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Advanced Drug Delivery Reviews (v.60, #8)
Clinical developments in drug delivery nanotechnology
by M. Laird Forrest Theme Editor; Glen S. Kwon Theme Editor (pp. 861-862).
Clinical developments in drug delivery nanotechnology
by M. Laird Forrest Theme Editor; Glen S. Kwon Theme Editor (pp. 861-862).
Targeted delivery of nanoparticles for the treatment of lung diseases by Shirzad Azarmi; Wilson H. Roa; Raimar Löbenberg (pp. 863-875).
Targeted delivery of drug molecules to organs or special sites is one of the most challenging research areas in pharmaceutical sciences. By developing colloidal delivery systems such as liposomes, micelles and nanoparticles a new frontier was opened for improving drug delivery. Nanoparticles with their special characteristics such as small particle size, large surface area and the capability of changing their surface properties have numerous advantages compared with other delivery systems. Targeted nanoparticle delivery to the lungs is an emerging area of interest. This article reviews research performed over the last decades on the application of nanoparticles administered via different routes of administration for treatment or diagnostic purposes. Nanotoxicological aspects of pulmonary delivery are also discussed.
Keywords: Pulmonary delivery; Nanoparticle; Lung cancer; Tuberculosis; Aerosol; Colloidal delivery; Nanotoxicology
Targeted delivery of nanoparticles for the treatment of lung diseases by Shirzad Azarmi; Wilson H. Roa; Raimar Löbenberg (pp. 863-875).
Targeted delivery of drug molecules to organs or special sites is one of the most challenging research areas in pharmaceutical sciences. By developing colloidal delivery systems such as liposomes, micelles and nanoparticles a new frontier was opened for improving drug delivery. Nanoparticles with their special characteristics such as small particle size, large surface area and the capability of changing their surface properties have numerous advantages compared with other delivery systems. Targeted nanoparticle delivery to the lungs is an emerging area of interest. This article reviews research performed over the last decades on the application of nanoparticles administered via different routes of administration for treatment or diagnostic purposes. Nanotoxicological aspects of pulmonary delivery are also discussed.
Keywords: Pulmonary delivery; Nanoparticle; Lung cancer; Tuberculosis; Aerosol; Colloidal delivery; Nanotoxicology
Protein nanoparticles as drug carriers in clinical medicine by Michael J. Hawkins; Patrick Soon-Shiong; Neil Desai (pp. 876-885).
Solvent-based delivery vehicles for chemotherapy agents have been instrumental in providing a means for hydrophobic agents to be administered intravenously. These solvents, however, have been associated with serious and dose-limiting toxicities. Solvent-based formulations of taxanes, a highly active class of cytotoxic agents, are associated with hypersensitivity reactions, neutropenia, and neuropathy. Nanoparticle technology utilizing the human protein albumin exploits natural pathways to selectively deliver larger amounts of drug to tumors while avoiding some of the toxicities of solvent-based formulations. 130 nM albumin-bound ( nab™) paclitaxel ( nab-paclitaxel; Abraxane®) was recently approved for use in patients with metastatic breast cancer who have failed combination therapy. In a randomized, phase III study in metastatic breast cancer, nab-paclitaxel was found to have improved efficacy and safety compared with conventional, solvent-based paclitaxel. Preliminary data also suggest roles for nab-paclitaxel as a single agent and in combination therapy for first-line treatment of metastatic breast cancer as well as in other solid tumors, including non-small-cell lung cancer, ovarian cancer, and malignant melanoma. The nab technology promises to have broad utility in cancer therapy, and clinical trials are underway using nab formulations of other water-insoluble anticancer agents such as docetaxel and rapamycin.
Keywords: Albumin; nab; -Paclitaxel; Paclitaxel; Abraxane; Polyethoxylated castor oil; Docetaxel; Polysorbate 80; SPARC; gp60; Rapamycin
Protein nanoparticles as drug carriers in clinical medicine by Michael J. Hawkins; Patrick Soon-Shiong; Neil Desai (pp. 876-885).
Solvent-based delivery vehicles for chemotherapy agents have been instrumental in providing a means for hydrophobic agents to be administered intravenously. These solvents, however, have been associated with serious and dose-limiting toxicities. Solvent-based formulations of taxanes, a highly active class of cytotoxic agents, are associated with hypersensitivity reactions, neutropenia, and neuropathy. Nanoparticle technology utilizing the human protein albumin exploits natural pathways to selectively deliver larger amounts of drug to tumors while avoiding some of the toxicities of solvent-based formulations. 130 nM albumin-bound ( nab™) paclitaxel ( nab-paclitaxel; Abraxane®) was recently approved for use in patients with metastatic breast cancer who have failed combination therapy. In a randomized, phase III study in metastatic breast cancer, nab-paclitaxel was found to have improved efficacy and safety compared with conventional, solvent-based paclitaxel. Preliminary data also suggest roles for nab-paclitaxel as a single agent and in combination therapy for first-line treatment of metastatic breast cancer as well as in other solid tumors, including non-small-cell lung cancer, ovarian cancer, and malignant melanoma. The nab technology promises to have broad utility in cancer therapy, and clinical trials are underway using nab formulations of other water-insoluble anticancer agents such as docetaxel and rapamycin.
Keywords: Albumin; nab; -Paclitaxel; Paclitaxel; Abraxane; Polyethoxylated castor oil; Docetaxel; Polysorbate 80; SPARC; gp60; Rapamycin
Polymer-drug conjugates: Recent development in clinical oncology by Chun Li; Sidney Wallace (pp. 886-898).
Targeted drug delivery aims to increase the therapeutic index by making more drug molecules available at the diseased sites while reducing systemic drug exposure. In this update, we provide an overview of polymer-drug conjugates that have advanced into clinical trials. These systems use synthetic water-soluble polymers as the drug carriers. The preclinical pharmacology and recent data in clinical trials with poly(l-glutamic acid)-paclitaxel (PG-TXL) are discussed. This is followed by a summary of a variety of polymeric conjugates with chemotherapeutic agents. Results from early clinical trials of these polymer-drug conjugates have demonstrated several advantages over the corresponding parent drugs, including fewer side effects, enhanced therapeutic efficacy, ease of drug administration, and improved patient compliance. Collectively, these data warrant further clinical development of polymer-drug conjugates as a new class of anticancer agents.
Keywords: Polymer-drug conjugates; Anticancer drugs; Nanocarriers; Paclitaxel; PG-TXL
Polymer-drug conjugates: Recent development in clinical oncology by Chun Li; Sidney Wallace (pp. 886-898).
Targeted drug delivery aims to increase the therapeutic index by making more drug molecules available at the diseased sites while reducing systemic drug exposure. In this update, we provide an overview of polymer-drug conjugates that have advanced into clinical trials. These systems use synthetic water-soluble polymers as the drug carriers. The preclinical pharmacology and recent data in clinical trials with poly(l-glutamic acid)-paclitaxel (PG-TXL) are discussed. This is followed by a summary of a variety of polymeric conjugates with chemotherapeutic agents. Results from early clinical trials of these polymer-drug conjugates have demonstrated several advantages over the corresponding parent drugs, including fewer side effects, enhanced therapeutic efficacy, ease of drug administration, and improved patient compliance. Collectively, these data warrant further clinical development of polymer-drug conjugates as a new class of anticancer agents.
Keywords: Polymer-drug conjugates; Anticancer drugs; Nanocarriers; Paclitaxel; PG-TXL
Poly (amino acid) micelle nanocarriers in preclinical and clinical studies by Yasuhiro Matsumura (pp. 899-914).
Polymeric micelles are expected to increase the accumulation of drugs in tumor tissues utilizing the EPR effect and to incorporate various kinds of drugs into the inner core by chemical conjugation or physical entrapment with relatively high stability. The size of the micelles can be controlled within the diameter range of 20 to 100 nm, to ensure that the micelles do not pass through normal vessel walls; therefore, a reduced incidence of the side effects of the drugs may be expected due to the decreased volume of distribution.These are several anticancer agent-incorporated micelle carrier systems under clinical evaluation. Phase 1 studies of a CDDP incorporated micelle, Nc-6004, and an sN-38 incorporated micelle, NK012, are now underway. A phase 2 study of a PTX incorporated micelle, NK105, against stomach cancer is also underway.
Keywords: Poly (amino acid) micelle nanocarrier; Drug delivery system; EPR effect; Clinical trial
Poly (amino acid) micelle nanocarriers in preclinical and clinical studies by Yasuhiro Matsumura (pp. 899-914).
Polymeric micelles are expected to increase the accumulation of drugs in tumor tissues utilizing the EPR effect and to incorporate various kinds of drugs into the inner core by chemical conjugation or physical entrapment with relatively high stability. The size of the micelles can be controlled within the diameter range of 20 to 100 nm, to ensure that the micelles do not pass through normal vessel walls; therefore, a reduced incidence of the side effects of the drugs may be expected due to the decreased volume of distribution.These are several anticancer agent-incorporated micelle carrier systems under clinical evaluation. Phase 1 studies of a CDDP incorporated micelle, Nc-6004, and an sN-38 incorporated micelle, NK012, are now underway. A phase 2 study of a PTX incorporated micelle, NK105, against stomach cancer is also underway.
Keywords: Poly (amino acid) micelle nanocarrier; Drug delivery system; EPR effect; Clinical trial
Nanotechnology in vaccine delivery by Laura J. Peek; C. Russell Middaugh; Cory Berkland (pp. 915-928).
With very few adjuvants currently being used in marketed human vaccines, a critical need exists for novel immunopotentiators and delivery vehicles capable of eliciting humoral, cellular and mucosal immunity. Such crucial vaccine components could facilitate the development of novel vaccines for viral and parasitic infections, such as hepatitis, HIV, malaria, cancer, etc. In this review, we discuss clinical trial results for various vaccine adjuvants and delivery vehicles being developed that are approximately nanoscale (<1000 nm) in size. Humoral immune responses have been observed for most adjuvants and delivery platforms while only viral vectors, ISCOMs and Montanide™ ISA 51 and 720 have shown cytotoxic T cell responses in the clinic. MF59 and MPL® have elicited Th1 responses, and virus-like particles, non-degradable nanoparticles and liposomes have also generated cellular immunity. Such vaccine components have also been evaluated for alternative routes of administration with clinical successes reported for intranasal delivery of viral vectors and proteosomes and oral delivery of a VLP vaccine.
Keywords: Adjuvant; Immunopotentiator; Humoral immunity; Cellular immunity; Immunization; Nanoparticle; Antigen
Nanotechnology in vaccine delivery by Laura J. Peek; C. Russell Middaugh; Cory Berkland (pp. 915-928).
With very few adjuvants currently being used in marketed human vaccines, a critical need exists for novel immunopotentiators and delivery vehicles capable of eliciting humoral, cellular and mucosal immunity. Such crucial vaccine components could facilitate the development of novel vaccines for viral and parasitic infections, such as hepatitis, HIV, malaria, cancer, etc. In this review, we discuss clinical trial results for various vaccine adjuvants and delivery vehicles being developed that are approximately nanoscale (<1000 nm) in size. Humoral immune responses have been observed for most adjuvants and delivery platforms while only viral vectors, ISCOMs and Montanide™ ISA 51 and 720 have shown cytotoxic T cell responses in the clinic. MF59 and MPL® have elicited Th1 responses, and virus-like particles, non-degradable nanoparticles and liposomes have also generated cellular immunity. Such vaccine components have also been evaluated for alternative routes of administration with clinical successes reported for intranasal delivery of viral vectors and proteosomes and oral delivery of a VLP vaccine.
Keywords: Adjuvant; Immunopotentiator; Humoral immunity; Cellular immunity; Immunization; Nanoparticle; Antigen
Clinical toxicities of nanocarrier systems by Karina R. Vega-Villa; Jody K. Takemoto; Jaime A. Yáñez; Connie M. Remsberg; M. Laird Forrest; Neal M. Davies (pp. 929-938).
Toxicity of nanocarrier systems involves physiological, physicochemical, and molecular considerations. Nanoparticle exposures through the skin, the respiratory tract, the gastrointestinal tract and the lymphatics have been described. Nanocarrier systems may induce cytotoxicity and/or genotoxicity, whereas their antigenicity is still not well understood. Nanocarrier may alter the physicochemical properties of xenobiotics resulting in pharmaceutical changes in stability, solubility, and pharmacokinetic disposition. In particular, nanocarriers may reduce toxicity of hydrophobic cancer drugs that are solubilized. Nano regulation is still undergoing major changes to encompass environmental, health, and safety issues. The rapid commercialization of nanotechnology requires thoughtful environmental, health and safety research, meaningful, and an open discussion of broader societal impacts, and urgent toxicological oversight action.
Keywords: Nanoparticle; Toxicity; Nanomedicine; Nanocarrier; Polymeric micelles; Dendrimer; Nanosphere; Nanopharmaceutics
Clinical toxicities of nanocarrier systems by Karina R. Vega-Villa; Jody K. Takemoto; Jaime A. Yáñez; Connie M. Remsberg; M. Laird Forrest; Neal M. Davies (pp. 929-938).
Toxicity of nanocarrier systems involves physiological, physicochemical, and molecular considerations. Nanoparticle exposures through the skin, the respiratory tract, the gastrointestinal tract and the lymphatics have been described. Nanocarrier systems may induce cytotoxicity and/or genotoxicity, whereas their antigenicity is still not well understood. Nanocarrier may alter the physicochemical properties of xenobiotics resulting in pharmaceutical changes in stability, solubility, and pharmacokinetic disposition. In particular, nanocarriers may reduce toxicity of hydrophobic cancer drugs that are solubilized. Nano regulation is still undergoing major changes to encompass environmental, health, and safety issues. The rapid commercialization of nanotechnology requires thoughtful environmental, health and safety research, meaningful, and an open discussion of broader societal impacts, and urgent toxicological oversight action.
Keywords: Nanoparticle; Toxicity; Nanomedicine; Nanocarrier; Polymeric micelles; Dendrimer; Nanosphere; Nanopharmaceutics
Suspensions for intravenous (IV) injection: A review of development, preclinical and clinical aspects by Joseph Wong; Andrew Brugger; Atul Khare; Mahesh Chaubal; Pavlos Papadopoulos; Barrett Rabinow; James Kipp; John Ning (pp. 939-954).
There has been growing interest in nanoparticles as an approach to formulate poorly soluble drugs. Besides enhanced dissolution rates, and thereby, improved bioavailability, nanoparticles can also provide targeting capabilities when injected intravenously. The latter property has led to increased research and development activities for intravenous suspensions. The first intravenously administered nanoparticulate product, Abraxane® (a reformulation of paclitaxel), was approved by the FDA in 2006. Additional clinical trials have been conducted or are ongoing for multiple other indications such as oncology, infective diseases, and restenosis. This article reviews various challenges associated with developing intravenous nanosuspension dosage forms. In addition, various formulation considerations specific to intravenous nanosuspensions as well as reported findings from various clinical studies have been discussed.
Keywords: Intravenous injection; Nanoparticles; Safety; Poorly water-soluble drugs; Insoluble drug delivery; Extended release
Suspensions for intravenous (IV) injection: A review of development, preclinical and clinical aspects by Joseph Wong; Andrew Brugger; Atul Khare; Mahesh Chaubal; Pavlos Papadopoulos; Barrett Rabinow; James Kipp; John Ning (pp. 939-954).
There has been growing interest in nanoparticles as an approach to formulate poorly soluble drugs. Besides enhanced dissolution rates, and thereby, improved bioavailability, nanoparticles can also provide targeting capabilities when injected intravenously. The latter property has led to increased research and development activities for intravenous suspensions. The first intravenously administered nanoparticulate product, Abraxane® (a reformulation of paclitaxel), was approved by the FDA in 2006. Additional clinical trials have been conducted or are ongoing for multiple other indications such as oncology, infective diseases, and restenosis. This article reviews various challenges associated with developing intravenous nanosuspension dosage forms. In addition, various formulation considerations specific to intravenous nanosuspensions as well as reported findings from various clinical studies have been discussed.
Keywords: Intravenous injection; Nanoparticles; Safety; Poorly water-soluble drugs; Insoluble drug delivery; Extended release