title: Multi-layered nanoparticles for combination gene and drug delivery to tumors.
abstract: 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 (CI) 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.
authors.affiliation: Department of Biomedical Engineering, Yale University, 55 Prospect Street, MEC 414, New Haven, CT 06511, USA.
authors.forename: Asiri
authors.initials: A
authors.lastname: Ediriwickrema
authors.affiliation: Department of Biomedical Engineering, Yale University, 55 Prospect Street, MEC 414, New Haven, CT 06511, USA; Department of Neurosurgery, Yale University, 333 Cedar Street, FMB 410, New Haven, CT 06520, USA.
authors.forename: Jiangbing
authors.initials: J
authors.lastname: Zhou
authors.affiliation: Department of Biomedical Engineering, Yale University, 55 Prospect Street, MEC 414, New Haven, CT 06511, USA.
authors.forename: Yang
authors.initials: Y
authors.lastname: Deng
authors.affiliation: Department of Biomedical Engineering, Yale University, 55 Prospect Street, MEC 414, New Haven, CT 06511, USA. Electronic address: mark.saltzman@yale.edu.
authors.forename: W Mark
authors.initials: WM
authors.lastname: Saltzman
mesh_terms: D002166:Camptothecin / Q000494:pharmacology; D045744:Cell Line, Tumor; D016503:Drug Delivery Systems / Q000379:methods*; D018014:Gene Transfer Techniques; D045325:HCT116 Cells; D057809:HEK293 Cells; D006801:Humans; D019344:Lactic Acid / Q000737:chemistry; D053758:Nanoparticles / Q000737:chemistry*; D009369:Neoplasms / Q000628:therapy*; D010957:Plasmids / Q000235:genetics / Q000378:metabolism; D011094:Polyethyleneimine / Q000737:chemistry; D011100:Polyglycolic Acid / Q000737:chemistry; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011108:Polymers / Q000737:chemistry*; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics / Q000378:metabolism; D014162:Transfection
chemical_list: D011108:Polymers; D053221:TNF-Related Apoptosis-Inducing Ligand; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid; D011094:Polyethyleneimine; D002166:Camptothecin
keywords: Drug delivery; Gene therapy; Nanoparticle; PLGA
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