Journal ArticleDOI
Pharmacokinetics of pegylated liposomal Doxorubicin: review of animal and human studies.
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TLDR
The ability of pegylated liposomes to extravasate through the leaky vasculature of tumours, as well as their extended circulation time, results in enhanced delivery of liposomal drug and/or radiotracers to the tumour site in cancer patients.Abstract:
Pegylated liposomal doxorubicin (doxorubicin HCl liposome injection; Doxil® or Caelyx®) is a liposomal formulation of doxorubicin, reducing uptake by the reticulo-endothelial system due to the attachment of polyethylene glycol polymers to a lipid anchor and stably retaining drug as a result of liposomal entrapment via an ammonium sulfate chemical gradient. These features result in a pharmacokinetic profile characterised by an extended circulation time and a reduced volume of distribution, thereby promoting tumour uptake. Preclinical studies demonstrated one- or two-phase plasma concentration-time profiles. Most of the drug is cleared with an elimination half-life of 20–30 hours. The volume of distribution is close to the blood volume, and the area under the concentration-time curve (AUC) is increased at least 60-fold compared with free doxorubicin. Studies of tissue distribution indicated preferential accumulation into various implanted tumours and human tumour xenografts, with an enhancement of drug concentrations in the tumour when compared with free drug. Clinical studies of pegylated liposomal doxorubicin in humans have included patients with AIDS-related Kaposi’s sarcoma (ARKS) and with a variety of solid tumours, including ovarian, breast and prostate carcinomas. The pharmacokinetic profile in humans at doses between 10 and 80 mg/m2 is similar to that in animals, with one or two distribution phases: an initial phase with a half-life of 1–3 hours and a second phase with a half-life of 30–90 hours. The AUC after a dose of 50 mg/m2 is approximately 300-fold greater than that with free drug. Clearance and volume of distribution are drastically reduced (at least 250-fold and 60-fold, respectively). Preliminary observations indicate that utilising the distinct pharmacokinetic parameters of pegylated liposomal doxorubicin in dose scheduling is an attractive possibility. In agreement with the preclinical findings, the ability of pegylated liposomes to extravasate through the leaky vasculature of tumours, as well as their extended circulation time, results in enhanced delivery of liposomal drug and/or radiotracers to the tumour site in cancer patients. There is evidence of selective tumour uptake in malignant effusions, ARKS skin lesions and a variety of solid tumours. The toxicity profile of pegylated liposomal doxorubicin is characterised by dose-limiting mucosal and cutaneous toxicities, mild myelosuppression, decreased cardiotoxicity compared with free doxorubicin and minimal alopecia. The mucocutaneous toxicities are dose-limiting per injection; however, the reduced cardiotoxicity allows a larger cumulative dose than that acceptable for free doxorubicin. Thus, pegylated liposomal doxorubicin represents a new class of chemotherapy delivery system that may significantly improve the therapeutic index of doxorubicin.read more
Citations
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Drug Delivery Systems: Entering the Mainstream
TL;DR: There is considerable interest in exploiting the advantages of DDS for in vivo delivery of new drugs derived from proteomics or genomics research and for their use in ligand-targeted therapeutics.
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Cancer nanomedicine: progress, challenges and opportunities.
TL;DR: Novel engineering approaches are discussed that capitalize on the growing understanding of tumour biology and nano–bio interactions to develop more effective nanotherapeutics for cancer patients.
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Anthracyclines: Molecular Advances and Pharmacologic Developments in Antitumor Activity and Cardiotoxicity
TL;DR: An overview of issues confirms that anthracyclines remain “evergreen” drugs with broad clinical indications but have still an improvable therapeutic index.
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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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PEGylation as a strategy for improving nanoparticle-based drug and gene delivery
TL;DR: The history of the development of PEGylated nanoparticle formulations for systemic administration is described, including how factors such as PEG molecular weight, PEG surface density, nanoparticle core properties, and repeated administration impact circulation time.
References
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Journal ArticleDOI
Regulation of transport pathways in tumor vessels: Role of tumor type and microenvironment
Susan K. Hobbs,Wayne L. Monsky,Fan Yuan,W. G. Roberts,Linda G. Griffith,Vladimir P. Torchilin,Rakesh K. Jain +6 more
TL;DR: Delivery may be less efficient in cranial tumors than in subcutaneous tumors, delivery may be reduced during tumor regression induced by hormonal ablation, and permeability to a molecule is independent of pore cutoff size as long as the diameter of the molecule is much less than the pore diameter.
Journal Article
Vascular Permeability in a Human Tumor Xenograft: Molecular Size Dependence and Cutoff Size
Fan Yuan,Marc Dellian,Dai Fukumura,Michael Leunig,David A. Berk,Vladimir P. Torchilin,Rakesh K. Jain +6 more
TL;DR: Tumor vessels in the model found that tumor vessels in this model were permeable to liposomes of up to 400 nm in diameter, suggesting that the cutoff size of the pores is between 400 and 600nm in diameter.
Journal ArticleDOI
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.
Journal ArticleDOI
Openings between Defective Endothelial Cells Explain Tumor Vessel Leakiness
Hiroya Hashizume,Peter Baluk,Shunichi Morikawa,John W. McLean,Gavin Thurston,Sylvie Roberge,Rakesh K. Jain,Donald M. McDonald +7 more
TL;DR: It is concluded that some tumor vessels have a defective cellular lining composed of disorganized, loosely connected, branched, overlapping or sprouting endothelial cells that contribute to tumor vessel leakiness and may permit access of macromolecular therapeutic agents to tumor cells.
Journal ArticleDOI
Reduced cardiotoxicity and comparable efficacy in a phase III trial of pegylated liposomal doxorubicin HCl (CAELYX™/Doxil®) versus conventional doxorubicin for first-line treatment of metastatic breast cancer
Mary O'Brien,Nely Wigler,Moshe Inbar,R. Rosso,E. Grischke,Armando Santoro,Raphael Catane,D. G. Kieback,Piotr Tomczak,Stephen P. Ackland,F. Orlandi,L. Mellars,L. Alland,C. Tendler +13 more
TL;DR: In first-line therapy for MBC, PLD provides comparable efficacy to doxorubicin, with significantly reduced cardiotoxicity, myelosuppression, vomiting and alopecia.
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