RESUMEN
Vasoactive intestinal peptide (VIP) is a neuropeptide capable of downregulating innate immune responses in antigen presenting cells (APCs) by suppressing their pro-inflammatory cytokine secretion and cell surface marker expression. Though VIP's bioactivity could possibly be leveraged as a treatment for transplant tolerance, drug delivery innovation is required to overcome its intrinsically limited cellular delivery capacity. One option is to employ peptide amphiphiles (PAs) which are lipidated peptides capable of self-assembling into micelles in water that can enhance cellular association. With this approach in mind, a series of triblock VIP amphiphiles (VIPAs) has been synthesized to explore the influence of block arrangement and hydrophobicity on micelle biocompatibility and bioactivity. VIPA formulation has been found to influence the shape, size, and surface charge of VIPA micelles (VIPAMs) as well as their cytotoxicity and immunomodulatory effects. Specifically, the enclosed work provides strong evidence that cylindrical VIPAMs with aspect ratios of 1.5-150 and moderate positive surface charge are able to potentiate the bioactivity of VIP limiting TNF-α secretion and MHC II and CD86 surface expression on APCs. With these criteria, we have identified PalmK-(EK)4-VIP as our lead formulation, which showed comparable or enhanced anti-inflammatory effects relative to the unmodified VIP at all dosages evaluated. Additionally, the relationships between peptide block location and lipid block size provide further information on the chemical structure-function relationships of PA micelles for the delivery of VIP as well as potentially for other peptides more broadly.
Asunto(s)
Micelas , Péptido Intestinal Vasoactivo , Sistemas de Liberación de Medicamentos , Interacciones Hidrofóbicas e Hidrofílicas , Factor de Necrosis Tumoral alfa/metabolismo , Péptido Intestinal Vasoactivo/farmacologíaRESUMEN
Two different vasoactive intestinal peptide (VIP) amphiphiles have been formulated which readily form micelles of varying shapes. Interestingly, VIP micelle structure has been found to directly correlate to anti-inflammatory behavior providing evidence that these biomaterials can serve as a promising new therapeutic modality.
Asunto(s)
Antiinflamatorios/farmacología , Células Dendríticas/efectos de los fármacos , Factores Inmunológicos/farmacología , Macrófagos/efectos de los fármacos , Linfocitos T Reguladores/efectos de los fármacos , Péptido Intestinal Vasoactivo/farmacología , Animales , Antígeno B7-2/genética , Antígeno B7-2/inmunología , Células Cultivadas , Quimiocina CCL22/genética , Quimiocina CCL22/inmunología , Células Dendríticas/citología , Células Dendríticas/inmunología , Expresión Génica , Humanos , Lipopolisacáridos/antagonistas & inhibidores , Lipopolisacáridos/farmacología , Macrófagos/citología , Macrófagos/inmunología , Ratones , Micelas , Estructura Secundaria de Proteína , Tensoactivos/química , Linfocitos T Reguladores/citología , Linfocitos T Reguladores/inmunología , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Factor de Necrosis Tumoral alfa/genética , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
Current vaccine research has shifted from traditional vaccines (i.e., whole-killed or live-attenuated) to subunit vaccines (i.e., protein, peptide, or DNA) as the latter is much safer due to delivering only the bioactive components necessary to produce a desirable immune response. Unfortunately, subunit vaccines are very weak immunogens requiring delivery vehicles and the addition of immunostimulatory molecules termed adjuvants to convey protective immunity. An interesting type of delivery vehicle is peptide amphiphile micelles (PAMs), unique biomaterials where the vaccine is part of the nanomaterial itself. Due to the modularity of PAMs, they can be readily modified to deliver both vaccine antigens and adjuvants within a singular construct. Through the co-delivery of a model antigenic epitope (Ovalbumin319-340-OVABT) and a known molecular adjuvant (e.g., 2,3-dipalmitoyl-S-glyceryl cysteine-Pam2C), greater insight into the mechanisms by which PAMs can exert immunostimulatory effects was gained. It was found that specific combinations of antigen and adjuvant can significantly alter vaccine immunogenicity both in vitro and in vivo. These results inform fundamental design rules that can be leveraged to fabricate optimal PAM-based vaccine formulations for future disease-specific applications. Graphical Abstract.