4.8 Article

Multi-layered nanoparticles for combination gene and drug delivery to tumors

Journal

BIOMATERIALS
Volume 35, Issue 34, Pages 9343-9354

Publisher

ELSEVIER SCI LTD
DOI: 10.1016/j.biomaterials.2014.07.043

Keywords

PLGA; Nanoparticle; Gene therapy; Drug delivery

Funding

  1. Howard Hughes Medical Research Fellowship
  2. Yale School of Medicine Office of Student Research
  3. National Institutes of Health [R01 CA149128]

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Drug resistance and toxicity are major obstacles in cancer chemotherapy. Combination therapies can overcome resistance, and synergies can minimize dosing. Polymer nanocarriers are interesting vehicles for cancer therapeutics for their delivery and tumor targeting abilities. We synthesized a multi-layered polymer nanoparticle (MLNP), comprising of poly(lactic-co-glycolic acid) with surface polyethyleneimine and functional peptides, for targeted drug and gene delivery. We confirmed the particle's ability to inhibit tumor growth through synergistic action of the drug and gene product. MLNPs achieved transfection levels similar to lipofectamine, while maintaining minimal cytotoxicity. The particles delivered camptothecin (CPT), and plasmid encoding TNF related apoptosis inducing ligand (pTRAIL) (CT MLNPs), and synergistically inhibited growth of multiple cancer cells in vitro. The synergy of co-delivering CPT and pTRAIL via CT MLNPs was confirmed using the Chou-Talalay method: the combination index (Cl) values at 50% inhibition ranged between 0.31 and 0.53 for all cell lines. Further, co-delivery with MLNPs resulted in a 3.1-15 fold reduction in CPT and 4.7-8.0 fold reduction in pTRAIL dosing. CT MLNPs obtained significant HCT116 growth inhibition in vivo compared to monotherapy. These results support our hypothesis that MLNPs can deliver both small molecules and genetic agents towards synergistically inhibiting tumor growth. (C) 2014 Elsevier Ltd. All rights reserved.

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