ABSTRACT
New therapeutic alternatives to fight against the spread of HIV-1 are based on peptides designed to inhibit the early steps of HIV-1 fusion in target cells. However, drawbacks, such as bioavailability, short half-life, rapid clearance, and poor ability to cross the physiological barriers, make such peptides unattractive for the pharmaceutical industry. Here we developed, optimized, and characterized polymeric nanoparticles (NPs) coated with glycol chitosan to incorporate and release an HIV-1 fusion inhibitor peptide (E1) inside the vaginal mucosa. The NPs were prepared by a modified double emulsion method, and optimization was carried out by a factorial design. In vitro, ex vivo, and in vivo studies were carried out to evaluate the optimized formulation. The results indicate that the physicochemical features of these NPs enable them to incorporate and release HIV fusion inhibitor peptides to the vaginal mucosa before the fusion step takes place.
Subject(s)
Drug Carriers/chemistry , HIV-1/drug effects , Peptides/administration & dosage , Viral Fusion Protein Inhibitors/administration & dosage , Administration, Intravaginal , Animals , Chitosan/chemistry , Drug Design , Female , HIV Envelope Protein gp41/antagonists & inhibitors , HIV Infections/prevention & control , HIV Infections/virology , HIV-1/physiology , Models, Animal , Mucous Membrane/drug effects , Mucous Membrane/metabolism , Mucous Membrane/virology , Nanoparticles/chemistry , Particle Size , Peptides/chemistry , Peptides/pharmacokinetics , Swine , Vagina/drug effects , Vagina/metabolism , Vagina/virology , Viral Envelope Proteins/chemistry , Viral Fusion Protein Inhibitors/chemistry , Viral Fusion Protein Inhibitors/pharmacokinetics , Virus Internalization/drug effectsABSTRACT
Despite the great effort to decrease the HIV infectivity rate, current antiretroviral therapy has several weaknesses; poor bioavailability, development of drug resistance and poor ability to access tissues. However, molecules such as peptides have emerged asa new expectative to HIV eradication. The vaginal mucosa is the main spreading point of HIV. There are natural barriers such as the vaginal fluid which protects the vaginal epithelium from any foreign agents reaching it. This work has developed and characterized Nanoparticles (NPs) coated with glycol chitosan (GC), loaded with an HIV-1 inhibitor peptide (E2). In vitro release and ex vivo studies were carried out using the vaginal mucosa of swine and the peptide was determined by HPLC MS/MS validated method. Moreover, the peptide was labeled with 5(6)-carboxyfluoresceine and entrapped into the NPs to carried out in vivo studies and to evaluate the NPs penetration and toxicity in the vaginal mucosa of the swine. The mean size of the NPs, ξ and the loading percentage were fundamental features for to reach the vaginal tissue and to release the peptide within intercellular space. The obtained results suggesting that the fusion inhibitor peptides loaded into the NPs coated with GC might be a new way to fight the HIV-1, due to the formulation might reach the human epithelial mucosa and release peptide without any side effects.
