Biodegradable dextran-based microspheres for delivery of anticancer drug mitomycin C

Abstract

The purpose of this work was to develop a biodegradable microsphere (MS) system for delivering mitomycin C (MMC). Various dextran-based MS systems were investigated for their loading and release characteristics, including nonionic MS, sulfopropyl dextran microspheres (SP-MS) with low or high cross-linking density, oxidized SP-MS (Ox-MS), and hydrophobically modified SP-MS. SP-MS were chemically modified by oxidation with sodium periodate or by reaction with anhydride. The chemical structure of modified SP-MS and MMC-loaded MS (MMC-MS) were examined using Fourier transform infrared (FTIR) and solid-state nuclear magnetic resonance (NMR) spectrophotometry. Drug release was conducted at 37 °C in aqueous solutions of 0.15 m phosphate buffer solution. The kinetics of drug absorption and release and the stability of MMC after loading and release were determined by spectrophotometry and high-performance liquid chromatography. Ionic SP-MS exhibited a higher drug-loading rate and capacity when compared to nonionic MS, while hydrophobically modified SP-MS showed an even greater loading capacity than SP-MS. These results suggest that both ionic complexation and hydrophobic interaction were important factors in MMC loading. The Ox-MS system demonstrated higher drug-loading capacity, more fractional drug release and a longer time to reach release equilibrium as compared to other investigated MS systems. Under optimized reaction and loading conditions, MMC released from Ox-MS was found to be unaltered. This work demonstrates that the Ox-MS system is a potentially useful system for the delivery of MMC.

Introduction

In the treatment of solid tumors, the efficacy of traditional chemotherapy is limited by the drug concentrations achievable in tumors, the toxicity of chemotherapeutic agents, and the development of drug resistance [1], [2]. Microspheres (MS) are intriguing since they have the potential to increase drug levels within tumors by circumventing the tumor vasculature, decrease normal tissue toxicities by reducing the level of drug in the systemic circulation, overcome noncellular drug resistance mechanisms and act as a depot for the extended release of drug.

An ionic MS system comprising sulfopropyl dextran MS (SP-MS) was developed for the local delivery of anticancer drugs and chemosensitizers to treat solid tumors [3], [4], [5], [6], [7]. The results from previous studies of loco-regional drug delivery to solid tumors suggested that the MS system could provide more effective solid tumor treatment because the drug would be localized to the tumor tissue [7], [8], [9], [10], [11]. The development of additional MS systems for the delivery of the anticancer agent mitomycin C (MMC) was initiated in an attempt to further advance cancer treatment.

MMC is a bifunctional alkylating agent with the structure shown in Fig. 1. It is a potent anticancer drug used in the treatment of superficial bladder cancer and breast cancers. Because of MMC's enhanced activity in hypoxic environments [12], it has great potential for loco-regional treatment of solid tumors since a significant percentage of viable cancer cells within a solid tumor can be hypoxic [13]. However, use of MMC is associated with a number of acute and chronic toxicities, such as irreversible myelosuppression and hemolytic-uremic syndrome, which limit its clinical application. Therefore, efforts have been made to lessen the toxic effects of MMC and improve its utility using various delivery methods.

The predominant method for MMC delivery involves drug encapsulation in MS using various polymers including gelatin and ethylcellulose [14]. Conjugation of MMC with linear dextran polymers has also been investigated [9]. While these systems have shown promise, involved synthesis and loading procedures could lead to significant drug degradation that may compromise drug efficacy. Furthermore, polymers such as poly(lactic-co-glycolic acid) are unsuitable for the delivery of acid-labile MMC [15] because polymer degradation produces a highly acidic local environment [16].

Based on successful loading and release studies of cationic drugs using SP-MS [3], [4], [5], [6], [7] and the fact that MMC has the potential to interact with anionic polymers owing to its amino groups, an attempt was made to load MMC into SP-MS. Nonionic dextran MS (NI-MS) and modified SP-MS were also investigated for selection of an effective MS system for MMC delivery and for the elucidation of MMC loading mechanisms. Dextran-based MS were employed because they are made of a material (i.e. dextran) that has been applied safely in vivo as a blood expander for years and the abundance of hydroxyl groups makes the system easily modifiable to control drug loading and release.