Paclitaxel-loaded PLGA nanoparticles: potentiation of anticancer activity by surface conjugation with wheat germ agglutinin.
OBJECTIVE
To potentiate the anticancer activity of paclitaxel-loaded PLGA nanoparticles through surface conjugation with wheat germ agglutinin (WGA).


METHODS
PLGA nanoparticles loaded with paclitaxel and isopropyl myristate (IPM) as release modifier were prepared by a solvent evaporation method. WGA was conjugated to the nanoparticle surface to give novel WIT-NP of 330+/-3 nm. In vitro cytotoxicity of WIT-NP against malignant (A549 and H1299) and normal (CCL-186) pulmonary cell lines was evaluated alongside control formulations. IC50 doses were determined by the MTT assay, while cellular apoptosis was detected by cell nuclei staining and DeadEndtrade mark Fluorometric TUNEL assay. Cell cycle arrest was confirmed by flow cytometry. Cellular uptake of 3[H]-paclitaxel from the test and control formulations was also quantified. In vivo anticancer efficacy was evaluated in the SCID mice model engrafted with the A549 tumor nodule.


RESULTS
WIT-NP had superior anti-proliferation activity against the A549 and H1299 cell lines compared with conventional paclitaxel formulations as measured by IC50 doses. This was attributed to a more efficient intracellular accumulation of paclitaxel via WGA-receptor-mediated endocytosis and IPM-facilitated intracellular paclitaxel release. WIT-NP activity was associated with paclitaxel-induced apoptosis and cell arrest in the G2/M phase. A single intratumoral injection of WIT-NP at paclitaxel dose of 10 mg/kg inhibited the growth of A549 tumor nodules without inducing significant weight loss in the SCID mice over a period of 25 days. Tumor doubling time was greater than 25 days, compared with 11 days for nodules treated with conventional paclitaxel formulation.


CONCLUSIONS
The formulation of WIT-NP, in which WGA is conjugated to the surface of paclitaxel and IPM-loaded PLGA nanoparticles, significantly potentiates the anticancer activity of paclitaxel.
Mo
Yun
Y
Department of Pharmacy, National University of Singapore, 18 Science Drive 4, Singapore 117543, Singapore.
Lim
Lee-Yong
LY
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage* / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002626:Chemistry, Pharmaceutical; D004357:Drug Synergism; D000431:Ethanol; D005079:Excipients; D005434:Flow Cytometry; D005990:Glycerol / Q000031:analogs & derivatives; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D051379:Mice; D016513:Mice, SCID; D049329:Nanostructures; D009368:Neoplasm Transplantation; D017239:Paclitaxel / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use*; D012997:Solvents; D013499:Surface Properties; D014909:Wheat Germ Agglutinins / Q000494:pharmacology*
D000972:Antineoplastic Agents, Phytogenic; D005079:Excipients; D012997:Solvents; D014909:Wheat Germ Agglutinins; D000431:Ethanol; C000515:cremophor EL; D017239:Paclitaxel; D005990:Glycerol