Biodegradable nanoparticles for use as an inhalable antimicrobial and as a receptor targeted delivery device.

摘要

Drug delivery challenges include drug instability, insolubility, dosing, toxicity, and targeting, which can be addressed by encapsulation into degradable nanoparticles that can be modified for numerous applications. Previous studies have demonstrated the synthesis and characterization of degradable nanoparticles formulated form L-tyrosine polyphosphate (LTP) that show promise for a wide array of drug delivery applications. One such application is inhalable antimicrobials to chronically infected lungs of cystic fibrosis patients, which currently suffer from fast clearance, poor stability, and resistance. An additional application is receptor targeted anticancer drug delivery, since current anticancer agents, such as cisplatin, may cause nonspecific toxicity. Therefore, we have produced and characterized nanoparticles formulated primarily from LTP that can be modified for use as an inhalable antimicrobial loaded with silver carbene complexes (SCC), or as a receptor targeted delivery system decorated with folic acid. Dynamic light scattering shows diameter ranges around 1mum that is optimal for inhalable delivery, or approximately 200 nm that is optimal for anticancer drug endocytosis. SCC's are release over 7 days in vitro from LTP nanoparticles. Furthermore, degrading LTP nanoparticles do not lower the pH unlike poly(lactic-co-glycolic acid) (PLGA) nanoparticles that lower the pH to acidic levels. This lack of acidic degradation products results in low fibroblast toxicity comparable to PLGA nanoparticles and buffers as shown by MTT and LIVE/DEAD assays. These toxicity assays also reveal mean lethal dosage values less than minimum inhibitory concentrations from clinically relevant in vitro planktonic and biofilm antibacterial assays. This antibacterial efficacy is reflected with an in vivo mouse model, in which SCC-LTP nanoparticles achieve a 100% survival advantage. Furthermore, folic acid decoration of LTP nanoparticles demonstrates a receptor mediated targeting with a 10-fold greater attachment to HeLa cancer cells under simulated physiological flow compared to undecorated nanoparticles and non-cancerous fibroblasts. This attachment is inhibited with excess folic acid in the perfusion solution. A 30 minute incubation and LIVE/DEAD assay show these folic acid decorated nanoparticles loaded with SCC's have increased anticancer efficacy compared to drug alone. Thus, LTP nanoparticles can be utilized for a wide array of drug delivery applications including inhalable antimicrobials or receptor targeted anticancer drug delivery.