Targeting Neuroimmune Interactions in Diabetic Neuropathy with Nanomedicine

Abstract

Significance: Diabetes is a major source of neuropathy and neuropathic pain that is set to continue growing in prevalence. Diabetic peripheral neuropathy (DPN) and pain associated with diabetes are not adequately managed by current treatment regimens. Perhaps the greatest difficulty in treating DPN is the complex pathophysiology, which involves aspects of metabolic disruption and neurotrophic deficits, along with neuroimmune interactions. There is, therefore, an urgent need to pursue novel therapeutic options targeting the key cellular and molecular players. Recent Advances: To that end, cellular targeting becomes an increasingly compelling drug delivery option as our knowledge of neuroimmune interactions continues to mount. These nanomedicine-based approaches afford a potentially unparalleled specificity and longevity of drug targeting, using novel or established compounds, all while minimizing off-target effects. Critical Issues: The DPN therapeutics directly targeted at the nervous system make up the bulk of currently available treatment options. However, there are significant opportunities based on the targeting of non-neuronal cells and neuroimmune interactions in DPN. Future Directions: Nanomedicine-based agents represent an exciting opportunity for the treatment of DPN with the goals of improving the efficacy and safety profile of analgesia, as well as restoring peripheral neuroregenerative capacity. Antioxid. Redox Signal. 36, 122-143.

Keywords: diabetes; diabetic neuropathy; nanomedicine; neuroimmune interaction; neuropathy; pain.

FIG. 1.

Stocking-and-glove distribution of DPN (red) and current mechanisms underlying pain and sensory loss associated with DPN. DPN, diabetic peripheral neuropathy. Created with Biorender.com Color images are available online.

FIG. 2.

Current and proposed mechanistic strategies to target pain and neuropathy in diabetes. Created with Biorender.com Color images are available online.

FIG. 3.

Schematic representation of synthesis, formation, and controlled release of fentanyl derivatives from Fen-PLA/PLGA nanoparticles. Fen-PLA/PLGA, fentanyl-bearing poly(L-lactide) and poly(lactic-co-glycolic acid). Reproduced with permission from Gonzalez-Rodriguez et al. (55). Color images are available online.

FIG. 4.

SEDDS strategy for oral delivery of macromolecules. SEDDS, self-emulsifying drug delivery systems. Image reproduced from AboulFotouh et al. (1). Color images are available online.

FIG. 5.

Macrophage M1–M2 phenotype shift induced by COX-2 inhibition. Macrophage polarity shifts from the pro-inflammatory M1 to the anti-inflammatory M2 phenotype in the day-12 nanomedicine treated (CXB-NE) group. (Day 12 refers to 12 days after CCI surgery.) There is a 27.5% reduction (p < 0.0001) in M1 pro-inflammatory macrophages in the day-12 CXB-NE group (B, F) compared with the day-12 DF-NE group (A, E). At day 18, the percentage of M1 macrophages increases by 56.7 to 85.7% in the nanomedicine-treated (CXB-NE) rats, compared with day 12 (D, H). At day 18, levels of M1-positive macrophages rise to 91.4% per ROI in the DF-NE group (C, G). There are no significant differences in nanomedicine colocalization with M1 macrophages. The percentage of anti-inflammatory M2 macrophages increases significantly (p < 0.0001) by 69.0% in the day-12 CXB-NE group (J, N) compared with the DF-NE animals (I, M). At day 18, the proportion of M2 macrophages in the CXB-NE group (L, P) drops significantly (p < 0.0001) by 41.8%, whereas there is no significant difference in the DF-NE group at day 18 (K, O), compared with day 12 (I, M). M2 macrophages in the day 18 conditions show a significantly lower nanomedicine NIRF colocalization compared with both the DF-NE (Fisher's exact test, p < 0.0001) and CXB-NE (Fisher's exact test, p < 0.0001) day 12 groups. At day 18, the percentage of M2 macrophages that are positive for nanomedicine NIRF signal is significantly lower in the CXB-NE group (Fisher's exact test, p = 0.000376) compared with the DF-NE group. All scale bars are 15 μm. The significance of M1- and M2-positive macrophage percent difference between conditions is represented as a Fisher's exact test p-value; 95% confidence interval. n = 3 animals, 21–33 ROI). CCI, chronic constriction injury; COX-2, cyclooxygenase-2; CXB-NE, celecoxib nanoemulsion; DF-NE, drug-free nanoemulsion; NIRF, near-infrared fluorescence; ROI, region of interest. Data, images and figure legends reproduced from Saleem et al. (144). Color images are available online.

FIG. 6.

Ang II induced macrophage density changes in mouse hind paw, and human skin. Ang II induces peripheral macrophage infiltration in mouse hind paw skin and increased macrophage density in skin biopsies from human patients with diabetic and chemotherapy-induced peripheral neuropathy. (A) Representative confocal microscopy images of mouse hind paw plantar punch tissue sections showing hind paw Ang II injection (100 pmol, ipl) enhances macrophage (green; Iba1) and neutrophil (red, Ly6g; blue, DAPI) infiltration both 1 and 5 h after injection compared with saline injection. Scale bar, 100 μm. Magnified views of area indicated as red dotted rectangular boxes are shown on the right top corner in each image group. (B) Representative confocal microscopy images of human plantar punch tissue sections showing increased macrophage density (Iba1) in human leg/ankle skin biopsies from diabetic neuropathy and chemotherapy-induced peripheral neuropathy patients compared with age-matched healthy controls. This is accompanied by a decrease in the density of nociceptive nerve fibers (PGP9.5) in the skin (bottom row images). Green dotted rectangular boxes on the top left corners in top row images represent magnified views of individual macrophages in indicated areas. Scale bar, 100 μm. (C) Density of both macrophages and nociceptive fibers in human skin biopsies that are quantified and presented as individual experimental replicates, with mean ± SEM marked therein (n = 2 sections each from n = 8 human subjects per group). *p < 0.05, ^###p < 0.001, and ns versus healthy control groups, one-way ANOVA with Tukey's multiple-comparisons post hoc test. Ang II, angiotensin II; DAPI, 4′,6-diamidino-2-phenylindole; ns, not significant. Data, images and figure legend reproduced from Shepherd et al. (153). Color images are available online.