Cholesterol-tethered platinum II-based supramolecular nanoparticle increases antitumor efficacy and reduces nephrotoxicity

Proc Natl Acad Sci U S A. 2012 Jul 10;109(28):11294-9. doi: 10.1073/pnas.1203129109. Epub 2012 Jun 25.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology*
  • Apoptosis
  • Carcinoma, Lewis Lung
  • Cell Line, Tumor
  • Cell Survival
  • Cholesterol / chemistry
  • Cholesterol / metabolism*
  • Cisplatin / administration & dosage
  • Drug Carriers
  • Drug Delivery Systems
  • Drug Screening Assays, Antitumor / methods*
  • Inhibitory Concentration 50
  • Kidney / drug effects*
  • Kidney / metabolism
  • Mice
  • Models, Chemical
  • Nanoparticles / chemistry*
  • Nanotechnology / methods
  • Platinum / administration & dosage*
  • Succinic Acid / chemistry

Substances

  • Antineoplastic Agents
  • Drug Carriers
  • Platinum
  • Cholesterol
  • Succinic Acid
  • Cisplatin