Supramolecular Peptide Nanofiber/PLGA Nanocomposites for Enhancing Pulmonary Drug Delivery

Abstract

Effective drug delivery to pulmonary sites will benefit from the design and synthesis of novel drug delivery systems that can overcome various tissue and cellular barriers. Cell penetrating peptides (CPPs) have shown promise for intracellular delivery of various imaging probes and therapeutics. Although CPPs improve delivery efficacy to a certain extent, they still lack the scope of engineering to improve the payload capacity and protect the payload from the physiological environment in drug delivery applications. Inspired by recent advances of CPPs and CPPfunctionalized nanoparticles, in this work, we demonstrate a novel nanocomposite consisting of fiber-forming supramolecular CPPs that are coated onto polylactic-glycolic acid (PLGA) nanoparticles to enhance pulmonary drug delivery. These nanocomposites show a threefold higher intracellular delivery of nanoparticles in various cells including primary lung epithelial cells, macrophages, and a 10-fold increase in endothelial cells compared to naked PLGA nanoparticles or a twofold increase compared to nanoparticles modified with traditional monomeric CPPs. Cell uptake studies suggest that nanocomposites likely enter cells through mixed macropinocytosis and passive energy-independent mechanisms, which is followed by endosomal escape within 24 h. Nanocomposites also showed potent mucus permeation. More importantly, freeze-drying and nebulizing formulated nanocomposite powder did not affect their physiochemical and biological activity, which further highlights the translative potential for use as a stable drug carrier for pulmonary drug delivery. We expect nanocomposites based on peptide nanofibers, and PLGA nanoparticles can be custom designed to encapsulate and deliver a wide range of therapeutics including nucleic acids, proteins, and small-molecule drugs when employed in inhalable systems to treat various pulmonary diseases.

Pulmonary inhalation for disease treatment: Basic research and clinical translations

“…Poly(lactic acid glycolic acid) (PLGA) NPs were coated with cell-penetrating peptides (CPP), showing a three-fold higher intracellular delivery of NPs in various cells compared with bare PLGA NPs, a ten-fold increase in endothelial cells, and a two-fold increase compared with conventional monomeric CPP-modified NPs ( Fig. 7 A) [ 228 ].…”

Material and Design Toolkit for Drug Delivery: State of the Art, Trends, and Challenges

“…The ester linkage of the PLA in the body naturally degrades to short oligomers that can be cleared from the body without inducing the immune system. 43 Its biological compatibility and degradation ability can be tuned through changes in molecular weight or dimensions, environmental temperature, or moisture and the addition of surfactants, which makes it easier to develop the ideal medication system for delivery in various formulations. 42 The PLA nanoparticles possessing amphipathic molecules and the copolymer PLA−PEG nanoparticles (amphiphilic nanomaterial) have been frequently used as delivery vehicles in the treatment of different forms of cancer, implantations, and many other diseases.…”

“…Confocal images on the right side demonstrate a greater uptake of NPs and NCs in primary rhodamine B-labeled type I alveolar epithelial cells. Reproduced with permission from ref . Copyright 2022 American Chemical Society.…”

“…Both polyesters are used in the pharmaceutical industry, thanks to their simplicity in production and modification. Chintapula et al reported a new nanocomposite that enhances pulmonary drug delivery by coating PLGA NPs with fiber-forming supramolecular cell-penetrating peptides (CPPs), as shown in Figure c. Compared to naked PLGA NPs or NPs modified with conventional monomeric CPPs, these nanocomposites exhibited 3-fold more intracellular delivery in various cells, including primary cells within the epithelial lungs and macrophages.…”

Self-assembled peptide-based nanoblocks for drug delivery

“…27 He and co-workers developed tumor-responsive nanomicelles through the co-assembly of curcumin and peptide bearing a cysteine residue. 28 Liang and co-workers constructed a novel nanofiber structure based on a peptide that conjugated with doxorubicin at the end, which was capable of increasing antitumor activity and reducing side effects. 29 It is worth noting that peptide assembly structures with a large size are not easily taken up by cells, and the small size of the peptide assembly has a poor drug loading rate, so preparing the appropriate size of peptide assembly with good biocompatibility to complete drug delivery is still a challenge.…”