The Experts below are selected from a list of 27 Experts worldwide ranked by ideXlab platform
Shanta Dhar - One of the best experts on this subject based on the ideXlab platform.
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engineering of blended nanoparticle platform for delivery of mitochondria acting Therapeutics
Proceedings of the National Academy of Sciences of the United States of America, 2012Co-Authors: Sean Marrache, Shanta DharAbstract:Mitochondrial dysfunctions cause numerous human disorders. A platform technology based on biodegradable polymers for carrying bioactive molecules to the mitochondrial matrix could be of enormous potential benefit in treating mitochondrial diseases. Here we report a rationally designed mitochondria-targeted polymeric nanoparticle (NP) system and its optimization for efficient delivery of various mitochondria-acting Therapeutics by blending a targeted poly(d,l-lactic-co-glycolic acid)-block (PLGA-b)-poly(ethylene glycol) (PEG)-triphenylphosphonium (TPP) polymer (PLGA-b-PEG-TPP) with either nontargeted PLGA-b-PEG-OH or PLGA-COOH. An optimized formulation was identified through in vitro screening of a library of charge- and size-varied NPs, and mitochondrial uptake was studied by qualitative and quantitative investigations of cytosolic and mitochondrial fractions of cells treated with blended NPs composed of PLGA-b-PEG-TPP and a triblock copolymer containing a fluorescent quantum dot, PLGA-b-PEG-QD. The versatility of this platform was demonstrated by studying various mitochondria-acting Therapeutics for different applications, including the mitochondria-targeting chemoTherapeutics lonidamine and α-tocopheryl succinate for cancer, the mitochondrial antioxidant curcumin for Alzheimer’s disease, and the mitochondrial uncoupler 2,4-dinitrophenol for obesity. These biomolecules were loaded into blended NPs with high loading efficiencies. Considering efficacy, the targeted PLGA-b-PEG-TPP NP provides a remarkable improvement in the Drug Therapeutic Index for cancer, Alzheimer’s disease, and obesity compared with the nontargeted construct or the Therapeutics in their free form. This work represents the potential of a single, programmable NP platform for the diagnosis and targeted delivery of Therapeutics for mitochondrial dysfunction-related diseases.
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targeted delivery of a cisplatin proDrug for safer and more effective prostate cancer therapy in vivo
Proceedings of the National Academy of Sciences of the United States of America, 2011Co-Authors: Shanta Dhar, Nagesh Kolishetti, Stephen J Lippard, Omid C FarokhzadAbstract:Targeted delivery and controlled release of inactive platinum (Pt) proDrugs may offer a new approach to improve the efficacy and tolerability of the Pt family of Drugs, which are used to treat 50% of all cancers today. Using prostate cancer (PCa) as a model disease, we previously described the engineering of aptamer (Apt)-targeted poly(D,L-lactic-co-glycolic acid)-b-poly(ethylene glycol) (PLGA-b-PEG) nanoparticles (NPs) encapsulating a Pt(IV) proDrug c,t,c[Pt(NH3)2-(O2CCH2CH2CH2CH2CH3)2Cl2] (1) (Pt-PLGA-b-PEG-Apt-NP), which target the extracellular domain of the prostate specific membrane antigen (PSMA), for enhanced in vitro cytotoxicity. Here we demonstrate enhanced in vivo pharmacokinetics (PK), biodistribution, tolerability, and efficacy of Pt-PLGA-b-PEG-Apt-NP (150±15 nm encapsulating ∼5% wt/wt Pt(IV) proDrug) when compared to cisplatin administered in its conventional form in normal Sprague Dawley rats, Swiss Albino mice, and the PSMA-expressing LNCaP subcutaneous xenograft mouse model of PCa, respectively. The 10-d maximum tolerated dose following a single i.v. injection of Pt-PLGA-b-PEG-NP in rats and mice was determined at 40 mg/kg and 5 mg/kg, respectively. PK studies with Pt-PLGA-b-PEG-NP revealed prolonged Pt persistence in systemic blood circulation and decreased accumulation of Pt in the kidneys, a major target site of cisplatin toxicity. Pt-PLGA-b-PEG-Apt-NPs further displayed the significant dose-sparing characteristics of the Drug, with equivalent antitumor efficacy in LNCaP xenografts at 1/3 the dose of cisplatin administered in its conventional form (0.3 mg/kg vs. 1 mg/kg). When considering the simultaneous improvement in tolerability and efficacy, the Pt-PLGA-b-PEG-Apt NP provides a remarkable improvement in the Drug Therapeutic Index.
Omid C Farokhzad - One of the best experts on this subject based on the ideXlab platform.
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targeted delivery of a cisplatin proDrug for safer and more effective prostate cancer therapy in vivo
Proceedings of the National Academy of Sciences of the United States of America, 2011Co-Authors: Shanta Dhar, Nagesh Kolishetti, Stephen J Lippard, Omid C FarokhzadAbstract:Targeted delivery and controlled release of inactive platinum (Pt) proDrugs may offer a new approach to improve the efficacy and tolerability of the Pt family of Drugs, which are used to treat 50% of all cancers today. Using prostate cancer (PCa) as a model disease, we previously described the engineering of aptamer (Apt)-targeted poly(D,L-lactic-co-glycolic acid)-b-poly(ethylene glycol) (PLGA-b-PEG) nanoparticles (NPs) encapsulating a Pt(IV) proDrug c,t,c[Pt(NH3)2-(O2CCH2CH2CH2CH2CH3)2Cl2] (1) (Pt-PLGA-b-PEG-Apt-NP), which target the extracellular domain of the prostate specific membrane antigen (PSMA), for enhanced in vitro cytotoxicity. Here we demonstrate enhanced in vivo pharmacokinetics (PK), biodistribution, tolerability, and efficacy of Pt-PLGA-b-PEG-Apt-NP (150±15 nm encapsulating ∼5% wt/wt Pt(IV) proDrug) when compared to cisplatin administered in its conventional form in normal Sprague Dawley rats, Swiss Albino mice, and the PSMA-expressing LNCaP subcutaneous xenograft mouse model of PCa, respectively. The 10-d maximum tolerated dose following a single i.v. injection of Pt-PLGA-b-PEG-NP in rats and mice was determined at 40 mg/kg and 5 mg/kg, respectively. PK studies with Pt-PLGA-b-PEG-NP revealed prolonged Pt persistence in systemic blood circulation and decreased accumulation of Pt in the kidneys, a major target site of cisplatin toxicity. Pt-PLGA-b-PEG-Apt-NPs further displayed the significant dose-sparing characteristics of the Drug, with equivalent antitumor efficacy in LNCaP xenografts at 1/3 the dose of cisplatin administered in its conventional form (0.3 mg/kg vs. 1 mg/kg). When considering the simultaneous improvement in tolerability and efficacy, the Pt-PLGA-b-PEG-Apt NP provides a remarkable improvement in the Drug Therapeutic Index.
Sean Marrache - One of the best experts on this subject based on the ideXlab platform.
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engineering of blended nanoparticle platform for delivery of mitochondria acting Therapeutics
Proceedings of the National Academy of Sciences of the United States of America, 2012Co-Authors: Sean Marrache, Shanta DharAbstract:Mitochondrial dysfunctions cause numerous human disorders. A platform technology based on biodegradable polymers for carrying bioactive molecules to the mitochondrial matrix could be of enormous potential benefit in treating mitochondrial diseases. Here we report a rationally designed mitochondria-targeted polymeric nanoparticle (NP) system and its optimization for efficient delivery of various mitochondria-acting Therapeutics by blending a targeted poly(d,l-lactic-co-glycolic acid)-block (PLGA-b)-poly(ethylene glycol) (PEG)-triphenylphosphonium (TPP) polymer (PLGA-b-PEG-TPP) with either nontargeted PLGA-b-PEG-OH or PLGA-COOH. An optimized formulation was identified through in vitro screening of a library of charge- and size-varied NPs, and mitochondrial uptake was studied by qualitative and quantitative investigations of cytosolic and mitochondrial fractions of cells treated with blended NPs composed of PLGA-b-PEG-TPP and a triblock copolymer containing a fluorescent quantum dot, PLGA-b-PEG-QD. The versatility of this platform was demonstrated by studying various mitochondria-acting Therapeutics for different applications, including the mitochondria-targeting chemoTherapeutics lonidamine and α-tocopheryl succinate for cancer, the mitochondrial antioxidant curcumin for Alzheimer’s disease, and the mitochondrial uncoupler 2,4-dinitrophenol for obesity. These biomolecules were loaded into blended NPs with high loading efficiencies. Considering efficacy, the targeted PLGA-b-PEG-TPP NP provides a remarkable improvement in the Drug Therapeutic Index for cancer, Alzheimer’s disease, and obesity compared with the nontargeted construct or the Therapeutics in their free form. This work represents the potential of a single, programmable NP platform for the diagnosis and targeted delivery of Therapeutics for mitochondrial dysfunction-related diseases.
Aziz Karim - One of the best experts on this subject based on the ideXlab platform.
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Drug meal and formulation interactions influencing Drug absorption after oral administration clinical implications
Clinical Pharmacokinectics, 1999Co-Authors: David Fleisher, Cheng Li, Yuji Zhou, Aziz KarimAbstract:Drug-Drug, Drug-formulation and Drug-meal interactions are of clinical concern for orally administered Drugs that possess a narrow Therapeutic Index. This review presents the current status of information regarding interactions which may influence the gastrointestinal (GI) absorption of orally administered Drugs. Absorption interactions have been classified on the basis of rate-limiting processes. These processes are put in the context of Drug and formulation physicochemical properties and oral input influences on variable GI physiology. Interaction categorisation makes use of a biopharmaceutical classification system based on Drug aqueous solubility and membrane permeability and their contributions towards absorption variability. Overlaying this classification it is important to be aware of the effect that the magnitudes of Drug dosage and volume of fluid administration can have on interactions involving a solubility rate limits. GI regional differences in membrane permeability are fundamental to the rational development of extended release dosage forms as well as to predicting interaction effects on absorption from immediate release dosage forms. The effect of meals on the regional-dependent intestinal elimination of Drugs and their involvement in Drug absorption interactions is also discussed. Although the clinical significance of such interactions is certainly dependent on the narrowness of the Drug Therapeutic Index, clinical aspects of absorption delays and Therapeutic failures resulting from various interactions are also important.
Stephen J Lippard - One of the best experts on this subject based on the ideXlab platform.
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targeted delivery of a cisplatin proDrug for safer and more effective prostate cancer therapy in vivo
Proceedings of the National Academy of Sciences of the United States of America, 2011Co-Authors: Shanta Dhar, Nagesh Kolishetti, Stephen J Lippard, Omid C FarokhzadAbstract:Targeted delivery and controlled release of inactive platinum (Pt) proDrugs may offer a new approach to improve the efficacy and tolerability of the Pt family of Drugs, which are used to treat 50% of all cancers today. Using prostate cancer (PCa) as a model disease, we previously described the engineering of aptamer (Apt)-targeted poly(D,L-lactic-co-glycolic acid)-b-poly(ethylene glycol) (PLGA-b-PEG) nanoparticles (NPs) encapsulating a Pt(IV) proDrug c,t,c[Pt(NH3)2-(O2CCH2CH2CH2CH2CH3)2Cl2] (1) (Pt-PLGA-b-PEG-Apt-NP), which target the extracellular domain of the prostate specific membrane antigen (PSMA), for enhanced in vitro cytotoxicity. Here we demonstrate enhanced in vivo pharmacokinetics (PK), biodistribution, tolerability, and efficacy of Pt-PLGA-b-PEG-Apt-NP (150±15 nm encapsulating ∼5% wt/wt Pt(IV) proDrug) when compared to cisplatin administered in its conventional form in normal Sprague Dawley rats, Swiss Albino mice, and the PSMA-expressing LNCaP subcutaneous xenograft mouse model of PCa, respectively. The 10-d maximum tolerated dose following a single i.v. injection of Pt-PLGA-b-PEG-NP in rats and mice was determined at 40 mg/kg and 5 mg/kg, respectively. PK studies with Pt-PLGA-b-PEG-NP revealed prolonged Pt persistence in systemic blood circulation and decreased accumulation of Pt in the kidneys, a major target site of cisplatin toxicity. Pt-PLGA-b-PEG-Apt-NPs further displayed the significant dose-sparing characteristics of the Drug, with equivalent antitumor efficacy in LNCaP xenografts at 1/3 the dose of cisplatin administered in its conventional form (0.3 mg/kg vs. 1 mg/kg). When considering the simultaneous improvement in tolerability and efficacy, the Pt-PLGA-b-PEG-Apt NP provides a remarkable improvement in the Drug Therapeutic Index.
