Abstract
In this study, a transferrin (Tf)-conjugated polymeric nanoparticle was developed for the targeted delivery of the chemotherapeutic agent doxorubicin (Dox) in order to overcome multi-drug resistance in cancer treatment. Our objective was to improve Dox delivery for producing significant antitumor efficacy in Dox-resistant (R) breast cancer cell lines with minimum toxicity to healthy cells. The results of our experiments revealed that Dox was successfully loaded inside a transferrin (Tf)-conjugated polymeric nanoparticle composed of poloxamer 407 (F127) and 123 (P123) (Dox/F127&P123-Tf), which produced nanosized particles (~90 nm) with a low polydispersity index (~0.23). The accelerated and controlled release profiles of Dox from the nanoparticles were characterized in acidic and physiological pH and Dox/F127&P123-Tf enhanced Dox cytotoxicity in OVCAR-3, MDA-MB-231, and MDA-MB-231(R) cell lines through induction of cellular apoptosis. Moreover, Dox/F127&P123-Tf inhibited cell migration and altered the cell cycle patterns of different cancer cells. In vivo study in MDA-MB-231(R) tumor-bearing mice demonstrated enhanced delivery of nanoparticles to the tumor site when coated in a targeting moiety. Therefore, Dox/F127&P123-Tf has been tailored, using the principles of nanotherapeutics, to overcome drug-resistant chemotherapy.
Highlights
Nanotechnology contributes greatly to the design and development of chemotherapeutic drug formulations to overcome various shortcomings of traditional chemotherapy by improving therapeutic efficacy [1]
Site-specific and efficient delivery of chemotherapeutic drug is important in multi-drug resistance (MDR) and chemotherapeutic drugs can be successfully delivered by passively and actively targeted nanoparticles
Poloxamers can sensitize MDR cancer cells to various chemotherapeutic agents by assimilation into biological membranes and subsequent interference with intracellular functions, mitochondrial respiration, and adenosine triphosphate (ATP) synthesis, which is essential for the action of ATP-binding cassette (ABC) efflux proteins [9]
Summary
Nanotechnology contributes greatly to the design and development of chemotherapeutic drug formulations to overcome various shortcomings of traditional chemotherapy by improving therapeutic efficacy [1]. Targeted nanocarriers have beneficial effects in chemotherapeutic drug delivery system such as enhancing drug retention in tumor cells by increasing cellular binding and drug accumulation, and improving cellular uptake by receptor-mediated endocytosis [4]. Tf is a blood plasma glycoprotein known to be an iron transporter and can be used as a targeting site for cancer-specific drug delivery to enhance therapeutic efficacy against various cancer cells that overexpress Tf receptors [17]. The half-life, tissue distribution, and drug release in the plasma can be controlled by Tf-conjugated PSNPs, creating an excellent tool for favoring the accumulation of non-selective chemotherapeutic drugs at targeted areas while reducing the exposure of normal healthy cells to these drugs In this way, overall therapeutic efficacy has been improved by increasing intracellular concentration and, anticancer activity [18,19,20]. These cells were used for further studies involving resistant cancer cells
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