Cholesterol-tethered platinum II-based supramolecular nanoparticle increases antitumor efficacy and reduces nephrotoxicity
Laboratory for Nanomedicine, Division of Biomedical Engineering, Department of Medicine and Center for Regenerative Therapeutics, Brigham and Women's Hospital, Cambridge, MA 02139, USA. Proceedings of the National Academy of Sciences
(Impact Factor: 9.67).
06/2012; 109(28):11294-9. DOI: 10.1073/pnas.1203129109
Nanoscale drug delivery vehicles have been harnessed extensively as carriers for cancer chemotherapeutics. However, traditional pharmaceutical approaches for nanoformulation have been a challenge with molecules that exhibit incompatible physicochemical properties, such as platinum-based chemotherapeutics. Here we propose a paradigm based on rational design of active molecules that facilitate supramolecular assembly in the nanoscale dimension. Using cisplatin as a template, we describe the synthesis of a unique platinum (II) tethered to a cholesterol backbone via a unique monocarboxylato and O→Pt coordination environment that facilitates nanoparticle assembly with a fixed ratio of phosphatidylcholine and 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[amino (polyethylene glycol)-2000]. The nanoparticles formed exhibit lower IC(50) values compared with carboplatin or cisplatin in vitro, and are active in cisplatin-resistant conditions. Additionally, the nanoparticles exhibit significantly enhanced in vivo antitumor efficacy in murine 4T1 breast cancer and in K-Ras(LSL/+)/Pten(fl/fl) ovarian cancer models with decreased systemic- and nephro-toxicity. Our results indicate that integrating rational drug design and supramolecular nanochemistry can emerge as a powerful strategy for drug development. Furthermore, given that platinum-based chemotherapeutics form the frontline therapy for a broad range of cancers, the increased efficacy and toxicity profile indicate the constructed nanostructure could translate into a next-generation platinum-based agent in the clinics.
Available from: Alexandre Detappe
- "Once in place, the smart RT biomaterials can then release the CNP as the polymer coating degrades. A number of recent studies have reported the design of CNP that would enhance cisplatin delivery in the tumor   . The feasibility of incorporating such nanoparticles in novel smart biomaterials has also been demonstrated recently where inert biomaterials were coated with biodegradable, biocompatible chitosan films containing nanoparticles loaded with a drug model for sustainable release as the polymer degrades . "
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ABSTRACT: We predict, for the first time, that by using United States Food and Drug Administration approved concentrations of cisplatin, major radiosensitization may be achieved via photoelectric mechanism during concomitant chemoradiotherapy (CCRT). Our analytical calculations estimate that radiotherapy (RT) dose to cancer cells may be enhanced via this mechanism by over 100% during CCRT. The results proffer new potential for significantly enhancing CCRT via an emerging clinical scenario, where the cisplatin is released in-situ from RT biomaterials loaded with cisplatin nanoparticles.
Available from: futuremedicine.com
Available from: Sara Abouelmagd
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ABSTRACT: Nanoparticles have received enormous attention as a promising tool to enhance target-specific drug delivery and diagnosis. Various in vitro and in vivo techniques are used to characterize a new system and predict its clinical efficacy. These techniques enable efficient comparison across nanoparticles and facilitate a product optimization process. On the other hand, we recognize their limitations as a prediction tool, which owe to inadequate applications and overly simplified test conditions. This article provides a critical review of in vitro and in vivo techniques currently used for evaluation of nanoparticles and introduces emerging techniques and models that may be used complementarily.
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