Drug delivery carriers with therapeutic functions

Abstract

Design of micro- or nanocarriers for drug delivery has primarily been focused on properties such as hydrophobicity, biodegradability, size, shape, surface charge, and toxicity, so that they can achieve optimal delivery with respect to drug loading, release kinetics, biodistribution, cellular uptake, and biocompatibility. Incorporation of stimulus-sensitive moieties into the carriers would lead to "smart" delivery systems. A further evolution would be to endow the carrier with a therapeutic function such that it no longer serves as a mere passive entity to release the drug at the target tissue but can be viewed as a therapeutic agent in itself. In this review, we will discuss recent and ongoing efforts over the past decade to design therapeutic drug carriers that confer a biological benefit, including ROS scavenging or generating, pro- or anti-inflammatory, and immuno-evasive properties, to enhance the overall therapeutic efficacy of the delivery systems.

Keywords: Anti-bacterial; Anti-fibrotic; Anti-inflammatory; Anti-microbial; Drug delivery; Immunoadjuvant; ROS generation; ROS scavenging; Therapeutic carriers.

Figure 1.. Diselenide-bridged MSNs with ROS scavenging ability for redox-responsive release of RNase A.

(A) Schematic illustration of biodegradable diselenide-bridged MSNs for protein delivery. (B) The cytotoxicity of MSNs against Hela cells at different concentrations for 48 h. MSN0 represents MSN with S-S bond (TEOS: BTESPT = 4:1), MSN1 represents MSN with Se-Se bond (TEOS: BTESePD = 4:1), and MSN2 represents MSN with Se-Se bond (TEOS: BTESePD = 3:2). (C) Tumor volumes of MSNs-treated HeLa-tumor bearing mice. Copyright 2018 WILEY-VCH. [22]

Figure 2.. Diselenide-containing nanoparticles combining treatment of chemotherapy, radiotherapy, and immunotherapy.

(A) Schematic illustration of DOX loaded diselenide-containing polymers for combination therapy. (B) 77 Se-NMR spectra indicating the formation of seleninic acid under γ-radiation. (C) Flow cytometry spectra demonstrating the generation of ROS. (D) Schematic illustration of pemetrexed loaded diselenide-containing self-assembled NPs for combination therapy. (E) Lactate dehydrogenase assay indicating the cell death rates of MDA-MB-231 cells co-cultured with NK92 cells. (F) ELISA results exhibiting the IFN-γ levels produced by NK92 cells in co-culture system. Copyright 2020 WILEY-VCH. [–32]

Figure 3.. Carrier interactions inducing anti-bacterial mechanisms.

Inset shows differences between gram-positive and -negative bacterial membranes. (Adapted from [41], created with BioRender.)

Figure 4.. Materials interactions and immunomodulatory effects of carriers targeting DAMP-associated pathways.

Inset on right shows general mechanisms employed by nanomaterials for immunomodulation. (Created with BioRender.)

Figure 5.. Chitosan-mediated cGAS-STING and inflammasome activation, and the promotion of Th1 responses.

Chitosan receptor binding and charged-based interactions with host cell triggers the cGAS-STING pathway and the NLRP3 inflammasome. cGAS-STING pathway induced by CS may further lead to the activation of IRF3 and NF-κB, inducing the transcription of genes encoding type I IFNs and proinflammatory cytokines. (Created with BioRender.)

Figure 6.. Dissolvable microneedle array for sustained release of the checkpoint inhibitor.

(A) Schematic illustration of encapsulation and release of IDO inhibitor 1-MT and aPD1. (B) The blockade of PD-1 via aPD1 may incite the immune system to demolish cancer cells in the skin. (C) Average tumor areas for the treated mice. (D) Survival curves for the treated and control groups. Reproduced with permission. [–75] Copyright 2016, American Chemical Society

Figure 7.. Heparin encapsulated topical “Nano-spray gel” liposomal formulation guarantees rapid on-site treatment of frostbite injury via inflammatory cytokines scavenging.

(A) Schematic illustration of the fabrication and mechanism of the “Nano-spray gel”. (B) The level of TNF-α in the wound site and blood circulation (a: No Frostbite, b: Frostbite induced-untreated, c: Sulfadiazine Ointment, d: Blank group, e: Heparin liposomes, f: Heparin liposomes and Ibuprofen). (C) Morphometric and histopathological images of frostbite healing dynamics in rats. Adapted from Vaghasiya et al. 2019 [126].

Figure 8.. Zwitterionic coatings endow anti-fibrotic properties.

(A) Basic mechanisms of fibrosis include inflammation and growth factor-driven fibroblast activation, leading to ECM deposition and myofibroblast build-up [6,142]. (Created with BioRender.) (B, D) Poly(MPC)-coated alginate microcapsules exhibit reduced immune cell activation [129]. (C) Islet-encapsulating SB-alginate microcapsules. (E) FITC-labeled fibrinogen and lysozyme on surfaces of hydrogel microcapsule quantified by ImageJ. (F) TNF-α secretion from macrophages cultured on various surfaces [141].