Three-step tumor targeting of paclitaxel using biotinylated PLA-PEG nanoparticles and avidin-biotin technology: Formulation development and in vitro anticancer activity.
Despite recent advances in cancer therapy, many malignant tumors still lack effective treatment and the prognosis is very poor. Paclitaxel is a potential anticancer drug, but its use is limited by the facts that paclitaxel is a P-gp substrate and its aqueous solubility is poor. In this study, three-step tumor targeting of paclitaxel using biotinylated PLA-PEG nanoparticles and avidin-biotin technology was evaluated in vitro as a way of enhancing delivery of paclitaxel. Paclitaxel was incorporated both in biotinylated (BP) and non-biotinylated (LP) PEG-PLA nanoparticles by the interfacial deposition method. Small (mean size approximately 110 nm), spherical and slightly negatively charged (-10 mV) BP and LP nanoparticles achieving over 90% paclitaxel incorporation were obtained. The successful biotinylation of nanoparticles was confirmed in a novel streptavidin assay. BP nanoparticles were targeted in vitro to brain tumor (glioma) cells (BT4C) by three-step avidin-biotin technology using transferrin as the targeting ligand. The three-step targeting procedure increased the anti-tumoral activity of paclitaxel when compared to the commercial paclitaxel formulation Taxol and non-targeted BP and LP nanoparticles. These results indicate that the efficacy of paclitaxel against tumor cells can be increased by this three-step targeting method.
Department of Pharmaceutics, University of Kuopio, Kuopio, Finland. Mika.Pulkkinen@uku.fi
Mika
M
Pulkkinen
Jere
J
Pikkarainen
Thomas
T
Wirth
Tommy
T
Tarvainen
Vesa
V
Haapa-aho
Harri
H
Korhonen
Jukka
J
Seppälä
Kristiina
K
Järvinen
D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D001360:Avidin / Q000378:metabolism*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002626:Chemistry, Pharmaceutical; D004305:Dose-Response Relationship, Drug; D004337:Drug Carriers; D005910:Glioma / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D053758:Nanoparticles; D009369:Neoplasms / Q000378:metabolism / Q000473:pathology*; D017239:Paclitaxel / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D010316:Particle Size; D011091:Polyesters / Q000737:chemistry* / Q000378:metabolism; D011092:Polyethylene Glycols / Q000737:chemistry* / Q000378:metabolism; D051381:Rats; D012995:Solubility; D013678:Technology, Pharmaceutical / Q000379:methods; D013997:Time Factors; D014168:Transferrin / Q000378:metabolism
D000970:Antineoplastic Agents; D004337:Drug Carriers; D011091:Polyesters; D014168:Transferrin; C093483:neutravidin; C469934:poly(lactic acid)-poly(ethylene glycol)-biotin; D001360:Avidin; D011092:Polyethylene Glycols; D017239:Paclitaxel