Development of novel multifunctional nanoparticles for targeted delivery of concurrent chemoradiotherapy

Abstract

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Concurrent chemoradiotherapy has been proven efficaciously superior than sequential therapy and is the current standard of care for a number of malignancies, including rectal, head and neck, lung, and esophageal cancers. However, combining chemotherapy and radiotherapy also significantly increases toxicity. Nanoparticle formulations of chemotherapy have been shown to increase efficacy and decrease toxicity when compared to small molecule counterparts. Therefore, we have developed a multifunctional nanoparticle platform for targeted delivery of concurrent chemoradiotherapy. A novel polymer-lipid nanoparticle platform was synthesized by nanoprecipitation of poly (D,L-lactide-co-glycolide) (PLGA) in an aqueous solution containing 1,2-distearoyl-glycero-3-phosphoethanolamine-carboxy polyethylene glycol 2000 (DSPE-PEG), 1,2-dimyristoyl glycero-3-phosphoethanolamine diethylene triamine pentaacetate (DMPE-DTPA) and lecithin. The resulting nanoparticles have a hydrophobic PLGA polymeric core covered by a self-assembled monolayer (SAM) of lecithin, DMPE-DTPA, and DSPE-PEG. The PLGA core can encapsulate chemotherapeutics, and the DMPE-DTPA can be used to chelate metal radioisotopes. The outer-most layer of PEG gives the nanoparticles antibiofouling properties and can be used to conjugate targeting molecules. These polymer-lipid nanoparticles have hydrodynamic diameter of 70+/-5 nm, zeta potential of -40+/-5 mV. TEM confirmed the particle size and the SAM of lecithin. We then studied the therapeutic release profile of the nanoparticles by encapsulating docetaxel in the PLGA core. The seven-day release profile showed a first-order release kinetic. Using 111In as the radioisotope, we showed the nanoparticles’ chelation efficiency was 94+/-1%. The seven-day chelate stability study showed no release of the chelate in the first 36 hours, and approximately a 50% release after 120 hours. As proof of principle, we used prostate cancer as a model and conjugated the A10 RNA aptamer that binds the prostate specific membrane antigen (PSMA) to the nanoparticles. We demonstrated the targeted uptake of these nanoparticles using LNCaP (PSMA+) and PC3 (PSMA-) prostate cancer cells. LNCaP cells incubated with nanoparticles encapsulating a fluorescent dye showed much higher fluorescence when compared to PC3 cells incubated with the same nanoparticles. Similarly, LNCaP cells showed much higher radioactivity when incubated with nanoparticles labeled with 111In compared with PC3 cells under the same conditions. In summary, we have developed a novel targeted nanoparticle platform that can carry both chemotherapeutics and metal radioisotopes, making nanoparticle delivery of concurrent chemoradiotherapy possible. Furthermore, this platform can be used for dual imaging and therapy when an imaging radioisotope such as 111In is used.