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Despite research efforts to discover new drugs for Parkinson treatment, the majority of candidates fail in preclinical and clinical trials due to inadequate pharmacokinetic properties, namely blood-brain barrier permeability. Within the high demand to introduce new drugs to market, nanotechnology can be used as a solution. Accordingly, PEGylated PLGA nanoparticles (NPs) were used as a smart delivery carrier to solve the suboptimal aqueous solubility, which precludes its use in in vivo assays, of a potent, reversible, and selective monoamine oxidase B inhibitor (IMAO-B) (coumarin C75, IC50 = 28.89 ± 1.18 nM). Long-term stable PLGA@C75 NPs were obtained by nanoprecipitation method, with sizes around 105 nm and a zeta potential of -10.1 mV. The encapsulation efficacy was around 50%, achieving the final C75 concentration of 807 ± 30 μM in the nanoformulation, which corresponds to a therapeutic concentration 27828-fold higher than its IC50 value. Coumarin C75 showed cytotoxic effects at 50 μM after 48 and 72 h of exposure in SH-SY5Y, Caco-2, and hCMEC/D3 cell lines. Remarkably, no cytotoxic effects were observed after nanoencapsulation. Furthermore, the data obtained from the P-gp-Glo assay and the cellular uptake studies showed that C75 is a P-glycoprotein (P-gp) substrate having a lower uptake profile in intestinal and brain endothelial cells. Moreover, it was shown that this membrane transporter influences C75 permeability profile in Caco-2 and hCMEC/D3 cells. Interestingly, PLGA NPs inhibited P-gp and were able to cross intestinal and brain membranes allowing the successful transport of C75 through this type of biological barriers. Overall, this work showed that nanotechnology can be used to solve drug discovery related drawbacks.

Antiretroviral drug nanocarriers hold great promise for developing anti-human immunodeficiency virus (HIV) rectal microbicides. However, challenges remain, namely, concerning which properties are more suited for enhancing colorectal distribution and retention of microbicide compounds. In this work, we developed and assessed the in vitro and in vivo performance of poly(lactic- co-glycolic acid) (PLGA)-based nanoparticles (NPs) as carriers for the model drug efavirenz (EFV). We particularly focused on the effect of noncovalent poly(ethylene glycol) coating of PLGA NPs (PEG-PLGA NPs) conferring a mucus-diffusive behavior on the pharmacokinetics (PK) of EFV following rectal administration to mice. Drug-loaded PLGA NPs and PEG-PLGA NPs (200-225 nm) were obtained by nanoprecipitation. Both types of systems were able to retain native antiretroviral activity of EFV in vitro, while featuring lower cytotoxicity against different epithelial cell lines and HIV target cells. Also, PLGA NPs and PEG-PLGA NPs were readily taken up by colorectal cell lines and mildly reduced EFV permeation while increasing membrane retention in Caco-2 and Caco-2/HT29-MTX cell monolayer models. When administered intrarectally to CD-1 mice in phosphate-buffered saline (pH 7.4), EFV-loaded PEG-PLGA NPs consistently provided higher drug levels in colorectal tissues and lavages, as compared to free EFV or drug-loaded PLGA NPs. Mean values for the area-under-the-curve between 15 min and 12 h following administration were particularly higher for PEG-PLGA NPs in distal and middle colorectal tissues, with relative bioavailability values of 3.7 and 29, respectively, as compared to free EFV (2.2 and 6.0 over PLGA NPs, respectively). Systemic exposure to EFV was reduced for all treatments. NPs were further shown safe after once-daily administration for 14 days, as assessed by histological analysis of colorectal tissues and chemokine/cytokine assay of rectal lavages. Overall, PEG-PLGA NPs demonstrated to be safe carriers for rectal microbicide drug delivery and able to provide enhanced local PK that could be valuable in preventing rectal HIV transmission.