Optimizing Liposomal Cisplatin Efficacy through Membrane Composition Manipulations

Sharon Johnstone,Natalia Zisman,Lawrence Mayer,David Bermudes,Nancy Dos Santos,Alan Tsang,Paul Tardi

doi:10.1155/2011/213848

Sharon Johnstone, Natalia Zisman + Show 5 more

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https://doi.org/10.1155/2011/213848

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Abstract

The first liposomal formulation of cisplatin to be evaluated clinically was SPI-077. Although the formulation demonstrated enhanced cisplatin tumor accumulation in preclinical models it did not enhance clinical efficacy, possibly due to limited cisplatin release from the formulation localized within the tumor. We have examined a series of liposomal formulations to address the in vivo relationship between cisplatin release rate and formulation efficacy in the P388 murine leukemia model. The base formulation of phosphatidylcholine: phosphatidylglycerol: cholesterol was altered in the C18 and C16 phospholipid content to influence membrane fluidity and thereby impacting drug circulation lifetime and drug retention. Phase transition temperatures (Tm) ranged from 42–55°C. The high Tm formulations demonstrated enhanced drug retention properties accompanied by low antitumor activity while the lowest Tm formulations released the drug too rapidly in the plasma, limiting drug delivery to the tumor which also resulted in low antitumor activity. A formulation composed of DSPC : DPPC : DSPG : Chol; (35 : 35 : 20 : 10) with an intermediate drug release rate and a cisplatin plasma half-life of 8.3 hours showed the greatest antitumor activity. This manuscript highlights the critical role that drug release rates play in the design of an optimized drug delivery vehicle.

Highlights

Cisplatin or cis-diamminedichloroplatinum (II) belongs to a family of platinum-containing complexes that are used clinically to treat cancer and include carboplatin, oxaliplatin, and nedaplatin
It is generally believed that increasing the retention of a drug within a delivery vehicle will result in enhanced drug accumulation at a tumor site
This was shown to be true with SPI-077, where high levels of platinum were detected at tumor sites [16, 17]

Summary

Introduction

Cisplatin or cis-diamminedichloroplatinum (II) belongs to a family of platinum-containing complexes that are used clinically to treat cancer and include carboplatin, oxaliplatin, and nedaplatin. Cisplatin is a widely used cytotoxic agent approved in the treatment of bladder, ovarian, testicular, cervical, head and neck, and nonsmall cell lung cancer [1,2,3]. Cisplatin was first documented in 1847 by M Peyrone, and it was approved by FDA for a variety of cancers in 1978. The resulting hydrolysis product is believed to be the active species, interacting with nucleophilic molecules including DNA [4], RNA, and protein. The interactions result in interstrand and intrastrand cross-links that effectively halt DNA, RNA, and protein synthesis leading to the activation of the apoptotic cascade [5, 6]. Cisplatin is a highly effective anticancer agent, it is noted for severe side effects including renal toxicity, gastrointestinal toxicity, nephrotoxicity, ototoxicity, and optic neuropathy which limits its use in the clinic [7,8,9,10]

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