Polycationic nanodrug covered with hyaluronic acid for treatment of P-glycoprotein overexpressing cancer cells.
To treat cancer cells overexpressing P-glycoprotein (P-gp), we propose a new concept using a nanodrug. The nanodrug was prepared from polyethyleneimine (PEI)/all-trans retinoic acid (ATRA) conjugates (PRA) and covered with hyaluronic acid (HA) to control the cytotoxicity of PRA (yielding PRA-H). The size distribution of PRA-H was narrow, with an average particle size of approximately 143 nm. Its superior stability in phosphate-buffered saline (PBS) was verified by monitoring changes in particle size and zeta potential for 24 h, which were negligible. In contrast, PEI-H (not conjugated with ATRA) exhibited a significant change in particle size and zeta potential. Although PRA was highly cytotoxic against HCT-8 and SNU-484 cancer cells, both of which overexpress P-gp, the cytotoxicity was significantly reduced by shielding with HA. The cytotoxicity of PRA-H was recovered by treatment with hyaluronidase (HAase), which degrades HA and is present in tumors at high concentrations. These results were confirmed by optical microscopy, fluorescence-activated cell sorting (FACs) analysis, and confocal microscopy. The cytotoxic mechanism of PRA was revealed as a type of necrotic lysis by FACs analysis with propidium iodide (PI) staining. Furthermore, PRA increased HCT-8 cell (colon cancer) permeability to doxorubicin (DOX). Therefore, we concluded that PRA-H is a promising new candidate for the treatment of cells with multidrug resistance (MDR) induced by overexpression of P-gp and cancer stem cells.
Yim
Hyeona
H
Department of Biotechnology, The Catholic University of Korea, 43-1 Yeokkok2-dong, Wonmi-gu, Bucheon-si, Gyeonggi-do 420-743, Korea.
Na
Kun
K
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D017209:Apoptosis / Q000187:drug effects; D002463:Cell Membrane Permeability / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D018432:Drug Resistance, Multiple / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D006801:Humans; D006820:Hyaluronic Acid / Q000737:chemistry*; D053758:Nanoparticles; D011094:Polyethyleneimine / Q000737:chemistry*; D011108:Polymers / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D014212:Tretinoin / Q000737:chemistry / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D011108:Polymers; D014212:Tretinoin; D011094:Polyethyleneimine; D006820:Hyaluronic Acid