Improving long-term subcutaneous drug delivery by regulating material-bioenvironment interaction

Abstract

Subcutaneous long-acting release (LAR) formulations have been extensively developed in the clinic to increase patient compliance and reduce treatment cost. Despite preliminary success for some LAR systems, a major obstacle limiting the therapeutic effect remains on their interaction with surrounding tissues. In this review, we summarize how living bodies respond to injected or implanted materials, and highlight some typical strategies based on smart material design, which may significantly improve long-term subcutaneous drug delivery. Moreover, possible strategies to achieve ultra-long (months, years) subcutaneous drug delivery systems are proposed. Based on these discussions, we believe the well-designed subcutaneous long-acting formulations will hold great promise to improve patient quality of life in the clinic.

Keywords: Drug retention; Foreign body reaction; Immunoisolation; Long-acting release (LAR); Non-fouling materials.

Fig. 1

Schematic diagram of the FBR leading to the encapsulation of injected or implanted materials. Adapted with permission from reference [43].

Fig. 2

(A) Typical structures of tEB modified exendin-4 (Adapted with permission from reference [69] and reference [71]). (B) Whole body PET images of BALB/c mice at different time points after subcutaneous injection of ⁶⁴Cu-Abextide, ⁶⁴Cu-Albiglutide and ⁶⁴Cu-Exendin-4, (Adapted with permission from reference [71]). (C) Fluorescence images of the lymphatic system in BALB/c mice treated with fluorine-18 aluminum fluoride-labeled NOTA (1,4,7-triazacyclononane-N,N′,N″-triacetic acid)-conjugated truncated Evans blue (¹⁸F-AlF-NEB) and normal EB following a chronological order. (D) Ex vivo optical imaging of LNs at 90 min postinjection (skin removed). (E) Bright field image showed the blue color in the lymphatic system. (F) Optical and PET imaging of popliteal LNs (white arrow). (G) Optical and PET imaging of the sciatic LNs (white arrow). Fig. 2C–G were adapted with permission from reference [73]).

Fig. 3

(A) Synthesis of exendin-C-POEGMA. Adapted with permission from reference [18]. (B) A fusion of ELP and GLP-1 can form an extended release subcutaneous depot and prolong peptide circulation time. Adapted with permission from reference [19]. (C) Schematic of mineralized exendin-4 generation and its disassembly in response to physiological supersaturation. Adapted with permission from reference [83].

Fig. 4

(A) Schematics of representative nanotopography geometries commonly used as cell culture substrates. Adapted with permission from reference [95]. (B) The effect of surface curvature on cell shape. Adapted with permission from reference [96]. (C) The influence of fiber size on FBR. Adapted with permission from reference [97]. (D) Schematic for guiding cell migration on isotropic and anisotropic topographies. Adapted with permission from reference [98].

Fig. 5

Size and shape effects of injected or implanted materials. (A) Three typical shapes of implants that are used to evaluate the FBR. Adapted with permission from reference [129] (B) Photomicrographs of H&E-stained sections after treatments by different shaped implants for 14 days. Blue arrows indicate the accumulated cells. Adapted with permission from reference [129]. (C) Bright-field images of different materials with distinct sizes after implantation for 14 days (upper panels). Immunofluorescence Z-stacked confocal images of retrieved materials. Blue (DAPI) indicates cell nuclei, green (CD68) indicates macrophages, and red (α-SMA) indicates fibrosis-associated activated myofibroblasts (lower panels). Scale bar, 300 μm. (D) Flow analysis using specific markers for the host macrophage. (E) Flow analysis using specific markers for the host neutrophils. (F) Cytokine array profiling of inflammatory cytokine protein production in response to implanted materials. Fig. 5C–F were adapted with permission from reference [126].

Fig. 6

Combining molecular level and macro-sized level strategies to extend long-term subcutaneous drug treatments.

Fig. 7

Bio-responsive modalities for controlled drug release (Adapted with permission from reference [27]). (A) Directly activated model. (B) Progressively activated model. (C) Self-regulated model.

Fig. 8

Long-term response of cell encapsulated alginate depots (Adapted with permission from reference [118]). (A) Representative dark-field, bright-field, and z-stacked confocal immunofluorescence images of SC-β cell implants. (B) Proteomic analysis of lysates from SC-β cell cluster implants retrieved from the STZ-treated C57BL/6J mice after 90 d implantation. (C) BGL in healthy mice or diabetic mice implanted with SC-β cell-encapsulated TMTD-1.5 spheres. (D) BGL of the STZ-treated C57BL/6 mice with or without TMTD alginate implantation that were subjected to an IVGTT after 174 d. (E) Blood human C-peptide levels of diabetic mice implanted with TMTD-1.5 spheres.

Fig. 9

Electronic/mechanical device-based long-acting systems. (A) Wearable diabetes monitoring and therapy system based on a smartphone and a microneedle-array patch. Adapted with permission from reference [141]. (B) Abstract diagram showing smartphone-controlled engineered cells enabling semiautomatic point of care for combating diabetes. Adapted with permission from reference [142].