Self-Assembled Redox-Sensitive Polymeric Nanostructures Facilitate the Intracellular Delivery of Paclitaxel for Improved Breast Cancer Therapy

A two-tier
approach has been proposed for targeted and synergistic
combination therapy against metastatic breast cancer. First, it comprises
the development of a paclitaxel (PX)-loaded redox-sensitive self-assembled
micellar system using betulinic acid–disulfide–d-α-tocopheryl poly(ethylene glycol) succinate (BA-Cys-T) through
carbonyl diimidazole (CDI) coupling chemistry. Second, hyaluronic
acid is anchored to TPGS (HA-Cys-T) chemically through
a cystamine spacer to achieve CD44 receptor-mediated targeting. We
have established that there is significant synergy between PX and
BA with a combination index of 0.27 at a molar ratio of 1:5. An integrated
system comprising both BA-Cys-T and HA-Cys-T (PX/BA-Cys-T-HA) exhibited
significantly higher uptake than PX/BA-Cys-T, indicating preferential
CD44-mediated uptake along with the rapid release of drugs in response
to higher glutathione concentrations. Significantly higher apoptosis
(42.89%) was observed with PX/BA-Cys-T-HA than those with BA-Cys-T
(12.78%) and PX/BA-Cys-T (33.38%). In addition, PX/BA-Cys-T-HA showed
remarkable enhancement in the cell cycle arrest, improved depolarization
of the mitochondrial membrane potential, and induced excessive generation
of ROS when tested in the MDA-MB-231 cell line. An in vivo administration
of targeted micelles showed improved pharmacokinetic parameters and
significant tumor growth inhibition in 4T1-induced tumor-bearing BALB/c
mice. Overall, the study indicates a potential role of PX/BA-Cys-T-HA
in achieving both temporal and spatial targeting against metastatic
breast cancer.