Development of a Novel, Sequentially Active-targeted Drug Delivery Nanoplatform for Breast Cancer Therapy

Date

2013

Authors

Satsangi, Arpan

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Abstract

Breast cancer is the second most common cause of cancer-related deaths in women. Chemotherapy is an important treatment modality, and paclitaxel (PTX) is often first-line therapy for the metastatic form. Two notable limitations related to PTX-based treatment are PTX's poor hydrophilicity and the systemic toxicity due to its non-specific distribution among tissues.

This work describes an approach to counter both challenges by designing a prodrug-conjugate of PTX with a hydrophilic macromolecule that is coupled through an active-targeting, enzyme-cleavable linker. However, the targeting of a single molecular cue on cancer cells often leads to serious cytotoxic risk to important normal cells with similar molecular expression profiles. Therefore, a multi-core, multi-targeting device for tumor specific delivery of PTX was designed for enhanced cancer cell selectivity and reduced toxic side-effects, while maintaining capabilities to overcome physiological barriers. The prodrug conjugate of PTX constituted the inner core and was encapsulated in an outer liposomal core that targets a cell surface receptor upregulated in cancer cells and is equipped to exploit the EPR effect for passive targeting of tumors.

As compared to unbound PTX, the non-encapsulated prodrug-conjugate demonstrated a higher cytotoxicity specific to cell lines with moderate-to-high cathepsin B activity and demonstrated higher tumor reduction in MDA-MB-231 xenograft models. Similarly, compared to standard single-targeting liposomal PTX, the multi-targeting construct showed better cytotoxicity against cell lines overexpressing both targeted molecular features and had a higher tumor reduction capability in xenografts. Thus, a novel drug delivery platform with great potential impact on cancer treatment has been developed.

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Keywords

Biocleavable linker, Breast cancer, Dendrosome, Drug delivery, Nanotechnology, Sequential active-targeting

Citation

Department

Biomedical Engineering