title: Polymeric nanoparticles with precise ratiometric control over drug loading for combination therapy.
abstract: We report a novel approach for nanoparticle-based combination chemotherapy by concurrently incorporating two different types of drugs into a single polymeric nanoparticle with ratiometric control over the loading of the two drugs. By adapting metal alkoxide chemistry, we synthesize highly hydrophobic drug-poly-L-lactide (drug-PLA) conjugates, of which the polymer has the same chain length while the drug may differ. These drug-polymer conjugates are then encapsulated into lipid-coated polymeric nanoparticles through a single-step nanoprecipitation method. Using doxorubicin (DOX) and camptothecin (CPT) as two model chemotherapy drugs, various ratios of DOX-PLA and CPT-PLA conjugates are loaded into the nanoparticles with over 90% loading efficiency. The resulting nanoparticles are uniform in size, size distribution and surface charge. The loading yield of DOX and CPT in the particles can be precisely controlled by simply adjusting the DOX-PLA:CPT-PLA molar ratio. Cellular cytotoxicity results show that the dual-drug loaded nanoparticles are superior to the corresponding cocktail mixtures of single-drug loaded nanoparticles. This dual-drug delivery approach offers a solution to the long-standing challenge in ratiometric control over the loading of different types of drugs onto the same drug delivery vehicle. We expect that this approach can be exploited for many types of chemotherapeutic agents containing hydroxyl groups and thus enable codelivery of various drug combinations for combinatorial treatments of diseases.
authors.affiliation: Department of NanoEngineering, University of California, San Diego, La Jolla, California 92093-0815, USA.
authors.forename: Santosh
authors.initials: S
authors.lastname: Aryal
authors.forename: Che-Ming Jack
authors.initials: CM
authors.lastname: Hu
authors.forename: Liangfang
authors.initials: L
authors.lastname: Zhang
mesh_terms: D002166:Camptothecin / Q000737:chemistry; D004317:Doxorubicin / Q000737:chemistry; D004337:Drug Carriers / Q000737:chemistry; D053758:Nanoparticles / Q000737:chemistry*; D011091:Polyesters / Q000737:chemistry; D011108:Polymers / Q000737:chemistry*
chemical_list: D004337:Drug Carriers; D011091:Polyesters; D011108:Polymers; C033616:poly(lactide); D004317:Doxorubicin; D002166:Camptothecin