Targeted Drug Delivery via the Use of ECM-Mimetic Materials

Abstract

The use of drug delivery vehicles to improve the efficacy of drugs and to target their action at effective concentrations over desired periods of time has been an active topic of research and clinical investigation for decades. Both synthetic and natural drug delivery materials have facilitated locally controlled as well as targeted drug delivery. Extracellular matrix (ECM) molecules have generated widespread interest as drug delivery materials owing to the various biological functions of ECM. Hydrogels created using ECM molecules can provide not only biochemical and structural support to cells, but also spatial and temporal control over the release of therapeutic agents, including small molecules, biomacromolecules, and cells. In addition, the modification of drug delivery carriers with ECM fragments used as cell-binding ligands has facilitated cell-targeted delivery and improved the therapeutic efficiency of drugs through interaction with highly expressed cellular receptors for ECM. The combination of ECM-derived hydrogels and ECM-derived ligand approaches shows synergistic effects, leading to a great promise for the delivery of intracellular drugs, which require specific endocytic pathways for maximal effectiveness. In this review, we provide an overview of cellular receptors that interact with ECM molecules and discuss examples of selected ECM components that have been applied for drug delivery in both local and systemic platforms. Finally, we highlight the potential impacts of utilizing the interaction between ECM components and cellular receptors for intracellular delivery, particularly in tissue regeneration applications.

Keywords: ECM cell receptors; ECM ligand; extracellular matrix; hydrogel; targeted drug delivery.

FIGURE 1

Schematic overview of extracellular matrix components and their cell surface receptors (Theocharis et al., 2016). Copyright 2016. Reproduced with permission from Elsevier Inc. Cells have specific surface receptors, such as integrins, cell surface proteoglycans (ex. syndecans and glypicans), the HA receptor CD44, and DDRs, to bind ECM components for regulation of various cellular functions.

FIGURE 2

Extracellular matrix-based targeted delivery of particle-based DDS. (A) Schematic of ELP-CLP conjugate-based thermoresponsive nanovesicles (Luo et al., 2017). Copyright 2017. Reproduced with permission from American chemical society. (B) RGD dendrimer peptide modified polyethyleneimine-grafted chitosan for siRNA delivery. In vivo tumor growth of treatment with non-RGD-modified system (PgWSC) and RGD-modified system (RpgWSC), and non-treatment (Y.M. Kim et al., 2017). Copyright 2017. Reproduced with permission from Elsevier Inc. (C) Confocal images of internalization of dendrimer particles (CMCht/PAMAM and YIGSR-CMCht/PAMAM) on HCT-116 cancer cells (red) and L929 fibroblasts (blue) (Carvalho et al., 2019). Copyright Wiley-VCH Verlag GmbH. & Co. KGaA. Reproduced with permission.

FIGURE 3

Simple diffusion of drugs from ECM based matrices. (A) Computed tomography (CT) images for the efficacy of INFUSE^® Bone Graft in clinical applications (McKay et al., 2007). Copyright 2007. Reproduced with permission from Springer Nature. (B) The scheme of overall study design. Histologic analysis using H&E, Saf-O/FG, and Gram staining of femurs after treating with hydrogel (UAMS-1), Lysostaphin-delivering hydrogel (UAMS-1 + Lst), and Lysostaphin, and sterilization (Johnson et al., 2018). Copyright 2018. Reproduced with permission from the National Academy of Sciences.

FIGURE 4

Extracellular matrix-based matrices and drug interaction-based delivery systems. (A) Growth factor retention in fibrin matrices with laminin-mimetic peptides (α2PI1–8-LAMA33043–3067 or α2PI1–8-LAMA53417–3436) or without peptide (**p < 0.01) (Ishihara et al., 2018). Copyright 2018. Reproduced with permission from Springer Nature. (B) The scheme of study design. Antimicrobial activity of LL37 and with collagen-binding domains (cCBD-LL37 or fCBD-LL37) on collagen scaffold after 12 h and 14 days (*p < 0.01, **p < 0.001, ⁺p < 0.05) (Lozeau et al., 2017). Copyright 2017. Reproduced with permission from Elsevier Inc.

FIGURE 5

Polyplex immobilized in an ECM-based matrix for gene delivery. (A) Flow-activated cell sorting (FACS) analysis of biotin-functionalized pGFP polyplex immobilized in avidin-modified collagen hydrogel through avidin-biotin interaction (right graph) and avidin-free collagen hydrogel (left) (Orsi et al., 2010). Copyright 2010. Reproduced with permission from Elsevier Inc. (B) pGluc expression for 30 days of cell culture in the presence of immobilized pGluc polyplex on the surface of hyaluronic acid hydrogel through electrostatic interaction, and bolus transfection controls (Truong and Segura, 2018). Copyright 2018. Reproduced with permission from the American Chemical Society. (C) pGluc expression of immobilized GPP-PEI in the collagen hydrogel and free GPP polyplex in hydrogel after a week of pre-incubation in media with and without the presence of metalloproteinase (Urello et al., 2014). Copyright 2014. Reproduced with permission from The Royal Society of Chemistry. (D) Colocalization study of FITC labeled collagen (Green) with Alexa Fluor 350 labeled GPP-PEI (Blue) in NIH3T3 cells after 5 days of pre-incubation in the media (Urello et al., 2017). The scale bar is 25 μm. Copyright 2017. Reproduced with permission from Elsevier Inc.