Hypoxia-Responsive Co-Loaded Liposomal Drug Delivery System for the Treatment of Breast Cancer.

Aim

A hypoxia-responsive drug-loaded liposomal drug delivery system was designed with the aim of effective treatment of breast cancer. This involves the synthesis and characterization of a nitroimidazole derivative incorporated within the optimized nanoprobe co-loaded with berberine and doxorubicin.

Background

Breast cancer is a major global health burden, demanding innovative therapeutic strategies to improve treatment modalities with minimal adverse effects. Although conventional chemotherapy is effective to some extent, it remains constrained by limited specificity, systemic toxicity, and undesirable side effects. These limitations can be addressed by spatiotemporal targeted drug delivery with minimal contact with healthy cells.

Purpose

Objective

The key objective of this study is to design a delivery system releasing the drug only in response to nitroreductase enzymes overexpressed in an altered hypoxic tumor microenvironment. This favors targeted drug release, tailoring breast cancer treatment.

Methods

The nitroimidazole derivative was synthesized by a one-step nucleophilic substitution reaction, which was further characterized by FTIR and 1H NMR spectroscopy. The liposomal formulations consisting of plain, PEGylated, and hypoxia-responsive liposomes were optimized using a Box-Behnken design with the aim of achieving the desired vesicle size and entrapment efficiency of berberine and doxorubicin. The liposomal formulations were prepared using DPPC, DMPC, DSPE-PEG2000, and cholesterol, which were further characterized by physicochemical evaluation. In addition, sodium dithionite was used to evaluate the hypoxia-responsive structural distortion releasing the drug. The formulations were further assessed for hemolytic toxicity and cytotoxicity assays against MDA-MB-231 breast cancer cells.

Results

The hypoxia-responsive derivative was successfully synthesized and characterized, affirming its suitability for the desired response. Liposomal formulations incorporating this nitroimidazole derivative met the desired standards, demonstrating optimal physicochemical characteristics. Notably, hypoxia-triggered drug release demonstrated a significant burst release under an induced hypoxic tumor microenvironment, with minimal hemolytic toxicity and superior cytotoxicity against the MDA-MB-231 breast cancer cell line compared to free drugs and other prepared liposomal formulations.

Conclusion

These findings suggest that hypoxia-responsive co-loaded liposomal drug delivery systems offer a promising approach for targeted therapy, enhancing efficacy with reduced systemic side effects.