Structure‐Guided Engineering of Cytotoxic Cabazitaxel for an Adaptive Nanoparticle Formulation: Enhancing the Drug Safety and Therapeutic Efficacy

Abstract

Development of a sophisticated nanotherapeutic platform to deliver potent agents effectively and safely to desired tumor sites remains challenging. Cabazitaxel (CTX) holds particular interest for clinical use because of its ability to overcome the drug resistance caused by other taxane drugs. However, investigations of this potent agent have been met with only limited success due to its high toxicity in patients, and thus the exploration of CTX as a safe chemotherapeutic remains a tremendous challenge. Here, it is reported that CTX can be structurally tailored to make it more compatible with a polymeric platform through chemical derivatization with oligolactide (oLA). Covalent conjugation of CTX to oLAs yields new entities that are sufficiently miscible with exogenous polymer matrices to form injectable nanomedicines (termed o(LA)n‐CTX‐NPs). Utilizing these o(LA)n‐CTX‐NPs, the remarkable increases in tumor accumulation and amelioration of drug toxicity in animals are demonstrated. In a xenograft model of lung cancer, administration of o(LA)18‐CTX‐NPs enhances the antitumor efficacy relative to administration of free CTX. Overall, the data show that precision editing of drug chemical structures can be harnessed to generate better tolerated and more efficient nanomedicines. This approach might be a complementary strategy to simultaneously augment the safety and potency of other anticancer agents.

Effects of Polymer 3D Architecture, Size, and Chemistry on Biological Transport and Drug Delivery In Vitro and in Orthotopic Triple Negative Breast Cancer Models

“…[4] The use of polymers as drug carriers aims to overcome these drawbacks through achieving longer circulation times, enhanced uptake in disease sites and increased specificity of delivery. [5][6][7] However, in order to obtain selective tumor uptake of nanoparticle drug carriers, the delivery systems must meet several criteria, such as an appropriate size range for diffusion out of the vasculature, prolonged circulation time in the bloodstream to allow for efficient uptake, reduced clearance from the bloodstream by avoidance of recognition by macrophages, and stability of the carrier during circulation. [8,9] Previous literature suggests that while larger nanocarriers have prolonged circulation times in the blood, particles over ≈100 nm suffer from poor tumor penetration, particularly in the case of poorly vascularized and necrotic/hypoxic tumors.…”

Orally Deliverable Nanotherapeutics for the Synergistic Treatment of Colitis-Associated Colorectal Cancer

“…In this study, we used near-infrared (NIR) fluorescence imaging to assess the biodistribution of the nanotherapeutics in animals. This is a noninvasive technique with high sensitivity and enables real-time and quantitative analysis of NIR dye-labeled nanotherapeutics 31. Therefore, we covalently tethered the amine-bearing NIR dye Cy5.5 to the excess carboxyl group of the chitosan-CUR conjugates, yielding Cy5.5-labeled nCUR (termed Cy5.5-nCUR).…”

Nanomedicine in lung cancer: Current states of overcoming drug resistance and improving cancer immunotherapy

“…Jianqin et al found that chemical derivatization between oligolactide (oLA) and CTX provided better compatibility with the polymeric platform. With exogenous PEG–PLA, CTX and oLAs could form injectable nanomedicines, which displayed enhanced antitumor efficacy and amelioration of drug toxicity in a lung cancer xenograft model (Wan et al, 2018).…”