHL is irreversible and managed with hearing aids or cochlear implants. Although there is increased understanding of the molecular pathophysiology of SNHL, biologic treatment options are limited due to lack of noninvasive targeted delivery systems. Obstacles of targeted inner ear delivery include anatomic inaccessibility, biotherapeutic instability, and nonspecific delivery. Advances in nanotechnology may provide a solution to these barriers. Nanoparticles can stabilize and carry biomaterials across the round window membrane into the inner ear, and ligand bioconjugation onto nanoparticle surfaces allows for specific targeting. A newer technology, nanohydrogel, may offer noninvasive and sustained biotherapeutic delivery into specific inner ear cells. Nanohydrogel may be used for inner ear dialysis, a potential treatment for ototoxicity-induced SNHL.
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      PubDate: 2017-01-29T07:42:20Z
      DOI: 10.1016/j.addr.2016.01.004
      Issue No: Vol. 108 (2017)
  • Nanomedicine-based intraperitoneal therapy for the treatment of peritoneal
           carcinomatosis — Mission possible?
    • Authors: George R. Dakwar; Molood Shariati; Wouter Willaert; Wim Ceelen; Stefaan C. De Smedt; Katrien Remaut
      Pages: 13 - 24
      Abstract: Publication date: 1 January 2017
      Source:Advanced Drug Delivery Reviews, Volume 108
      Author(s): George R. Dakwar, Molood Shariati, Wouter Willaert, Wim Ceelen, Stefaan C. De Smedt, Katrien Remaut
      Intraperitoneal (IP) drug delivery represents an attractive strategy for the local treatment of peritoneal carcinomatosis (PC). Over the past decade, a lot of effort has been put both in the academia and clinic in developing IP therapeutic approaches that maximize local efficacy while limiting systemic side effects. Also nanomedicines are under investigation for the treatment of tumors confined to the peritoneal cavity, due to their potential to increase the peritoneal retention and to target drugs to the tumor sites as compared to free drugs. Despite the progress reported by multiple clinical studies, there are no FDA approved drugs or formulations for specific use in the IP cavity yet. This review discusses the current clinical management of PC, as well as recent advances in nanomedicine-based IP delivery. We address important challenges to be overcome towards designing optimal nanocarriers for IP therapy in vivo.
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      PubDate: 2017-01-29T07:42:20Z
      DOI: 10.1016/j.addr.2016.07.001
      Issue No: Vol. 108 (2017)
  • Challenges and strategies in anti-cancer nanomedicine development: An
           industry perspective
    • Authors: Jennifer I. Hare; Twan Lammers; Marianne B. Ashford; Sanyogitta Puri; Gert Storm; Simon T. Barry
      Pages: 25 - 38
      Abstract: Publication date: 1 January 2017
      Source:Advanced Drug Delivery Reviews, Volume 108
      Author(s): Jennifer I. Hare, Twan Lammers, Marianne B. Ashford, Sanyogitta Puri, Gert Storm, Simon T. Barry
      Successfully translating anti-cancer nanomedicines from pre-clinical proof of concept to demonstration of therapeutic value in the clinic is challenging. Having made significant advances with drug delivery technologies, we must learn from other areas of oncology drug development, where patient stratification and target-driven design have improved patient outcomes. We should evolve our nanomedicine development strategies to build the patient and disease into the line of sight from the outset. The success of small molecule targeted therapies has been significantly improved by employing a specific decision-making framework, such as AstraZeneca's 5R principle: right target/efficacy, right tissue/exposure, right safety, right patient, and right commercial potential. With appropriate investment and collaboration to generate a platform of evidence supporting the end clinical application, a similar framework can be established for enhancing nanomedicine translation and performance. Building informative data packages to answer these questions requires the following: (I) an improved understanding of the heterogeneity of clinical cancers and of the biological factors influencing the behaviour of nanomedicines in patient tumours; (II) a transition from formulation-driven research to disease-driven development; (III) the implementation of more relevant animal models and testing protocols; and (IV) the pre-selection of the patients most likely to respond to nanomedicine therapies. These challenges must be overcome to improve (the cost-effectiveness of) nanomedicine development and translation, and they are key to establishing superior therapies for patients.
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      PubDate: 2017-01-29T07:42:20Z
      DOI: 10.1016/j.addr.2016.04.025
      Issue No: Vol. 108 (2017)
  • A new chapter in pharmaceutical manufacturing: 3D-printed drug products
    • Authors: James Norman; Rapti D. Madurawe; Christine M.V. Moore; Mansoor A. Khan; Akm Khairuzzaman
      Pages: 39 - 50
      Abstract: Publication date: 1 January 2017
      Source:Advanced Drug Delivery Reviews, Volume 108
      Author(s): James Norman, Rapti D. Madurawe, Christine M.V. Moore, Mansoor A. Khan, Akm Khairuzzaman
      FDA recently approved a 3D-printed drug product in August 2015, which is indicative of a new chapter for pharmaceutical manufacturing. This review article summarizes progress with 3D printed drug products and discusses process development for solid oral dosage forms. 3D printing is a layer-by-layer process capable of producing 3D drug products from digital designs. Traditional pharmaceutical processes, such as tablet compression, have been used for decades with established regulatory pathways. These processes are well understood, but antiquated in terms of process capability and manufacturing flexibility. 3D printing, as a platform technology, has competitive advantages for complex products, personalized products, and products made on-demand. These advantages create opportunities for improving the safety, efficacy, and accessibility of medicines. Although 3D printing differs from traditional manufacturing processes for solid oral dosage forms, risk-based process development is feasible. This review highlights how product and process understanding can facilitate the development of a control strategy for different 3D printing methods. Overall, the authors believe that the recent approval of a 3D printed drug product will stimulate continual innovation in pharmaceutical manufacturing technology. FDA encourages the development of advanced manufacturing technologies, including 3D-printing, using science- and risk-based approaches.
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      PubDate: 2017-01-29T07:42:20Z
      DOI: 10.1016/j.addr.2016.03.001
      Issue No: Vol. 108 (2017)
  • Impact of particle elasticity on particle-based drug delivery systems
    • Authors: Aaron C. Anselmo; Samir Mitragotri
      Pages: 51 - 67
      Abstract: Publication date: 1 January 2017
      Source:Advanced Drug Delivery Reviews, Volume 108
      Author(s): Aaron C. Anselmo, Samir Mitragotri
      Modification of nano/micro-particle physical parameters (e.g. size, shape, surface charge) has proven to be an effective method to enhance their delivery abilities. Recently, advances in particle synthesis have facilitated investigations into the role that particle elasticity plays in modulating drug delivery processes. This review will highlight: (i) methods to tune particle elasticity, (ii) the role particle elasticity plays in cellular internalization, (iii) the role of particle elasticity in modulating circulation times, (iv) the effect of particle elasticity on altering biodistribution and tissue targeting, and (v) the application of computational methods to explain the differences in cellular internalization of particles of different elasticities. Overall, literature reports suggest a complex relationship between particle elasticity and drug delivery processes. Despite this complex relationship, it is clear from numerous in vitro and in vivo studies that particle elasticity is an important parameter that can be leveraged to improve blood circulation, tissue targeting, and specific interactions with cells.
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      PubDate: 2017-01-29T07:42:20Z
      DOI: 10.1016/j.addr.2016.01.007
      Issue No: Vol. 108 (2017)
  • Mechanoresponsive materials for drug delivery: Harnessing forces for
           controlled release
    • Authors: Julia Wang; Jonah A. Kaplan; Yolonda L. Colson; Mark W. Grinstaff
      Pages: 68 - 82
      Abstract: Publication date: 1 January 2017
      Source:Advanced Drug Delivery Reviews, Volume 108
      Author(s): Julia Wang, Jonah A. Kaplan, Yolonda L. Colson, Mark W. Grinstaff
      Mechanically-activated delivery systems harness existing physiological and/or externally-applied forces to provide spatiotemporal control over the release of active agents. Current strategies to deliver therapeutic proteins and drugs use three types of mechanical stimuli: compression, tension, and shear. Based on the intended application, each stimulus requires specific material selection, in terms of substrate composition and size (e.g., macrostructured materials and nanomaterials), for optimal in vitro and in vivo performance. For example, compressive systems typically utilize hydrogels or elastomeric substrates that respond to and withstand cyclic compressive loading, whereas, tension-responsive systems use composites to compartmentalize payloads. Finally, shear-activated systems are based on nanoassemblies or microaggregates that respond to physiological or externally-applied shear stresses. In order to provide a comprehensive assessment of current research on mechanoresponsive drug delivery, the mechanical stimuli intrinsically present in the human body are first discussed, along with the mechanical forces typically applied during medical device interventions, followed by in-depth descriptions of compression, tension, and shear-mediated drug delivery devices. We conclude by summarizing the progress of current research aimed at integrating mechanoresponsive elements within these devices, identifying additional clinical opportunities for mechanically-activated systems, and discussing future prospects.
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      PubDate: 2017-01-29T07:42:20Z
      DOI: 10.1016/j.addr.2016.11.001
      Issue No: Vol. 108 (2017)
  • Poly(lactic acid) stereocomplexes: A decade of progress
    • Authors: Hideto Tsuji
      Abstract: Publication date: 15 December 2016
      Source:Advanced Drug Delivery Reviews, Volume 107
      Author(s): Hideto Tsuji
      Upon blending enantiomeric poly(l-lactide) [i.e., poly(l-lactic acid) (PLLA)] and poly(d-lactide) (PDLA) [i.e., poly(d-lactic acid) (PDLA)] or synthesis of stereo block poly(lactide) [i.e., poly(lactic acid) (PLA)], a stereocomplex (SC) is formed. PLA SC has a higher melting temperature (or heat resistance), mechanical performance, and hydrolysis-resistance compared to those of neat PLLA and PDLA. Because of such effects, PLA SC has been extensively studied in terms of biomedical and pharmaceutical applications as well as commodity, industrial, and environmental applications. Stereocomplexation stabilizes and strengthens PLA-based hydrogel or nanoparticles for biomedical applications. Stereocomplexation increases the barrier property of PLA-based materials and thereby prolongs drug release from PLA based materials. In addition, PLA SC is attracting significant attention because it can act as a nucleating agent for the widely used biobased polymer PLLA and thereby the heat resistance of PLLA-based materials can be enhanced. Interestingly, a wide variety of SCs other than PLA SC are found to have been formed in the enantiomeric substituted PLA blends and stereo block substituted PLA polymers. In the present review article, a decade of progress in investigation of PLA SCs is summarized.
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      PubDate: 2017-01-08T03:20:18Z
      DOI: 10.1016/j.addr.2015.12.025
      Issue No: Vol. 107 (2017)
  • Special issue: Polylactide (PLA) Based Biopolymers
    • Authors: Robert Langer; Arijit Basu; Abraham J. Domb
      Pages: 1 - 2
      Abstract: Publication date: 15 December 2016
      Source:Advanced Drug Delivery Reviews, Volume 107
      Author(s): Robert Langer, Arijit Basu, Abraham J. Domb

      PubDate: 2017-01-08T03:20:18Z
      DOI: 10.1016/j.addr.2016.11.002
      Issue No: Vol. 107 (2017)
  • Polylactides—Methods of synthesis and characterization
    • Authors: Julia Pretula; Stanislaw Slomkowski; Stanislaw Penczek
      Pages: 3 - 16
      Abstract: Publication date: 15 December 2016
      Source:Advanced Drug Delivery Reviews, Volume 107
      Author(s): Julia Pretula, Stanislaw Slomkowski, Stanislaw Penczek
      Polylactides with various molar masses, microstructures and crystallinities are used as degradable and biocompatible polymers suitable for preparation of drug carriers and temporary medical implants. This paper presents state of current knowledge on synthesis of lactic acids, high purity lactide monomers and their polymerization. Syntheses of high molar mass polylactides by polycondensation of lactic acid and by ring-opening polymerization of lactides are described and their advantages and disadvantages are discussed. Mechanisms of lactide polymerization initiated by metal alkoxides are described. There are presented also results of more recent studies of polymerization initiated with the so-called “no metal” organocatalysts; both anionic and cationic. Presented are advantages and limitations of synthesis of PLA by all the major polymerization processes until now. Some properties of PLA and most important methods used for PLA characterization are also described.
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      PubDate: 2017-01-08T03:20:18Z
      DOI: 10.1016/j.addr.2016.05.002
      Issue No: Vol. 107 (2017)
  • PLA composites: From production to properties
    • Authors: Marius Murariu; Philippe Dubois
      Pages: 17 - 46
      Abstract: Publication date: 15 December 2016
      Source:Advanced Drug Delivery Reviews, Volume 107
      Author(s): Marius Murariu, Philippe Dubois
      Poly(lactic acid) or polylactide (PLA), a biodegradable polyester produced from renewable resources, is used for various applications (biomedical, packaging, textile fibers and technical items). Due to its inherent properties, PLA has a key-position in the market of biopolymers, being one of the most promising candidates for further developments. Unfortunately, PLA suffers from some shortcomings, whereas for the different applications specific end-use properties are required. Therefore, the addition of reinforcing fibers, micro- and/or nanofillers, and selected additives within PLA matrix is considered as a powerful method for obtaining specific end-use characteristics and major improvements of properties. This review highlights recent developments, current results and trends in the field of composites based on PLA. It presents the main advances in PLA properties and reports selected results in relation to the preparation and characterization of the most representative PLA composites. To illustrate the possibility to design the properties of composites, a section is devoted to the production and characterization of innovative PLA-based products filled with thermally-treated calcium sulfate, a by-product from the lactic acid production process. Moreover, are emphasized the last tendencies strongly evidenced in the case of PLA, i.e., the high interest to diversify its uses by moving from biomedical and packaging (biodegradation properties, “disposables”) to technical applications (“durables”).
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      PubDate: 2017-01-08T03:20:18Z
      DOI: 10.1016/j.addr.2016.04.003
      Issue No: Vol. 107 (2017)
  • Poly(lactic acid) blends in biomedical applications
    • Authors: P. Saini; M. Arora; M.N.V. Ravi Kumar
      Pages: 47 - 59
      Abstract: Publication date: 15 December 2016
      Source:Advanced Drug Delivery Reviews, Volume 107
      Author(s): P. Saini, M. Arora, M.N.V. Ravi Kumar
      Poly(lactic acid) (PLA) has become a “material of choice” in biomedical applications for its ability to fulfill complex needs that typically include properties such as biocompatibility, biodegradability, mechanical strength, and processability. Despite the advantages of pure PLA in a wider spectrum of applications, it is limited by its hydrophobicity, low impact toughness, and slow degradation rate. Blending PLA with other polymers offers a convenient option to enhance its properties or generate novel properties for target applications without the need to develop new materials. PLA blends with different natural and synthetic polymers have been developed by solvent and melt blending techniques and further processed based on end-use applications. A variety of PLA blends has been explored for biomedical applications such as drug delivery, implants, sutures, and tissue engineering. This review discusses the opportunities for PLA blends in the biomedical arena, including the overview of blending and postblend processing techniques and the applications of PLA blends currently in use and under development.
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      PubDate: 2017-01-08T03:20:18Z
      DOI: 10.1016/j.addr.2016.06.014
      Issue No: Vol. 107 (2017)
  • Branched polyesters: Preparative strategies and applications
    • Authors: Richard d'Arcy; Jason Burke; Nicola Tirelli
      Pages: 60 - 81
      Abstract: Publication date: 15 December 2016
      Source:Advanced Drug Delivery Reviews, Volume 107
      Author(s): Richard d'Arcy, Jason Burke, Nicola Tirelli
      In the last 20years, the availability of precision chemical tools (e.g. controlled/living polymerizations, ‘click’ reactions) has determined a step change in the complexity of both the macromolecular architecture and the chemical functionality of biodegradable polyesters. A major part in this evolution has been played by the possibilities that controlled macromolecular branching offers in terms of tailored physical/biological performance. This review paper aims to provide an updated overview of preparative techniques that derive hyperbranched, dendritic, comb, grafted polyesters through polycondensation or ring-opening polymerization mechanisms.
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      PubDate: 2017-01-08T03:20:18Z
      DOI: 10.1016/j.addr.2016.05.005
      Issue No: Vol. 107 (2017)
  • Poly(α-hydroxy acid)s and poly(α-hydroxy acid-co-α-amino acid)s derived
           from amino acid
    • Authors: Arijit Basu; Konda Reddy Kunduru; Joshua Katzhendler; Abraham J. Domb
      Pages: 82 - 96
      Abstract: Publication date: 15 December 2016
      Source:Advanced Drug Delivery Reviews, Volume 107
      Author(s): Arijit Basu, Konda Reddy Kunduru, Joshua Katzhendler, Abraham J. Domb
      Polyesters derived from the α-hydroxy acids, lactic acid, and glycolic acid, are the most common biodegradable polymers in clinical use. These polymers have been tailored for a range of applications that require a physical material possessing. The physical and mechanical properties of these polymers fit the specific application and also safely biodegrade. These polymers are hydrophobic and do not possess functional side groups. This does not allow hydrophilic or hydrophobic manipulation, conjugation of active agents along the polymer chain, etc. These manipulations have partly been achieved by block copolymerization with, for example, poly(ethylene glycol), to obtain an amphiphilic copolymer. The objective of this review is to survey PLA functional copolymers in which functional α-hydroxy acids derived from amino acids are introduced along the polymer chain, allowing endless manipulation of PLA. Biodegradable functional polyesters are one of the most versatile biomaterials available to biomedical scientists. Amino acids with their variable side chains are ideal candidates for synthesizing such structural as well as stereochemically diverse polymers. They render control over functionalization, conjugation, crosslinking, stimulus responsiveness, and tunable mechanical/thermal properties. Functionalized amino acid derived polyesters are widely used, mainly due to advancement in ring opening polymerization (primarily O-carboxyanhydride mediated). The reaction proceeds under milder conditions and yields high molecular weight polymers. We reviewed on advances in the synthetic methodologies for poly-α-hydroxy esters derived from amino acids with appropriate recent examples.
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      PubDate: 2017-01-08T03:20:18Z
      DOI: 10.1016/j.addr.2016.08.003
      Issue No: Vol. 107 (2017)
  • Recent advances in degradable lactide-based shape-memory polymers
    • Authors: Maria Balk; Marc Behl; Christian Wischke; Jörg Zotzmann; Andreas Lendlein
      Pages: 136 - 152
      Abstract: Publication date: 15 December 2016
      Source:Advanced Drug Delivery Reviews, Volume 107
      Author(s): Maria Balk, Marc Behl, Christian Wischke, Jörg Zotzmann, Andreas Lendlein
      Biodegradable polymers are versatile polymeric materials that have a high potential in biomedical applications avoiding subsequent surgeries to remove, for example, an implanted device. In the past decade, significant advances have been achieved with poly(lactide acid) (PLA)-based materials, as they can be equipped with an additional functionality, that is, a shape-memory effect (SME). Shape-memory polymers (SMPs) can switch their shape in a predefined manner upon application of a specific external stimulus. Accordingly, SMPs have a high potential for applications ranging from electronic engineering, textiles, aerospace, and energy to biomedical and drug delivery fields based on the perspectives of new capabilities arising with such materials in biomedicine. This study summarizes the progress in SMPs with a particular focus on PLA, illustrates the design of suitable homo- and copolymer structures as well as the link between the (co)polymer structure and switching functionality, and describes recent advantages in the implementation of novel switching phenomena into SMP technology.

      PubDate: 2017-01-08T03:20:18Z
      DOI: 10.1016/j.addr.2016.05.012
      Issue No: Vol. 107 (2017)
  • Current state and challenges in developing oral vaccines
    • Authors: Julia E. Vela Ramirez; Lindsey A. Sharpe; Nicholas A. Peppas
      Abstract: Publication date: Available online 22 April 2017
      Source:Advanced Drug Delivery Reviews
      Author(s): Julia E. Vela Ramirez, Lindsey A. Sharpe, Nicholas A. Peppas
      While vaccination remains the most cost effective strategy for disease prevention, communicable diseases persist as the second leading cause of death worldwide. There is a need to design safe, novel vaccine delivery methods to protect against unaddressed and emerging diseases. Development of vaccines administered orally is preferable to traditional injection-based formulations for numerous reasons including improved safety and compliance, and easier manufacturing and administration. Additionally, the oral route enables stimulation of humoral and cellular immune responses at both systemic and mucosal sites to establish broader and long-lasting protection. However, oral delivery is challenging, requiring formulations to overcome the harsh gastrointestinal (GI) environment and avoid tolerance induction to achieve effective protection. Here we address the rationale for oral vaccines, including key biological and physicochemical considerations for next-generation oral vaccine design.
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      PubDate: 2017-04-23T07:42:45Z
      DOI: 10.1016/j.addr.2017.04.008
  • Dual-functional drug liposomes in treatment of resistant cancers
    • Authors: Li-Min Mu; Rui-Jun Ju; Rui Liu; Ying-Zi Bu; Jing-Ying Zhang; Xue-Qi Li; Fan Zeng; Wan-Liang Lu
      Abstract: Publication date: Available online 20 April 2017
      Source:Advanced Drug Delivery Reviews
      Author(s): Li-Min Mu, Rui-Jun Ju, Rui Liu, Ying-Zi Bu, Jing-Ying Zhang, Xue-Qi Li, Fan Zeng, Wan-Liang Lu
      Efficacy of regular chemotherapy is significantly hampered by multidrug resistance (MDR) and severe systemic toxicity. The reduced toxicity has been evidenced after administration of drug liposomes, consisting of the first generation of regular drug liposomes, the second generation of long-circulation drug liposomes, and the third generation of targeting drug liposomes. However, MDR of cancers remains as an unsolved issue. The objectives of this article are to review the dual-functional drug liposomes, which demonstrate the potential in overcoming MDR. Herein, dual-functional drug liposomes are referring to the drug-containing phospholipid bilayer vesicles that possess a dual-function of providing the basic efficacy of drug and the extended effect of the drug carrier. They exhibit unique roles in treatment of resistant cancer via circumventing drug efflux caused by adenosine triphosphate binding cassette (ABC) transporters, eliminating cancer stem cells, destroying mitochondria, initiating apoptosis, regulating autophagy, destroying supply channels, utilizing microenvironment, and silencing genes of the resistant cancer. As the prospect of an estimation, dual-functional drug liposomes would exhibit more strength in their extended function, hence deserving further investigation for clinical validation.
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      PubDate: 2017-04-23T07:42:45Z
      DOI: 10.1016/j.addr.2017.04.006
  • In vivo reprogramming of immune cells: Technologies for induction of
           antigen-specific tolerance
    • Authors: Ryan Pearson; Liam Casey Kevin Hughes Stephen Miller Lonnie Shea
      Abstract: Publication date: Available online 14 April 2017
      Source:Advanced Drug Delivery Reviews
      Author(s): Ryan M. Pearson, Liam M. Casey, Kevin R. Hughes, Stephen D. Miller, Lonnie D. Shea
      Technologies that induce antigen-specific immune tolerance by mimicking naturally occurring mechanisms have the potential to revolutionize the treatment of many immune-mediated pathologies such as autoimmunity, allograft rejection, and allergy. The immune system intrinsically has central and peripheral tolerance pathways for eliminating or modulating antigen-specific responses, which are being exploited through emerging technologies. Antigen-specific tolerogenic responses have been achieved through the functional reprogramming of antigen-presenting cells or lymphocytes. Alternatively, immune privileged sites have been mimicked using biomaterial scaffolds to locally suppress immune responses and promote long-term allograft survival. This review describes natural mechanisms of peripheral tolerance induction and the various technologies being developed to achieve antigen-specific immune tolerance in vivo. As currently approved therapies are non-specific and carry significant associated risks, these therapies offer significant progress towards replacing systemic immune suppression with antigen-specific therapies to curb aberrant immune responses.
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      PubDate: 2017-04-16T05:32:47Z
  • Designing metal-contained enzyme mimics for prodrug activation
    • Authors: Baoji Dan; Jin Wang Erkang Wang
      Abstract: Publication date: Available online 12 April 2017
      Source:Advanced Drug Delivery Reviews
      Author(s): Baoji Du, Dan Li, Jin Wang, Erkang Wang
      Enzyme-activated prodrug therapy (EAPT) is a widely-used and effective treatment method for cancer by converting the prodrugs into the drugs at the demanded time and space, whose key step is prodrug activation. Traditional prodrug activations are mostly dependent on the natural enzymes, which are unstable, expensive and hard to be functionalized. The emerging enzyme mimics, especially the metal-contained enzyme mimics (MEMs), provide a potential chance for improving the traditional EAPT because of their high stability, low cost and easiness of preparation and functionalization. The existing MEMs can be classified into three categories: catalytic core-scaffold MEM (csMEM), nanoparticle MEM (npMEMs) and metal-organic framework (MOF) MEM (mofMEM). These MEMs can mimic diverse functions corresponding to natural enzymes, and some of which are potentially used in prodrug activation, such as DNase, RNase, carbonate esterase, etc.. In this review, we briefly summarize the MEMs according to their structure and composition, and highlight the successful and potential applications for prodrug activation mediated by hydrolase-like and oxidoreductase-like MEMs.
      Graphical abstract image

      PubDate: 2017-04-16T05:32:47Z
  • Nanoformulation-based sequential combination cancer therapy
    • Authors: Gayong Shim; Mi-Gyeong Kim Dongyoon Kim Joo Yeon Park Yu-Kyoung
      Abstract: Publication date: Available online 12 April 2017
      Source:Advanced Drug Delivery Reviews
      Author(s): Gayong Shim, Mi-Gyeong Kim, Dongyoon Kim, Joo Yeon Park, Yu-Kyoung Oh
      Although combining two or more treatments is regarded as an indispensable approach for effectively treating cancer, the traditional cocktail-based combination therapies are seriously limited by coordination issues that fail to account for differences in the pharmacokinetics and action sites of each drug. The careful manipulation of dosing regimens, such as by the sequential application of combination treatments, may satisfy the temporal and spatial needs of each drug and achieve successful combination antitumor therapy. Nanotechnology-based carriers might be the best tools for sequential combination therapy, as they can be loaded with multiple cargos and may provide targeted and sustained delivery to target tumor cells. Single nanoformulations capable of sequentially releasing drugs have shown synergistic anticancer activity, such as by sensitizing tumor cells through cascaded drug delivery or remodeling the tumor vasculature and microenvironment to enhance the tumor distribution of nanotherapeutics. This review highlights the use of nanotechnology-based multistage drug delivery for cancer treatment, focusing on the ability of such formulations to enhance antitumor efficacy by applying sequential treatment and modulating dosing regimens, which are challenges currently being faced in the clinic.
      Graphical abstract image

      PubDate: 2017-04-16T05:32:47Z
  • Responsive Nanocarriers as an emerging platform for cascaded delivery of
           nucleic acids to cancer
    • Authors: Yang Liu; Cong-Fei Xu; Shoaib Iqbal; Xian-Zhu Yang; Jun Wang
      Abstract: Publication date: Available online 7 April 2017
      Source:Advanced Drug Delivery Reviews
      Author(s): Yang Liu, Cong-Fei Xu, Shoaib Iqbal, Xian-Zhu Yang, Jun Wang
      Cascades of systemic and intracellular obstacles, including low stability in blood, little tumor accumulation, weak tumor penetration, poor cellular uptake, inefficient endosomal escape and deficient disassembly in the cytoplasm, must be overcome in order to deliver nucleic acid drugs for cancer therapy. Nanocarriers that are sensitive to a variety of physiological stimuli, such as pH, redox status, and cell enzymes, are substantially changing the landscape of nucleic acid drug delivery by helping to overcome cascaded systemic and intracellular barriers. This review discusses nucleic acid-based therapeutics, systemic and intracellular barriers to efficient nucleic acid delivery, and nanocarriers responsive to extracellular and intracellular biological stimuli to overcome individual barriers. In particular, responsive nanocarriers for the cascaded delivery of nucleic acids in vivo are highlighted. Developing novel cascaded nanocarriers that transform their physicochemical properties in response to various stimuli in a timely and spatially controlled manner for nucleic acid drug delivery holds great potential for translating the promise of nucleic acid drugs and achieving clinically successful cancer therapy.
      Graphical abstract image

      PubDate: 2017-04-09T05:28:40Z
      DOI: 10.1016/j.addr.2017.03.004
  • Engineering self-assembled materials to study and direct immune function
    • Authors: Lisa H. Tostanoski; Christopher M. Jewell
      Abstract: Publication date: Available online 6 April 2017
      Source:Advanced Drug Delivery Reviews
      Author(s): Lisa H. Tostanoski, Christopher M. Jewell
      The immune system is an awe-inspiring control structure that maintains a delicate and constantly changing balance between pro-immune functions that fight infection and cancer, regulatory or suppressive functions involved in immune tolerance, and homeostatic resting states. These activities are determined by integrating signals in space and time; thus, improving control over the densities, combinations, and durations with which immune signals are delivered is a central goal to better combat infectious disease, cancer, and autoimmunity. Self-assembly presents a unique opportunity to synthesize materials with well-defined compositions and controlled physical arrangement of molecular building blocks. This review highlights strategies exploiting these capabilities to improve the understanding of how precisely-displayed cues interact with immune cells and tissues. We present work centered on fundamental properties that regulate the nature and magnitude of immune response, highlight pre-clinical and clinical applications of self-assembled technologies in vaccines, cancer, and autoimmunity, and describe some of the key manufacturing and regulatory hurdles facing these areas.
      Graphical abstract image

      PubDate: 2017-04-09T05:28:40Z
      DOI: 10.1016/j.addr.2017.03.005
  • Nanoparticles for drug delivery to the anterior segment of the eye
    • Authors: Dileep R. Janagam; Linfeng Wu; Tao L. Lowe
      Abstract: Publication date: Available online 6 April 2017
      Source:Advanced Drug Delivery Reviews
      Author(s): Dileep R. Janagam, Linfeng Wu, Tao L. Lowe
      Commercially available ocular drug delivery systems are effective but less efficacious to manage diseases/disorders of the anterior segment of the eye. Recent advances in nanotechnology and molecular biology offer a great opportunity for efficacious ocular drug delivery for the treatments of anterior segment diseases/disorders. Nanoparticles have been designed for preparing eye drops or injectable solutions to surmount ocular obstacles faced after administration. Better drug pharmacokinetics, pharmacodynamics, non-specific toxicity, immunogenicity, and biorecognition can be achieved to improve drug efficacy when drugs are loaded in the nanoparticles. Despite the fact that a number of review articles have been published at various points in the past regarding nanoparticles for drug delivery, there is not a review yet focusing on the development of nanoparticles for ocular drug delivery to the anterior segment of the eye. This review fills in the gap and summarizes the development of nanoparticles as drug carriers for improving the penetration and bioavailability of drugs to the anterior segment of the eye.
      Graphical abstract image

      PubDate: 2017-04-09T05:28:40Z
      DOI: 10.1016/j.addr.2017.04.001
  • Pharmaceutical cocrystals, salts and multicomponent systems;
           intermolecular interactions and property based design
    • Authors: David J. Berry; Jonathan W. Steed
      Abstract: Publication date: Available online 23 March 2017
      Source:Advanced Drug Delivery Reviews
      Author(s): David J. Berry, Jonathan W. Steed
      As small molecule drugs become harder to develop and less cost effective for patient use, efficient strategies for their property improvement become increasingly important to global health initiatives. Improvements in the physical properties of Active Pharmaceutical Ingredients (APIs), without changes in the covalent chemistry, have long been possible through the application of binary component solids. This was first achieved through the use of pharmaceutical salts, within the last 10–15years with cocrystals and more recently coamorphous systems have also been consciously applied to this problem. In order to rationally discover the best multicomponent phase for drug development, intermolecular interactions need to be considered at all stages of the process. This review highlights the current thinking in this area and the state of the art in: pharmaceutical multicomponent phase design, the intermolecular interactions in these phases, the implications of these interactions on the material properties and the pharmacokinetics in a patient.
      Graphical abstract image

      PubDate: 2017-03-27T08:58:53Z
      DOI: 10.1016/j.addr.2017.03.003
  • Pharmaceutical Solvates, Hydrates and Amorphous Forms
    • Authors: Anne Marie Healy; Zelalem Ayenew Worku; Dinesh Kumar; Atif M. Madi
      Abstract: Publication date: Available online 22 March 2017
      Source:Advanced Drug Delivery Reviews
      Author(s): Anne Marie Healy, Zelalem Ayenew Worku, Dinesh Kumar, Atif M. Madi
      Active pharmaceutical ingredients (APIs) may exist in various solid forms, which can lead to differences in the intermolecular interactions, affecting the internal energy and enthalpy, and the degree of disorder, affecting the entropy. Differences in solid forms often lead to differences in thermodynamic parameters and physicochemical properties for example solubility, dissolution rate, stability and mechanical properties of APIs and excipients. Hence, solid forms of APIs play a vital role in drug discovery and development in the context of optimization of bioavailability, filing intellectual property rights and developing suitable manufacturing methods. In this review, the fundamental characteristics and trends observed for pharmaceutical hydrates, solvates and amorphous forms are presented, with special emphasis, due to their relative abundance, on pharmaceutical hydrates with single and two-component (i.e. cocrystal) host molecules.
      Graphical abstract image

      PubDate: 2017-03-27T08:58:53Z
      DOI: 10.1016/j.addr.2017.03.002
  • Combination antitumor therapy with targeted dual-nanomedicines
    • Authors: Wenbing Dai; Xiaoyou Wang; Ge Song; Tongzhou Liu; Bing He; Hua Zhang; Xueqing Wang; Qiang Zhang
      Abstract: Publication date: Available online 7 March 2017
      Source:Advanced Drug Delivery Reviews
      Author(s): Wenbing Dai, Xiaoyou Wang, Ge Song, Tongzhou Liu, Bing He, Hua Zhang, Xueqing Wang, Qiang Zhang
      Combination therapy is one of important treatment strategies for cancer at present. However, the outcome of current combination therapy based on the co- administration of conventional dosage forms is suboptimal, due to the short half-lives of chemodrugs, their deficient tumor selectivity and so forth. Nanotechnology-based targeted delivery systems show great promise in addressing the associated problems and providing superior therapeutic benefits. In this review, we focus on the combination therapeutic strategies between different nanomedicines or drug-loaded nanocarriers, rather than the co-delivery of different drugs via a single nanocarrier. We introduce the general concept of various targeting strategies of nanomedicines, present the principles of combination antitumor therapy with dual-nanomedicines, analyze their advantages and limitations compared with co-delivery strategies, and overview the recent advances of combination therapy based on targeted nanomedicines. Finally, we reviewed the challenges and future perspectives regarding the selection of therapeutic agents, targeting efficiency and the gap between the preclinical and clinical outcome.
      Graphical abstract image

      PubDate: 2017-03-09T05:40:54Z
      DOI: 10.1016/j.addr.2017.03.001
  • β-hairpin peptide hydrogels for package delivery
    • Authors: Peter Worthington; Sigrid Langhans; Darrin Pochan
      Abstract: Publication date: Available online 28 February 2017
      Source:Advanced Drug Delivery Reviews
      Author(s): Peter Worthington, Sigrid Langhans, Darrin Pochan
      The underlying challenge of drug delivery is the safe, controlled transport of a supply of therapeutic agent to its intended location at its effective dose. New and expanding solutions to payload delivery are being discovered in the field of hydrogels. Hydrogels are highly hydrated polymer networks that vary greatly depending on the underlying molecular structure. The subgroup of hydrogels that will be the focus of this chapter is the β-hairpin peptide hydrogel. These peptide-based materials are formed through a molecular self-assembly mechanism that only occurs after desired triggering of intramolecular peptide folding. Once folded, the β-hairpins assemble intermolecularly into a nanofibrillar network. The physical properties of the hydrogel network and its peptide foundation result in advantageous material properties which can be used for multiple biomedical applications including drug delivery. As a shear thinning solid that is easily injectable, cytocompatible, customizable, and well characterized, β-hairpin hydrogels are an exciting candidate as a drug delivery vehicle.
      Graphical abstract image

      PubDate: 2017-03-03T10:21:47Z
      DOI: 10.1016/j.addr.2017.02.002
  • The Battle of “Nano” Paclitaxel
    • Authors: Alexandros Marios Sofias; Michael Dunne; Gert Storm; Christine Allen
      Abstract: Publication date: Available online 28 February 2017
      Source:Advanced Drug Delivery Reviews
      Author(s): Alexandros Marios Sofias, Michael Dunne, Gert Storm, Christine Allen
      Paclitaxel (PTX) is one of the three most widely used chemotherapeutic agents, together with doxorubicin and cisplatin, and is first or second line treatment for several types of cancers. In 2000, Taxol, the conventional formulation of PTX, became the best selling cancer drug of all time with annual sales of 1.6 billion. In 2005, the introduction of the albumin-based formulation of PTX, known as Abraxane, ended Taxol's monopoly of the PTX market. Abraxane's ability to push the Taxol innovator and generic formulations aside attracted fierce competition amongst competitors worldwide to develop their own unique, new and improved formulation of PTX. At this time there are at least 18 companies focused on pre-clinical and/or clinical development of nano-formulations of PTX. These pharmaceutical companies are investing substantial capital to capture a share of the lucrative global PTX market. It is hoped that any formulation that dominates the market will result in tangible benefits to patients in terms of both survival and quality of life. Given all of this activity, here we address the question: Who is going to win the battle of “nano” paclitaxel?
      Graphical abstract image

      PubDate: 2017-03-03T10:21:47Z
      DOI: 10.1016/j.addr.2017.02.003
  • Mimicking Oxygen delivery and waste removal functions of blood
    • Authors: Huaifa Zhang; Jake E. Barralet
      Abstract: Publication date: Available online 16 February 2017
      Source:Advanced Drug Delivery Reviews
      Author(s): Huaifa Zhang, Jake E. Barralet
      In addition to immunological and wound healing cell and platelet delivery, ion stasis and nutrient supply, blood delivers oxygen to cells and tissues and removes metabolic wastes. For decades researchers have been trying to develop approaches that mimic these two immediately vital functions of blood. Oxygen is crucial for the long-term survival of tissues and cells in vertebrates. Hypoxia (oxygen deficiency) and even at times anoxia (absence of oxygen) can occur during organ preservation, organ and cell transplantation, wound healing, in tumors and engineering of tissues. Different approaches have been developed to deliver oxygen to tissues and cells, including hyperbaric oxygen therapy (HBOT), normobaric hyperoxia therapy (NBOT), using biochemical reactions and electrolysis, employing liquids with high oxygen solubility, administering hemoglobin, myoglobin and red blood cells (RBCs), introducing oxygen-generating agents, using oxygen-carrying microparticles, persufflation, and peritoneal oxygenation. Metabolic waste accumulation is another issue in biological systems when blood flow is insufficient. Metabolic wastes change the microenvironment of cells and tissues, influence the metabolic activities of cells, and ultimately cause cell death. This review examines advances in blood mimicking systems in the field of biomedical engineering in terms of oxygen delivery and metabolic waste removal.
      Graphical abstract image

      PubDate: 2017-02-17T03:15:22Z
      DOI: 10.1016/j.addr.2017.02.001
  • Angiogenesis regulation by nanocarriers bearing RNA interference
    • Authors: Paula Ofek; Galia Tiram; Ronit Satchi-Fainaro
      Abstract: Publication date: Available online 2 February 2017
      Source:Advanced Drug Delivery Reviews
      Author(s): Paula Ofek, Galia Tiram, Ronit Satchi-Fainaro
      Since the approval of bevacizumab as antiangiogenic therapy in 2004 by the FDA, an array of angiogenesis inhibitors have been developed and approved. However, results were disappointing with regards to their therapeutic efficacy. RNA interference approaches offer the possibility of rational design with high specificity, lacking in many current drug treatments for various diseases including cancer. However, in vivo delivery issues still represent a significant obstacle for widespread clinical applications. In the current review, we summarize the advances in the last decade in the field of angiogenesis-targeted RNA interference approaches, with special emphasis on oncology applications. We present pro-angiogenic and anti-angiogenic factors as potential targets, experimental evidence and clinical trials data on angiogenesis regulation by RNA interference. Consequent challenges and opportunities are discussed.
      Graphical abstract image

      PubDate: 2017-02-04T21:57:57Z
      DOI: 10.1016/j.addr.2017.01.008
  • Recent Coating Developments for Combination Devices in Orthopedic and
           Dental Applications: A Literature Review
    • Authors: Eric J. Tobin
      Abstract: Publication date: Available online 1 February 2017
      Source:Advanced Drug Delivery Reviews
      Author(s): Eric J. Tobin
      Orthopedic and dental implants have been used successfully for decades to replace or repair missing or damaged bones, joints, and teeth, thereby restoring patient function subsequent to disease or injury. However, although device success rates are generally high, patient outcomes are sometimes compromised due to device-related problems such as insufficient integration, local tissue inflammation, and infection. Many different types of surface coatings have been developed to address these shortcomings, including those that incorporate therapeutic agents to provide localized delivery to the surgical site. While these coatings hold enormous potential for improving device function, the list of requirements that an ideal combination coating must fulfill is extensive, and no single coating system today simultaneously addresses all of the criteria. Some of the primary challenges related to current coatings are non-optimal release kinetics, which most often are too rapid, the potential for inducing antibiotic resistance in target organisms, high susceptibility to mechanical abrasion and delamination, toxicity, difficult and expensive regulatory approval pathways, and high manufacturing costs. This review provides a survey of the most recent developments in the field, i.e., those published in the last 2-3 years, with a particular focus on technologies that have potential for overcoming the most significant challenges facing therapeutically-loaded coatings. It is concluded that the ideal coating remains an unrealized target, but that advances in the field and emerging technologies are bringing it closer to reality. The significant amount of research currently being conducted in the field provides a level of optimism that many functional combination coatings will ultimately transition into clinical practice, significantly improving patient outcomes.
      Graphical abstract image

      PubDate: 2017-02-04T21:57:57Z
      DOI: 10.1016/j.addr.2017.01.007
  • Improving Drug-Like Properties of Insulin and GLP-1 via Molecule Design
           and Formulation and Improving Diabetes Management with Device & Drug
    • Authors: Sergei Pechenov; Himanshu Bhattacharjee; Daniel Yin; Sachin Mittal; Anand Subramony
      Abstract: Publication date: Available online 30 January 2017
      Source:Advanced Drug Delivery Reviews
      Author(s): Sergei Pechenov, Himanshu Bhattacharjee, Daniel Yin, Sachin Mittal, Anand Subramony
      There is an increased incidence of diabetes worldwide. The discovery of insulin revolutionized the management of diabetes, the revelation of glucagon-like peptide -1 (GLP-1) and introduction of GLP-1 mimetics to clinical practice was another breakthrough. Continued translational research resulted in better understanding of diabetes, which, in combination with cutting-edge biology, chemistry, and pharmaceutical tools, have allowed for the development of safer, more effective and convenient insulins and GLP-1s. Advances in self-administration of insulin and GLP-1 therapies with use of drug-device combination products have improved the outcomes of diabetes management and quality of life for diabetic patients. The synergies of insulin and GLP-1 actions have led to development of devices that can deliver both molecules simultaneously. New chimeric GLP-1-incretins and insulin-GLP-1-incretin molecules are also being developed. The objective of this review is to summarize molecular designs to improve the drug-like properties of insulin and GLP-1 and to highlight the continued advancement of drug-device combinations to improve diabetes management.
      Graphical abstract image

      PubDate: 2017-02-04T21:57:57Z
      DOI: 10.1016/j.addr.2017.01.006
  • Editorial Board Members
    • Abstract: Publication date: 1 January 2017
      Source:Advanced Drug Delivery Reviews, Volume 108

      PubDate: 2017-01-29T07:42:20Z
  • Xenobiotic transporters and kidney injury
    • Authors: Blessy George; Dahea You; Melanie S. Joy; Lauren M. Aleksunes
      Abstract: Publication date: Available online 20 January 2017
      Source:Advanced Drug Delivery Reviews
      Author(s): Blessy George, Dahea You, Melanie S. Joy, Lauren M. Aleksunes
      Renal proximal tubules are targets for toxicity due in part to the expression of transporters that mediate the secretion and reabsorption of xenobiotics. Alterations in transporter expression and/or function can enhance the accumulation of toxicants and sensitize the kidneys to injury. This can be observed when xenobiotic uptake by carrier proteins is increased or efflux of toxicants and their metabolites is reduced. Nephrotoxic chemicals include environmental contaminants (halogenated hydrocarbon solvents, the herbicide paraquat, the fungal toxin ochratoxin, and heavy metals) as well as pharmaceuticals (certain beta-lactam antibiotics, antiviral drugs, and chemotherapeutic drugs). This review explores the mechanisms by which transporters mediate the entry and exit of toxicants from renal tubule cells and influence the degree of kidney injury. Delineating how transport proteins regulate the renal accumulation of toxicants is critical for understanding the likelihood of nephrotoxicity resulting from competition for excretion or genetic polymorphisms that affect transporter function.
      Graphical abstract image

      PubDate: 2017-01-22T21:31:57Z
      DOI: 10.1016/j.addr.2017.01.005
  • Design control considerations for biologic-device combination products
    • Authors: Dave Anderson; Roger Liu; J. Anand Subramony; Jon Cammack
      Abstract: Publication date: Available online 11 January 2017
      Source:Advanced Drug Delivery Reviews
      Author(s): Dave Anderson, Roger Liu, J. Anand Subramony, Jon Cammack
      Combination products are therapeutic and diagnostic medical products that combine drugs, devices, and/or biological products with one another. Historically, biologics development involved identifying efficacious doses administered to patients intravenously or perhaps by a syringe. Until fairly recently, there has been limited focus on developing an accompanying medical device, such as a prefilled syringe or auto-injector, to enable easy and more efficient delivery. For the last several years, and looking forward, where there may be little to distinguish biologics medicines with relatively similar efficacy profiles, the biotechnology market is beginning to differentiate products by patient-focused, biologic-device based combination products. As innovative as biologic-device combination products are, they can pose considerable development, regulatory, and commercialization challenges due to unique physicochemical properties and special clinical considerations (e.g., dosing volumes, frequency, co-medications, etc.) of the biologic medicine. A biologic-device combination product is a marriage between two partners with “cultural differences,” so to speak. There are clear differences in the development, review, and commercialization processes of the biologic and the device. When these two cultures come together in a combination product, developers and reviewers must find ways to address the design controls and risk management processes of both the biologic and device, and knit them into a single entity with supporting product approval documentation. Moreover, digital medicine and connected health trends are pushing the boundaries of combination product development and regulations even further. Despite an admirable cooperation between industry and FDA in recent years, unique product configurations and design features have resulted in review challenges. These challenges have prompted agency reviewers to modernize consultation processes, while at the same time, promoting development of innovative, safe and effective combination products. It remains the manufacturer's responsibility to comply with the relevant requirements and regulations, and develop good business practices that clearly describe how these practices comply with FDA's final rule (21 CFR Part 4) and aligns with the company's already established quality system.
      Graphical abstract image

      PubDate: 2017-01-16T00:39:26Z
      DOI: 10.1016/j.addr.2017.01.003
  • Molecular links among non-biodegradable nanoparticles, reactive oxygen
           species, and autophagy
    • Authors: Uche C. Anozie; Paul Dalhaimer
      Abstract: Publication date: Available online 6 January 2017
      Source:Advanced Drug Delivery Reviews
      Author(s): Uche C. Anozie, Paul Dalhaimer
      For nanoparticles to be successful in combating diseases in the clinic in the 21st century and beyond, they must localize to target areas of the body and avoid damaging non-target, healthy tissues. Both soft and stiff, bio-degradable and non-biodegradable nanoparticles are anticipated to be used to this end. It has been shown that stiff, non-biodegradable nanoparticles cause reactive oxygen species (ROS) generation and autophagy in a variety of cell lines in vitro. Both responses can lead to significant remodeling of the cytosol and even apoptosis. Thus these are crucial cellular functions to understand. Improved assays have uncovered crucial roles of the Akt/mTOR signaling pathway in both ROS generation and autophagy initiation after cells have internalized stiff, non-biodegradable nanoparticles over varying geometries in culture. Of particular – yet unresolved – interest is how these nanoparticles cause the activation of these pathways. This article reviews the most recent advances in nanoparticle generation of ROS and autophagy initiation with a focus on stiff, non-biodegradable technologies. We provide experimental guidelines to the reader for fleshing out the effects of their nanoparticles on the above pathways with the goal of tuning nanoparticle design.
      Graphical abstract image

      PubDate: 2017-01-08T03:20:18Z
      DOI: 10.1016/j.addr.2017.01.001
  • Heparin coatings for improving blood compatibility of medical devices
    • Authors: Roy Biran; Daniel Pond
      Abstract: Publication date: Available online 29 December 2016
      Source:Advanced Drug Delivery Reviews
      Author(s): Roy Biran, Daniel Pond
      Blood contact with biomaterials triggers activation of multiple reactive mechanisms that can impair the performance of implantable medical devices and potentially cause serious adverse clinical events. This includes thrombosis and thromboembolic complications due to activation of platelets and the coagulation cascade, activation of the complement system, and inflammation. Numerous surface coatings have been developed to improve blood compatibility of biomaterials. For more than thirty years, the anticoagulant drug heparin has been employed as a covalently immobilized surface coating on a variety of medical devices. This review describes the fundamental principles of non-eluting heparin coatings, mechanisms of action, and clinical applications with focus on those technologies which have been commercialized. Because of its extensive publication history, there is emphasis on the Carmeda® Bioactive Surface (CBAS® Heparin Surface), a widely used commercialized technology for the covalent bonding of heparin.
      Graphical abstract image

      PubDate: 2017-01-08T03:20:18Z
      DOI: 10.1016/j.addr.2016.12.002
  • Stereotactic ablative body radiosurgery (SABR) or Stereotactic body
           radiation therapy (SBRT)
    • Authors: Michael R. Folkert; Robert D. Timmerman
      Abstract: Publication date: Available online 5 December 2016
      Source:Advanced Drug Delivery Reviews
      Author(s): Michael R. Folkert, Robert D. Timmerman
      While conventional treatment relies on protracted courses of therapy using relatively small dose-per-fraction sizes of 1.8–2Gy, there is substantial evidence gathered over decades that this may not be the optimal approach for all targetable disease. Stereotactic ablative body radiosurgery (SABR) or stereotactic body radiation therapy (SBRT) is a technique which uses precise targeting to deliver high doses of radiation capable of ablating tumors directly. In this review, we will discuss the justification for and techniques used to deliver ablative doses to improve treatment outcomes, interactions with biological and immunologic therapy, and special procedures to spare normal tissue, which have facilitated the expanding role for these techniques in the management of a wide range of malignant histologies and disease states.
      Graphical abstract image

      PubDate: 2017-01-08T03:20:18Z
      DOI: 10.1016/j.addr.2016.11.005
  • Proton therapy – Present and future
    • Authors: Radhe Mohan; David Grosshans
      Abstract: Publication date: Available online 3 December 2016
      Source:Advanced Drug Delivery Reviews
      Author(s): Radhe Mohan, David Grosshans
      In principle, proton therapy offers a substantial clinical advantage over conventional photon therapy. This is because of the unique depth-dose characteristics of protons, which can be exploited to achieve significant reductions in normal tissue doses proximal and distal to the target volume. These may, in turn, allow escalation of tumor doses and greater sparing of normal tissues, thus potentially improving local control and survival while at the same time reducing toxicity and improving quality of life. Protons, accelerated to therapeutic energies ranging from 70 to 250MeV, typically with a cyclotron or a synchrotron, are transported to the treatment room where they enter the treatment head mounted on a rotating gantry. The initial thin beams of protons are spread laterally and longitudinally and shaped appropriately to deliver treatments. Spreading and shaping can be achieved by electro-mechanical means to treat the patients with “passively-scattered proton therapy” (PSPT) or using magnetic scanning of thin “beamlets” of protons of a sequence of initial energies. The latter technique can be used to treat patients with optimized intensity modulated proton therapy (IMPT), the most powerful proton modality. Despite the high potential of proton therapy, the clinical evidence supporting the broad use of protons is mixed. It is generally acknowledged that proton therapy is safe, effective and recommended for many types of pediatric cancers, ocular melanomas, chordomas and chondrosarcomas. Although promising results have been and continue to be reported for many other types of cancers, they are based on small studies. Considering the high cost of establishing and operating proton therapy centers, questions have been raised about their cost effectiveness. General consensus is that there is a need to conduct randomized trials and/or collect outcomes data in multi-institutional registries to unequivocally demonstrate the advantage of protons. Treatment planning and plan evaluation of PSPT and IMPT require special considerations compared to the processes used for photon treatment planning. The differences in techniques arise from the unique physical properties of protons but are also necessary because of the greater vulnerability of protons to uncertainties, especially from inter- and intra-fractional variations in anatomy. These factors must be considered in designing as well as evaluating treatment plans. In addition to anatomy variations, other sources of uncertainty in dose delivered to the patient include the approximations and assumptions of models used for computing dose distributions for planning of treatments. Furthermore, the relative biological effectiveness (RBE) of protons is simplistically assumed to have a constant value of 1.1. In reality, the RBE is variable and a complex function of the energy of protons, dose per fraction, tissue and cell type, end point, etc. These uncertainties, approximations and current technological limitations of proton therapy may limit the achievement of its true potential. Ongoing research is aimed at better understanding the consequences of the various uncertainties on proton therapy and reducing the uncertainties through image-guidance, adaptive radiotherapy, further study of biological properties of protons and the development of novel dose computation and optimization methods. However, residual uncertainties will remain in spite of the best efforts. To increase the resilience of dose distributions in the face of uncertainties and improve our confidence in dose distributions seen on treatment plans, robust optimization techniques are being developed and implemented. We assert that, with such research, proton therapy will be a commonly applied radiotherapy modality for most types of solid cancers in the near future.
      Graphical abstract image

      PubDate: 2017-01-08T03:20:18Z
      DOI: 10.1016/j.addr.2016.11.006
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