ABSTRACT
Peptide-drug conjugates (PDCs) are a promising class of drug delivery systems that utilize covalently conjugated carrier peptides with therapeutic agents. PDCs offer several advantages over traditional drug delivery systems including enhanced target engagement, improved bioavailability, and increased cell permeability. However, the development of efficient transcellular peptides capable of effectively transporting drugs across biological barriers remains an unmet need. In this study, physicochemical criteria based on cell-penetrating peptides are employed to design transcellular peptides derived from an antimicrobial peptides library. Among the statistically designed transcellular peptides (SDTs), SDT7 exhibits higher skin permeability, faster kinetics, and improved cell permeability in human keratinocyte cells compared to the control peptide. Subsequently, it is found that 6-Paradol (PAR) exhibits inhibitory activity against phosphodiesterase 4, which can be utilized for an anti-inflammatory PDC. The transcellular PDC (SDT7-conjugated with PAR, named TM5) is evaluated in mouse models of psoriasis, exhibiting superior therapeutic efficacy compared to PAR alone. These findings highlight the potential of transcellular PDCs (TDCs) as a promising approach for the treatment of inflammatory skin disorders.
Subject(s)
Psoriasis , Psoriasis/drug therapy , Psoriasis/metabolism , Animals , Humans , Mice , Keratinocytes/drug effects , Keratinocytes/metabolism , Inflammation/drug therapy , Inflammation/metabolism , Skin/metabolism , Skin/drug effects , Drug Delivery Systems/methods , Cell-Penetrating Peptides/chemistry , Cell-Penetrating Peptides/pharmacology , Cell-Penetrating Peptides/pharmacokinetics , Phosphodiesterase 4 Inhibitors/chemistry , Phosphodiesterase 4 Inhibitors/pharmacology , Phosphodiesterase 4 Inhibitors/pharmacokineticsABSTRACT
High-density lipoprotein (HDL) therapy has demonstrated beneficial effects in acute stroke and acute myocardial infarction models by reducing infarct size. In this study, we investigated the inhibitory effects of reconstituted HDL (rHDL) on neointimal hyperplasia and elucidated its underlying mechanism using a balloon injury rat model. Our finding revealed a significant 37% reduction in the intima to media ratio in the arteries treated with 80 mg/kg rHDL compared to those subjected to injury alone (p < 0.05), indicating a specific inhibition of neointimal hyperplasia. In vivo analysis further supported the positive effects of rHDL by demonstrating a reduction in smooth muscle cell (SMC) proliferation and an increase in endothelial cell (EC) proliferation. Additionally, rHDL treatment led to decreased infiltration of leukocytes and downregulated the expression of matrix metallopeptidase 9 (MMP9) in the neointimal area. Notably, rHDL administration resulted in decreased expression of VCAM1 and HIF1α, alongside increased expression of heme oxygenase 1 (HO1) and heat shock protein 27 (HSP27). Overexpression of HSP27 and HO1 effectively inhibited SMC proliferation. Moreover, rHDL-mediated suppression of injury-induced HIF1α coincided with upregulation of HSP27. Interestingly, HSP27 and HO1 had varying effects on the expression of chemokine receptors and rHDL did not exert significant effect on chemokine receptor expression in THP1 cells. These findings underscore the distinct roles of HSP27 and HO1 as potential regulatory factors in the progression of restenosis. Collectively, our study demonstrates that rHDL exerts a potent anti-neointimal hyperplasia effect by reducing leukocytes infiltration and SMC proliferation while promoting EC proliferation.
Subject(s)
HSP27 Heat-Shock Proteins , Heme Oxygenase-1 , Animals , Rats , Cells, Cultured , HSP27 Heat-Shock Proteins/genetics , Hyperplasia , Lipoproteins, HDL/pharmacology , Neointima/drug therapyABSTRACT
Nanomaterials hybridized with biological components have widespread applications. among many candidates, peptides are attractive in that their peptide sequences can self-assemble with the surface of target materials with high specificity without perturbing the intrinsic properties of nanomaterials. Here, a 1D hybrid nanomaterial was developed through self-assembly of a designed peptide. A hexagonal coiled-coil motif geometrically matched to the diameter of the inorganic nanomaterial was fabricated, whose hydrophobic surface was wrapped along the axis of the hydrophobic core of the coiled coil. Our morphological and spectroscopic analyses revealed rod-shaped, homogeneous peptide-inorganic nanomaterial complexes. Culturing embryonic stem cells on surfaces coated with this peptide-assembled single-chain atomic crystal increased the growth and adhesion of the embryonic stem cells. The hybridized nanomaterial also served as an ECM for brain organoids, accelerating the maturation of neurons. New methods to fabricate hybrid materials through peptide assembly can be applied.
