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Enhancement of surface ligand display on PLGA nanoparticles with amphiphilic ligand conjugates.

ABSTRACT: Biodegradable polymeric nanoparticles are widely recognized as efficacious drug delivery vehicles, yet the rational engineering of nanoparticle surfaces in order to improve biodistribution, reduce clearance, and/or improve targeting remains a significant challenge. We have previously demonstrated that an amphiphilic conjugate of avidin and palmitic acid can be used to modify poly(lactic-co-glycolic acid) (PLGA) particle surfaces to display functional avidin groups, allowing for the facile attachment of biotinylated ligands for targeting or steric stabilization. Here, we hypothesized that the incorporation, density, and stability of surface-presented avidin could be modulated through varying the lipophilicity of its fatty acid conjugate partner. We tested this hypothesis by generating a set of novel conjugates incorporating avidin and common fatty acids. We found that conjugation to linoleic acid resulted in a ~60% increase in the incorporation of avidin on the nanoparticle surface compared to avidin-palmitic acid, which exhibited the highest avidin incorporation in previous studies. Further, the linoleic acid-avidin conjugate yielded nanoparticles with enhanced ability to bind biotinylated ligands compared to the previous method; nanoparticles modified with avidin-linoleic acid bound ~170% more biotin-HRP than those made with avidin-palmitic acid and ~1300% more than particles made without conjugated avidin. Most critically, increased ligand density on anti-CD4-targeted nanoparticles formulated with the linoleic acid-avidin conjugate resulted in a 5% increase in binding of CD4(+) T cells. Thus we conclude that the novel avidin-linoleic acid conjugate facilitates enhanced ligand density on PLGA nanoparticles, resulting in functional enhancement of cellular targeting.

SUBMITTER: Park J

PROVIDER: S-EPMC3800156 | biostudies-literature | 2011 Nov

REPOSITORIES: biostudies-literature

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Enhancement of surface ligand display on PLGA nanoparticles with amphiphilic ligand conjugates.

Park Jason J Mattessich Thomas T Jay Steven M SM Agawu Atu A Saltzman W Mark WM Fahmy Tarek M TM

Journal of controlled release : official journal of the Controlled Release Society 20110624 1

Biodegradable polymeric nanoparticles are widely recognized as efficacious drug delivery vehicles, yet the rational engineering of nanoparticle surfaces in order to improve biodistribution, reduce clearance, and/or improve targeting remains a significant challenge. We have previously demonstrated that an amphiphilic conjugate of avidin and palmitic acid can be used to modify poly(lactic-co-glycolic acid) (PLGA) particle surfaces to display functional avidin groups, allowing for the facile attach ...[more]

PMID: 21723893

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Project description:An amphiphilic copolymer, folic acid (FA) modified poly(ethylene glycol)-poly(lactic-co-glycolic acid) (FA-PEG-PLGA) was prepared and explored as a nanometer carrier for the co-delivery of cisplatin (cis-diaminodichloroplatinum, CDDP) and paclitaxel (PTX). CDDP and PTX were encapsulated inside the hydrophobic inner core and chelated to the middle shell, respectively. PEG provided the outer corona for prolonged circulation. An in vitro release profile of the CDDP + PTX-encapsulated nanoparticles revealed that the PTX chelation cross-link prevented an initial burst release of CDDP. After an incubation period of 24 hours, the CDDP+PTX-encapsulated nanoparticles exhibited a highly synergistic effect for the inhibition of A549 (FA receptor negative) and M109 (FA receptor positive) lung cancer cell line proliferation. Pharmacokinetic experiment and distribution research shows that nanoparticles have longer circulation time in the blood and can prolong the treatment times of chemotherapeutic drugs. For the in vivo treatment of A549 cells xeno-graft lung tumor, the CDDP+PTX-encapsulated nanoparticles displayed an obvious tumor inhibiting effect with an 89.96% tumor suppression rate (TSR). This TSR was significantly higher than that of free chemotherapy drug combination or nanoparticles with a single drug. For M109 cells xeno-graft tumor, the TSR was 95.03%. In vitro and in vivo experiments have all shown that the CDDP+PTX-encapsulated nanoparticles have better targeting and antitumor effects in M109 cells than CDDP+PTX-loaded PEG-PLGA nanoparticles (p < 0.05). In addition, more importantly, the enhanced anti-tumor efficacy of the CDDP+PTX-encapsulated nanoparticles came with reduced side-effects. No obvious body weight loss or functional changes occurred within blood components, liver, or kidneys during the treatment of A549 and M109 tumor-bearing mice with the CDDP+PTX-encapsulated nanoparticles. Thus, the FA modified amphiphilic copolymer-based combination of CDDP and PTX may provide useful guidance for effective and safe cancer chemotherapy, especially in tumors with high FA receptor expression.

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Enhancement of surface ligand display on PLGA nanoparticles with amphiphilic ligand conjugates.

Publications

Enhancement of surface ligand display on PLGA nanoparticles with amphiphilic ligand conjugates.

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