BV2 Membrane-Coated PEGylated-Liposomes Delivered hFGF21 to Cortical and Hippocampal Microglia for Alzheimer's Disease Therapy.

Microglia-mediated inflammation is involved in the pathogenesis of Alzheimer's disease (AD), whereas human fibroblast growth factor 21 (hFGF21) has demonstrated the ability to regulate microglia activation in Parkinson's disease, indicating a potential therapeutic role in AD. However, challenges such as aggregation, rapid inactivation, and the blood-brain barrier hinder its effectiveness in treating AD. This study develops targeted delivery of hFGF21 to activated microglia using BV2 cell membrane-coated PEGylated liposomes (hFGF21@BCM-LIP), preserving the bioactivity of hFGF21. In vitro, hFGF21@BCM-LIP specifically targets Aß1-42-induced BV2 cells, with uptake hindered by anti-VCAM-1 antibody, indicating the importance of VCAM-1 and integrin α4/ß1 interaction in targeted delivery to BV2 cells. In vivo, following subcutaneous injection near the lymph nodes of the neck, hFGF21@BCM-LIP diffuses into lymph nodes and distributes along the meningeal lymphatic vasculature and brain parenchyma in amyloid-beta (Aß1-42)-induced mice. Furthermore, the administration of hFGF21@BCM-LIP to activated microglia improves cognitive deficits caused by Aß1-42 and reduces levels of tau, p-Tau, and BACE1. It also decreases interleukin-6  (IL-6) and tumor necrosis factor-α (TNF-α) release while increasing interleukin-10 (IL-10) release both in vivo and in vitro. These results indicate that hFGF21@BCM-LIP can be a promising treatment for AD, by effectively crossing the blood-brain barrier and targeting delivery to brain microglia via the neck-meningeal lymphatic vasculature-brain parenchyma pathways.

Intradermal injection of icariin-HP-ß-cyclodextrin improved traumatic brain injury via the trigeminal epineurium-brain dura pathway.

The lower bioavailability after oral administration limited icariin applications in central nervous system. Icariin/HP-ß-cyclodextrin (HP-ß-CD) inclusion complex was prepared for acute severe opening traumatic brain injury (TBI) via facial intradermal (i.d.) in the mystacial pad. After fluid percussion-induced TBI, icariin/HP-ß-CD at 0.4 mg/kg i.d. preserved more neurons and oligodendrocytes than intranasal injection (i.n.) or intravenous injection via tail vein (i.v.) and decreased microglia and astrocyte activation. Icariin/HP-ß-CD i.d. reduced apoptosis in cortical penumbra while i.n. and i.v. showed weak or no effects. Icariin/HP-ß-CD i.d. reduced Evans blue leakage and altered CD34, ZO-1, Claudin-5, and beta-catenin expression after TBI. Moreover, icariin/HP-ß-CD promoted human umbilical vein endothelial cells proliferation. Thus, Icariin/HP-ß-CD i.d. improved TBI, including blood-brain barrier opening. Fluorescein 5-isothiocyanate (FITC) and 3,3'-Dioctadecyloxacarbocyanine perchlorate (DiOC18(3)) mimic HP-ß-CD and icariin respectively. FITC and DiOC18(3) were similarly delivered to trigeminal epineurium, perineurium and perivascular spaces or tissues, caudal dura mater, and scattered in trigeminal fasciculus, indicating that icariin/HP-ß-CD was delivered to the brain via trigeminal nerve-dura mater-brain pathways. In sum, intradermal injection in mystacial pad might deliver icariin/HP-ß-CD to the brain and icariin/HP-ß-CD improved acute severe opening TBI.

Glucose-responsive hydrogel enhances the preventive effect of insulin and liraglutide on diabetic nephropathy of rats.

Diabetic nephropathy (DN) is one of the most serious complications of diabetes mellitus. The combination of insulin (Ins) with liraglutide (Lir) has a greater potential for preventing DN than monotherapy. However, the renal protective effect of the combined Ins/Lir therapy is largely compromised due to their short half-lives after subcutaneous injection. Herein, a glucose-responsive hydrogel was designed in situ forming the dynamic boronic esters bonds between phenylboronic acid-grafted γ-Polyglutamic acid (PBA-PGA) and konjac glucomannan (KGM). It was hypothesized that the KGM/PBA-PGA hydrogel as the delivery vehicle of Ins/Lir would enhance the combinational effect of the latter on preventing the DN progress. Scan electronic microscopy and rheological studies showed that KGM/PBA-PGA hydrogel displayed good glucose-responsive property. Besides, the glucose-sensitive release profile of either Ins or Lir from KGM/PBA-PGA hydrogel was uniformly displayed at hyperglycemic level. Furthermore, the preventive efficacy of KGM/PBA-PGA hydrogel incorporating insulin and liraglutide (Ins/Lir-H) on DN progress was evaluated on streptozotocin-induced rats with diabetic mellitus (DM). At 6 weeks after subcutaneous injection of Ins/Lir-H, not only the morphology of kidneys was obviously recovered as shown by ultrasonography, but also the renal hemodynamics was significantly improved. Meanwhile, the 24-h urinary protein and albumin/creatinine ratio were well modulated. Inflammation and fibrosis were also largely inhibited. Besides, the glomerular NPHS-2 was obviously elevated after treatment with Ins/Lir-H. The therapeutic mechanism of Ins/Lir-H was highly associated with the alleviation of oxidative stress and activation of autophagy. Conclusively, the better preventive effect of the combined Ins/Lir via KGM/PBA-PGA hydrogel on DN progress was demonstrated as compared with their mixed solution, suggesting KGM/PBA-PGA hydrogel might be a potential vehicle of Ins/Lir to combat the progression of DN.

Localized Controlled Release of Bilirubin from ß-Cyclodextrin-Conjugated ε-Polylysine To Attenuate Oxidative Stress and Inflammation in Transplanted Islets.

Islet transplantation has been considered the most promising therapeutic option with the potential to restore the physiological regulation of blood glucose concentrations in type 1 diabetes treatment. However, islets suffer from oxidative stress and nonspecific inflammation in the early stage of transplantation, which attributed to the leading cause of islet graft failure. Our previous study reported that bilirubin exerted antioxidative and anti-inflammatory effects on hypothermic preserved islets, which inspire us to utilize bilirubin to address the survival issue of grafted islets. However, the application of bilirubin for islet transplantation is limited by its poor solubility and fast clearance. In this study, we designed a supramolecular carrier (PLCD) that could improve the solubility of bilirubin and slowly release bilirubin to protect islets after cotransplantation. PLCD was synthesized by conjugating activated ß-cyclodextrin (ß-CD) to the side chain of ε-polylysine (PLL) and acted as a carrier to load bilirubin via host-guest interactions. The constructed bilirubin supramolecular system (PLCD-BR) significantly improved the solubility and prolonged the action time of bilirubin. In vitro results confirmed that PLCD-BR coculture substantially enhanced the resistance of islets to excessive oxidative stress and proinflammatory stimulation and maximumly maintained the islet function. In vivo, PLCD could prolong drug duration at the transplant site, and the localized released bilirubin could protect the islets from oxidative stress and suppress the production of inflammatory cytokines. Crucially, islet transplantation with PLCD-BR significantly extended the stable blood glucose time of diabetic mice and produced a faster glucose clearance compared to those cotransplanted with free bilirubin. Additionally, immunohistochemical analysis showed that PLCD-BR had superior antioxidative and anti-inflammatory abilities and beneficial effects on angiogenesis. These findings demonstrate that the PLCD-BR has great potentials to support successful islet transplantation.

In vivo 783-channel diffuse reflectance imaging system and its application.

A fiber-based reflectance imaging system was constructed to produce in vivo absorption spectroscopic images of biological tissues with diffuse light in the cw domain. The principal part of this system is the 783-channel fiber probe, composed of 253 illumination fibers and 530 detection fibers distributed in a 20x20 mm square region. During illumination with the 253 illumination fibers, diffuse reflected lights are collected by the 530 detection fibers and recorded simultaneously as an image with an electron multiplying CCD camera for fast data acquisition. After signal acquisition, a diffuse reflectance image was reconstructed by applying the spectral normalization method we devised. To test the applicability of the spectral normalization, we conducted two phantom experiments with chicken breast tissue and white Delrin resin by using animal blood as an optical inhomogeneity. In the Delrin phantom experiment, we present images produced by two methods, spectral normalization and reference signal normalization, along with a comparison of the two. To show the feasibility of our system for biomedical applications, we took images of a human vein in vivo with the spectral normalization method.