Influence of surface chemistry on cytotoxicity and cellular uptake of nanocapsules in breast cancer and phagocytic cells.
The present work tests the hypothesis that stabilizers have a critical role on nanocarrier stealthiness and anticancer drug efficacy. Two different types of docetaxel (Doc)-loaded nanocapsules (NCs) stabilized with polysorbate 80 (NC(T80)) and polyvinyl alcohol (NC(PVA)) were synthesized using the emulsion solvent diffusion method. These NCs were characterized for particle mean diameter (PMD), drug content, morphology, surface composition, and degree of crystallinity. Furthermore, the cytotoxicity and cellular uptake of the NCs were investigated in MDA-MB 231 cells, THP-1 monocytes, and THP-1-derived macrophages. The optimized spherical NC(T80) had 123.02 ± 14.6 nm, 0.27 ± 0.1, and 101 ± 37.0% for PMD, polydispersity index, and drug encapsulation efficiency, respectively. Doc release kinetics from NC(T80) and NC(PVA) mostly provided better fit to zero-order and Higuchi models, respectively. Powder X-ray diffraction (PXRD) and X-ray photoelectron spectroscopy (XPS) results revealed the presence of amorphous stabilizers on the surface of the NCs. At high drug concentration, the cytotoxicity of NC(T80) was substantially improved (1.3-1.6-fold) compared with that of NC(PVA) in MDA-MB 231 cells. The uptake of both NCs was inhibited by latrunculin A and dynasore, indicating an actin- and dynamin-dependent endocytosis in MDA-MB 231 cells. This occurred via a multifaceted mechanism involving clathrin, caveolin, cytoskeleton, and macropinocytosis. Interestingly, the uptake of NC(PVA) was 2.7-fold greater than that of NC(T80) and occurred through phagocytosis in monocytes and macrophages. This study demonstrates the potential impact of the surface chemistry on the cytotoxicity and phagocytic clearance of nanocarriers for a subsequent improvement of the efficacy of Doc intended for breast cancer chemotherapy.
Laboratory of Future Nanomedicines and Theoretical Chronopharmaceutics, Division of Pharmaceutical Sciences, University of Missouri-Kansas City, 2464 Charlotte Street, Kansas City, Missouri, 64108, USA.
Ibrahima
I
Youm
Joseph D
JD
Bazzil
Joseph W
JW
Otto
Anthony N
AN
Caruso
James B
JB
Murowchick
Bi-Botti C
BB
Youan
D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000378:metabolism* / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000378:metabolism*; D045744:Cell Line, Tumor; D000077143:Docetaxel; D004337:Drug Carriers; D005079:Excipients; D005260:Female; D006801:Humans; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D053769:Nanocapsules; D010316:Particle Size; D010586:Phagocytes / Q000378:metabolism*; D013499:Surface Properties; D043823:Taxoids / Q000008:administration & dosage / Q000378:metabolism* / Q000494:pharmacology*
D000972:Antineoplastic Agents, Phytogenic; D004337:Drug Carriers; D005079:Excipients; D053769:Nanocapsules; D043823:Taxoids; D000077143:Docetaxel