Targeted delivery of a cisplatin prodrug for safer and more effective prostate cancer therapy in vivo
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- 13 January 2011
- journal article
- Published by Proceedings of the National Academy of Sciences in Proceedings of the National Academy of Sciences of the United States of America
- Vol. 108 (5), 1850-1855
- https://doi.org/10.1073/pnas.1011379108
Abstract
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(NH(3))(2)-(O(2)CCH(2)CH(2)CH(2)CH(2)CH(3))(2)Cl(2)] (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.Keywords
This publication has 31 references indexed in Scilit:
- Engineering of self-assembled nanoparticle platform for precisely controlled combination drug therapyProceedings of the National Academy of Sciences of the United States of America, 2010
- Mitaplatin, a potent fusion of cisplatin and the orphan drug dichloroacetateProceedings of the National Academy of Sciences of the United States of America, 2009
- Molecular Assembly of an Aptamer–Drug Conjugate for Targeted Drug Delivery to Tumor CellsChemBioChem, 2009
- Targeted delivery of cisplatin to prostate cancer cells by aptamer functionalized Pt(IV) prodrug-PLGA–PEG nanoparticlesProceedings of the National Academy of Sciences of the United States of America, 2008
- Factors Affecting the Clearance and Biodistribution of Polymeric NanoparticlesMolecular Pharmaceutics, 2008
- Targeted Single-Wall Carbon Nanotube-Mediated Pt(IV) Prodrug Delivery Using Folate as a Homing DeviceJournal of the American Chemical Society, 2008
- Precise engineering of targeted nanoparticles by using self-assembled biointegrated block copolymersProceedings of the National Academy of Sciences of the United States of America, 2008
- Conjugated Platinum(IV)−Peptide Complexes for Targeting Angiogenic Tumor VasculatureBioconjugate Chemistry, 2007
- Targeted nanoparticle-aptamer bioconjugates for cancer chemotherapy in vivoProceedings of the National Academy of Sciences of the United States of America, 2006
- Cellular processing of platinum anticancer drugsNature Reviews Drug Discovery, 2005