Balancing the stability and drug activation in adaptive nanoparticles potentiates chemotherapy in multidrug-resistant cancer

Abstract

Rationale: Prodrug strategies that render the drug temporarily inactive through a cleavable linkage are able to modulate the physicochemical properties of drugs for adaptive nanoparticle (NP) formulation. Here we used cabazitaxel as a model compound to test the validity of our “balancing NP stability and specific drug activation” strategy. Methods: Cabazitaxel is conjugated to hydrophobic polylactide fragments with varying chain lengths via a self-immolation linkage, yielding polymeric prodrugs that can be reactivated by reductive agents in cells. Following a nanoprecipitation protocol, cabazitaxel prodrugs can be stably entrapped in amphiphilic polyethylene- block -polylactide matrices to form core-shell nanotherapies with augmented colloidal stability. Results: Upon cellular uptake followed by intracellular reduction, the NPs spontaneously release chemically unmodified cabazitaxel and exert high cytotoxicity. Studies with near-infrared dye-labeled NPs demonstrate that the nanodelivery of the prodrugs extends their systemic circulation, accompanied with increased drug concentrations at target tumor sites. In preclinical mouse xenograft models, including two paclitaxel-resistant xenograft models, the nanotherapy shows a remarkably higher efficacy in tumor suppression and an improved safety profile than free cabazitaxel. Conclusion: Collectively, our approach enables more effective and less toxic delivery of the cabazitaxel drug, which could be a new generalizable strategy for re-engineering other toxic and water-insoluble therapeutics.

Combinatorial nanococktails via self-assembling lipid prodrugs for synergistically overcoming drug resistance and effective cancer therapy

“…To further elucidate the uptake mechanism, different inhibitors that specifically target endocytosis pathways were examined [ 39 ]. When A549 cisR cells were pretreated with chlorpromazine, an inhibitor of clathrin-mediated endocytosis, flow cytometry analysis showed that the cellular uptake of the NC was substantially decreased by ~ 40% compared to that of the untreated cells (Fig.…”

An esterase-activatable prodrug formulated liposome strategy: potentiating the anticancer therapeutic efficacy and drug safety

“…As depicted in Fig. 4i and j, the administration of chlorpromazine (clathrin-dependent endocytosis inhibitor) signicantly decreased the cellular uptake of liposomes (reduction to 9.4 AE 0.05%), while cytochalasin D (pinocytosis inhibitor) and lipin (caveolin-mediated endocytosis inhibitor) [29][30][31] did not affect the internalization of DiI/SN38@LP. The FCM analysis presented in Fig.…”

Reduction-Responsive Stearyl Alcohol-Cabazitaxel Prodrug Nanoassemblies for Cancer Chemotherapy

“…Formulating drugs into prodrugs by introducing covalent and coordinate bonds holds great promise to improve drug loading and self-assembly capabilities [ 18 , 19 ]. Recently, prodrug-based nano-DDS have integrated the advantages of both prodrug strategy and biomedical nanotechnology, attracting tremendous scientific interest [ 20 , 21 ]. Particularly, small-molecule prodrug-based nanoassemblies, as both carriers and cargos, are characterized by distinct high drug-loading (>50%, w / w ), accurate dosages, superior self-assembly properties and reduced excipient-related toxicity, showing more potential in cancer chemotherapy [ 22 , 23 ].…”