Characterization and Pharmacokinetic Evaluation of Oxaliplatin Long-Circulating Liposomes.

Nihad Cheraga,Ning-Ping Huang,Ammar Ouahab,Yan Shen,Manish K Chourasia

doi:10.1155/2021/5949804

Abstract

The clinical efficacy of Oxaliplatin (L-OHP) is potentially limited by dose-dependent neurotoxicity and high partitioning to erythrocytes in vivo. Long-circulating liposomes could improve the pharmacokinetic profile of L-OHP and thus enhance its therapeutic efficacy and reduce its toxicity. The purpose of this study was to prepare L-OHP long-circulating liposomes (L-OHP PEG lip) by reverse-phase evaporation method (REV) and investigate their pharmacokinetic behavior based on total platinum in rat plasma using atomic absorption spectrometry (AAS). A simple and a sensitive AAS method was developed and validated to determine the total platinum originated from L-OHP liposomes in plasma. Furthermore, long-circulating liposomes were fully characterized in vitro and showed great stability when stored at 4°C for one month. The results showed that the total platinum in plasma of L-OHP long-circulating liposomes displayed a biexponential pharmacokinetic profile with five folds higher bioavailability and longer distribution half-life compared to L-OHP solution. Thus, long-circulating liposomes prolonged L-OHP circulation time and may present a potential candidate for its tumor delivery. Conclusively, the developed AAS method could serve as a reference to investigate the pharmacokinetic behavior of total platinum in biological matrices for other L-OHP delivery systems.

Highlights

Oxaliplatin (L-OHP) is a third generation of platinum-based anticancer agents with a wide spectrum of antitumor activity and lower toxicity compared to previous generations, cisplatin, and carboplatin [1]
The mean particle size obtained from dynamic light scattering (DLS) analysis was 235 ± 20:30 and 204 ± 1:10 for L-OHP bare lip and L-OHP PEG lip, respectively
The size determined from Transmission Electron Microscopy (TEM) images using the Image J software was smaller than the one by DLS (Table 2), and this could be explained by the shrinkage of the liposomes during the drying process [35]

Summary

Introduction

Oxaliplatin (L-OHP) is a third generation of platinum-based anticancer agents with a wide spectrum of antitumor activity and lower toxicity compared to previous generations, cisplatin, and carboplatin [1]. Its clinical efficacy is potentially limited due to its high and irreversible binding to plasma proteins and erythrocytes leading to low plasma concentrations [2]. Liposomes have repeatedly shown their ability to improve the therapeutic index of anticancer drugs, and to reduce toxicity by minimizing drug uptake by healthy tissues. L-OHP undergoes a rapid biotransformation in vivo due to its strong electrophilicity, yielding reactive platinum metabolites that can irreversibly bind to plasma proteins, erythrocytes, or other low molecular weight compounds [10, 11]. Long-circulating liposomes or PEGylated liposomes can prolong the circulation time of drug in blood by preventing the rapid clearance of liposomes by the reticuloendothelial system (RES), leading to improved drug accumulation in the tumor interstitium by the enhanced

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