Hydrophobically modified inulin-based micelles: Transport mechanisms and drug delivery applications for breast cancer

Carbohydrate-based polymers are gaining interest as drug delivery materials with improved safety profile and cost effectiveness. Understanding the cellular uptake mechanisms of nanoparticle prepared with carbohydrate-based polymers is very critical in advancing them as drug delivery vehicles. In the current study, we utilized self-assembling nano-micelles of lauryl carbamate derivative of plant-based polymer inulin (Inutec-SP1 (R), INT) to deliver single or a combination of chemotherapeutic drugs for breast cancer. INT micelles loaded with doxorubicin (DOX) and/or paclitaxel (PTX) were prepared using thin-film hydration method. INT formed micelles with a large core as shown by transmission electron microscopy and are 302.3 +/- 16.3 nm in diameter. The efficiency of drug encapsulation was very high with INT micelles (89.5% with DOX and 76.6% for PTX). The in-vitro drug release from the micelles was sustained for > 72 hat pH 7.4. Clathrin-mediated endocytosis was the predominant pathway involved in the internalization of INT micelles as studied using pharmacological inhibitors of various endocytosis pathways and flow cytometry. The internalized micelles were transported to lysosomes as evident from localization studies with Lysotracker-Green. Both DOX and PTX were more efficient (similar to 100-250 folds) in inhibiting the cell viability when delivered through INT-micelles compared to respective drugs in soluble form. Furthermore, combination micelles containing both DOX and PTX were more efficient than micelles with individual drugs. With reported enhanced circulation time in-vivo along with the availability of a network of functional groups for active targeting, INT-micelles offer a unique delivery system for a single/combination of chemotherapeutic agents.