Open AccessJournal Article
Prolonged circulation time and enhanced accumulation in malignant exudates of doxorubicin encapsulated in polyethylene-glycol coated liposomes.
Alberto Gabizon,Raphael Catane,Beatrice Uziely,Bela Kaufman,Tamar Safra,Rivka Cohen,Francis Martin,Anthony Huang,Yechezkel Barenholz +8 more
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TLDR
The results of this study are consistent with preclinical findings indicating that the pharmacokinetics of doxorubicin are drastically altered using Doxil and follow a pattern dictated by the liposome carrier.Abstract:
In preclinical studies, a doxorubicin liposome formulation containing polyethylene-glycol (Doxil) shows a long circulation time in plasma, enhanced accumulation in murine tumors, and a superior therapeutic activity over free (unencapsulated) doxorubicin (DOX). The purpose of this study was to characterize the pharmacokinetics of Doxil in cancer patients in comparison with free DOX and examine its accumulation in malignant effusions. The pharmacokinetics of doxorubicin and/or liposome-associated doxorubicin were analyzed in seven patients after injections of equivalent doses of free DOX and Doxil and in an additional group of nine patients after injection of Doxil only. Two dose levels were examined, 25 and 50 mg/m2. When possible, drug levels were also measured in malignant effusions. The plasma elimination of Doxil followed a biexponential curve with half-lives of 2 and 45 h (median values), most of the dose being cleared from plasma under the longer half-life. Nearly 100% of the drug detected in plasma after Doxil injection was in liposome-encapsulated form. A slow plasma clearance (0.1 liter/h for Doxil versus 45 liters/h for free DOX) and a small volume of distribution (4 liters for Doxil versus 254 liters for free DOX) are characteristic of Doxil. Doxorubicin metabolites were detected in the urine of Doxil-treated patients with a pattern similar to that reported for free DOX, although the overall urinary excretion of drug and metabolites was significantly reduced. Doxil treatment resulted in a 4- to 16-fold enhancement of drug levels in malignant effusions, peaking between 3 to 7 days after injection. Stomatitis related to Doxil occurred in 5 of 15 evaluable patients and appears to be the most significant side effect in heavily pretreated patients. The results of this study are consistent with preclinical findings indicating that the pharmacokinetics of doxorubicin are drastically altered using Doxil and follow a pattern dictated by the liposome carrier. The enhanced drug accumulation in malignant effusions is apparently related to liposome longevity in circulation. Further clinical investigation is needed to establish the relevance of these findings with regard to the ability of liposomes to modify the delivery of doxorubicin to solid tumors and its pattern of antitumor activity.read more
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Liposomal drug delivery systems: from concept to clinical applications.
TL;DR: Lipidic nanoparticles are the first nanomedicine delivery system to make the transition from concept to clinical application, and they are now an established technology platform with considerable clinical acceptance.
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Doxil®--the first FDA-approved nano-drug: lessons learned.
TL;DR: This review summarizes historical and scientific perspectives of Doxil development and lessons learned from its development and 20 years of its use and demonstrates the obligatory need for applying an understanding of the cross talk between physicochemical, nano-technological, and biological principles.
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Solid lipid nanoparticles: Production, characterization and applications
W. Mehnert,Karsten Mäder +1 more
TL;DR: An overview about the selection of the ingredients, different ways of SLN production and SLN applications, and the in vivo fate of the carrier are presented.
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Cancer Nanotechnology: The impact of passive and active targeting in the era of modern cancer biology
TL;DR: The fundamental concepts of enhanced permeability and retention effect (EPR) are revisited and the mechanisms proposed to enhance preferential "retention" in the tumor, whether using active targeting of nanoparticles, binding of drugs to their tumoral targets or the presence of tumor associated macrophages are explored.
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Nanoparticle-Based Medicines: A Review of FDA-Approved Materials and Clinical Trials to Date.
Daniel Bobo,Kye J. Robinson,Jiaul Islam,Jiaul Islam,Kristofer J. Thurecht,Simon R. Corrie,Simon R. Corrie +6 more
TL;DR: An up to date snapshot of nanomedicines either currently approved by the US FDA, or in the FDA clinical trials process is provided, and there is a trend towards the development of more complex materials comprising micelles, protein-based NPs, and also the emergence of a variety of inorganic and metallic particles in clinical trials.
References
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Journal ArticleDOI
Amphipathic polyethyleneglycols effectively prolong the circulation time of liposomes
TL;DR: The PEG‐PE's activity to prolong the circulation time of liposomes is greater than that of the ganglioside GM1, awell‐described glycolipid with this activity.
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Sterically stabilized liposomes: improvements in pharmacokinetics and antitumor therapeutic efficacy.
Demetrios Papahadjopoulos,Theresa M. Allen,Alberto Gabizon,E Mayhew,Katherine K. Matthay,Shi Kun Huang,Karim Lee,M C Woodle,D D Lasic,C Redemann +9 more
TL;DR: Liposome formulations incorporating a synthetic polyethylene glycol-derivatized phospholipid can produce a large increase in the pharmacological efficacy of encapsulated antitumor drugs and have expanded considerably the prospects of liposomes as an effective carrier system for a variety of pharmacologically active macromolecules.
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Liposomes containing synthetic lipid derivatives of poly(ethylene glycol) show prolonged circulation half-lives in vivo
TL;DR: A carbamate derivative of PEG-1900 with distearoylphosphatidylethanolamine (PEG-DSPE) had the greatest ability to decrease MPS uptake of liposomes, at optimum concentrations of 5-7 mol% in liposome composed of sphingomyelin/egg phosphatidylcholine/cholesterol (SM/PC/Chol, 1:1:1, molar ratio).
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Liposome formulations with prolonged circulation time in blood and enhanced uptake by tumors.
TL;DR: By selective changes in lipid composition, up to a 60-fold increase in the fraction of recovered dose present in blood 24 hr after i.v. injection is achieved, which has considerable therapeutic potential in cancer for increasing the concentration of cytotoxic agents in tumors while minimizing the likelihood of toxicity to the reticuloendothelial system.
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Sterically stabilized liposomes
Martin C. Woodle,Danilo D. Lasic +1 more
TL;DR: The structure-function relationship of PEG-derivatized phosphatidylethanolamine (PEG-PE) has been examined by measurement of blood lifetime and tissue distribution in both mice and rats and Steric stabilization has been proposed as a theoretical basis for the results.