Biodegradable dextran-based microspheres for delivery of anticancer drug mitomycin C
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.
Section snippets
Materials
All MS systems, including: SP-MS (Sephadex SP C-25, sulfopropyl dextran MS with high cross-linking density, separation of small molecules up to molecular weight of 3×104), NI-MS (Sephadex G-50, cross-linked nonionic dextran MS, separation of intermediate-sized molecules with molecular weights ranging from 3×104 to 2×105), LXLD-SP-MS (Sephadex SP C-50, sulfopropyl dextran MS with low cross-linking density, separation of intermediate-sized molecules with molecular weights ranging from 3×104 to
MMC loading into cross-linked dextran microspheres
Based on results from previous studies involving loading cationic drugs into SP-MS by Liu et al. [3], and the structure of MMC, drug loading was initially investigated using the same SP-MS system. To delineate the possible role of ionic and hydrophobic interactions in drug loading, NI-MS and hydrophobic-MS were compared with SP-MS. As depicted in Fig. 2, under similar loading conditions, SP-MS show higher MMC loading capacity (approximately 75% of MMC remaining in solution over 24 h) than NI-MS
Discussion
The present work led to the selection of Ox-MS for the delivery of MMC because Ox-MS have a higher loading efficiency and capacity, more sustained release when compared to other dextran-based MS and do not jeopardize the stability of MMC like hydrophobic-MS. Although extra chemical modification of SP-MS is needed, MMC is readily loaded into Ox-MS by simple incubation in MMC solutions. Furthermore, the gain in drug loading efficiency and sustained release offset the additional preparation costs.
Conclusion
Various biodegradable dextran-based MS systems with different hydrophobicity, charge, and cross-linking density have been investigated for the delivery of an anticancer drug, MMC. The characteristics of these MS systems as a carrier of MMC have been evaluated, such as drug loading capacity, drug release rate, and drug stability following release. Among the systems studied in this work, Ox-MS possess superior properties for MMC delivery by offering a higher drug loading capacity and more
Acknowledgements
The authors would like to thank the Canadian Institutes of Health Research for sponsoring this project (MOP53165, MOP63005). The Ontario Graduate Scholarship, University of Toronto Open Fellowships, Pharmacy Alumni Award, and Ben Cohen Fund to R. Cheung, consultation with Dr. R. McClelland on chemical binding of MMC and polymer and with Dr. A. Baer on the interpretation and analysis of the NMR spectra are also acknowledged.
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