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

Abstract

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.

The utilization of nanotechnology in the female reproductive system and related disorders

“…Zhang et al employed polymer micelles to deliver cationic steroidal antibiotics into cells, thereby improving their stability and cellular uptake, leading to a potent therapeutic efficacy against infections [ 72 ]. Gautam et al designed a responsive redox environment polymer micelle that releases drugs within tumor cells, resulting in improved treatment outcomes [ 73 ]. Zhou et al demonstrated a dual-stimuli-responsive hybrid liposome-polymer micelle complex that attained precise drug delivery through temperature and pH changes, offering controlled drug release [ 74 ].…”

Surface-Modified Lyotropic Crystalline Nanoconstructs Bearing Doxorubicin and Buparvaquone Target Sigma Receptors through pH-Sensitive Charge Conversion to Improve Breast Cancer Therapy

“…Developing a stimuli-sensitive nanocarrier system is a potential strategy for enhancing therapeutic efficacy and reducing adverse drug reactions. − A large range of pH-responsive nanocarriers have therefore been created and reported. Consequently, a wide variety of pH-responsive nanocarriers have been developed and described; however, those with pH-dependent charge conversion characteristics stand out as particularly intriguing and promising. , Wang et al reported an excellent pH-sensitive tumor-activated charge conversion delivery system, wherein this form boosts drug release, increases cellular absorption, and strengthens the killing effect on cancer cells. In healthy tissue (pH 6.5), the charge conversion nanocarriers are thought to be negatively charged and unable to easily interact with anionic biomacromolecules, which can prolong circulation time. , The positively charged nanocarriers can interact with negatively charged cell membranes in acidic tumor tissues (pH 7.4) to increase cellular absorption and therapeutic impact.…”

“…Consequently, a wide variety of pH-responsive nanocarriers have been developed and described; however, those with pH-dependent charge conversion characteristics stand out as particularly intriguing and promising. 22,23 Wang et al reported an excellent pH-sensitive tumor-activated charge conversion delivery system, wherein this form boosts drug release, increases cellular absorption, and strengthens the killing effect on cancer cells. In healthy tissue (pH 6.5), the charge conversion nanocarriers are thought to be negatively charged and unable to easily interact with anionic biomacromolecules, which can prolong circulation time.…”