Inhibiting Multidrug Resistance with Transferrin-Targeted Polymersomes through Optimization of Ligand Density

Abstract

Transferrin-conjugated polymersomes, transferrin–biotin/avidin/biotin–Pluronic F127–poly­(lactic acid) (Tf-F127-PLA), were successfully prepared through a biotin–avidin bridging technique to study their ability to inhibit multidrug resistance of cancer cells. Hydrophilic doxorubicin (DOX) was selected as the model drug to be loaded into Tf-F127-PLA polymersomes. DOX loaded in Tf-F127-PLA polymersomes was released fast initially, followed by a slow release. The effect of the transferrin ligand density of Tf-F127-PLA/DOX polymersomes on their targeting properties was studied by both cytotoxicity and cellular uptake assays against A549 lung cancer cells. It was shown that Tf-F127-PLA/DOX polymersomes had better targeting ability than nontargeted drug-loaded polymersomes. Furthermore, Tf-F127-PLA/DOX polymersomes with 2% Tf molar content have more effective antitumor activity and a higher cellular uptake than those with 4 and 5% Tf molar content. 2% Tf-F127-PLA/DOX polymersomes also exhibited better anticancer ability in multidrug resistant cancer cells A549/ADR than nontargeted PLA-F127-PLA/DOX polymersomes. It was further proved that the endocytosis of polymersomes by A549/ADR cells was an energy-dependent endocytosis process, which was related to clathrin, macrocytosis, and caveolin. Also, the endocytosis of Tf-F127-PLA/DOX polymersomes was proven to be mediated by the transferrin receptor.

Polymersomes as the Next Attractive Generation of Drug Delivery Systems: Definition, Synthesis and Applications

“…However, the influence of the order in which the solvents are mixed on the size was demonstrated in the case of PEG-PTMC polymersomes [28]. To prepare Dox-loaded PLA-based polymersomes, a solution of polymer and Dox was added slowly into PBS to prevent polymer precipitation [96]. Although polymersomes can be loaded during nanoprecipitation by dissolving API in an appropriate solvent phase, polymersomes can be previously prepared, lyophilized, and loaded during rehydration with an aqueous solution.…”

Polyurethane Nanoparticles as Versatile Tools in Nanomedicine: A Review

“…These polymeric nanocarriers regulate the optimal biodistribution of the drug depending on the characteristics of the nanoparticulate system, enabling a more lasting therapeutic impact due to the delayed drug release from the polymeric matrix . They enhance the drug’s bioavailability and shield it from in vivo breakdown. , To achieve precision targeting and raise therapeutic efficacy while lowering toxicity, the design of the polymeric nanoparticles is crucial. , The effectiveness of the nanovector in comparison to administering the medicine in solution can be assessed using in vitro and in vivo experiments. The criterion for choosing the polymer is also based on the biodegradability of the material .…”

Poly(Photosensitizer-Prodrug) Unimolecular Micelles for Chemo-Photodynamic Synergistic Therapy of Antitumor and Antibacteria

“…However, the dual-drug approach would increase toxic side effects and lead to the emergence of some drug-resistant bacteria, posing a challenge to treatment. − Multidrug resistance poses a global public health risk. The development of a single mode of traditional treatment cannot solve this problem, for which the drug resistance mechanism is activated, reducing the efficacy of drugs. , In response to these challenges, the photodynamic antibacterial process, unlike the antibiotic mechanism, utilizes ROS to induce nonspecific oxidative stress reactions, attacking multiple microbial sites simultaneously. Importantly, the harmless byproducts produced during this process pose minimal risk to the human body. , Currently, self-assembled micelles have been reported in the literature for dual antitumor and antibacterial effects, , as well as unimolecular micelles for antitumor effects. , However, there is no literature reporting the use of unimolecular micelles for dual cancer and bacterial therapy.…”