Last modified: 2019-06-15
Abstract
Receptor-Mediated Delivery of Doxorubicin in Doxorubicin-Resistant Breast Cancer Cells by using Transferrin-Conjugated Polymeric Nanoparticle
Zar Chi Soe, Wenquan Ou, Milan Gautam, Kishwor Poudel, Srijan Maharjan, Pham Le Minh, Chul Soon Yong*, Jong Oh Kim*
College of Pharmacy, Yeungnam University, Gyeongsan 38541, Republic of Korea
*Corresponding authors
Background: Site-specific and efficient delivery of the chemotherapeutic drugs exerts important role in multi-drug resistance (MDR). Chemotherapeutic drugs can be successfully delivered by passively and actively targeted nanoparticles. Transferrin (Tf) is an iron transporter and can be used as a targeting moiety for cancer-specific drug delivery to enhance therapeutic efficacy against various cancer cells that overexpress the Tf receptor.
Objective: In this study, Tf -conjugated polymeric nanoparticles were developed for the targeted delivery of chemotherapeutic agent doxorubicin (Dox) to overcome MDR in cancer treatment and to improve Dox delivery for producing significant antitumor efficacy in Dox-resistant (R) breast cancer cell lines with minimum toxicity to healthy cells.
Materials and Methods: A modified thin-film hydration method with TMOS was used to prepare Dox/F127&P123 and Dox/F127&P123-Tf. Quantitative cellular uptake, anti-metastatic properties, cytotoxic effects of Dox/F127&P123-Tf and specific apoptosis-related protein levels in Dox-resistant breast cancer cells, MDA-MB-231 (R), were investigated in vitro. In vivo imaging and biodistribution analysis had been conducted in BALB/c nude mice bearing MDA-MB-231 (R) xenografts.
Results: Dox was successfully loaded into Tf-conjugated polymeric nanoparticles. 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. It also 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 with a targeting moiety.
Conclusion: Drug resistance can be overcome by the accumulation of Dox in the nuclear region of the cancer cells via inhibition of P-gp mediated efflux. In addition, Dox/F127&P123-Tf was successfully accumulated in xenograft mouse models bearing Dox-resistant cell lines, MDA-MB-231(R), with minimum toxicity to healthy organs.
Keywords: doxorubicin; doxorubicin-resistant cancer; polymeric nanoparticles; transferrin