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

Abstract

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 βcyclodextrin (β-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.

Bioinspired biliverdin/silk fibroin hydrogel for antiglioma photothermal therapy and wound healing

“…Biliverdin, as one main component in the BVSF hydrogel system, also contributed to the wound repair. Our previous research indicated that bilirubin possesses a power anti-inflammatory property, which showed significant cytoprotective effects against oxidative and inflammatory damage in multiple cell lines 40 , 63 - 65 . Biliverdin, as a precursor substance of bilirubin, has also been demonstrated as an important cytoprotective and anti-inflammatory molecule 34 , 35 .…”

“…Fluorescence-based live/dead assays were carried out as previously reported 40 with modification. Briefly, C6 or GL261 cells were seeded into 6-well plates and incubated with or without BVSF for 24 h. Due to the gel state could affect the detection of cell viability and the photothermal conversion ability of BVSF in solution state is consistent with that in hydrogel state, we thereby used liquid pre-BVSF solutions here for live/dead staining assay.…”

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“…In recent years, a large number of active drugs have emerged to improve therapy for acute pancreatitis by inhibiting the NF-κB signaling pathway in experiments (Cen et al., 2016 ; Tao et al., 2019 ). Bilirubin is a bioproduct, and possessed potent antioxidant and anti-inflammatory properties (Yao, Jiang, et al., 2019 ; Yao, Jiang, 2019 ; Yao, Huang, 2020 ; Yao, Sun, 2020 ). Our previous study also indicated that bilirubin could inhibit the NF-κB mediated pro-inflammatory signaling pathway, and significant reduced the progression of acute pancreatitis in a rat model (Wang et al., 2016 ).…”

Dual Targeting EGFR and STAT3 With Erlotinib and Alantolactone Co-Loaded PLGA Nanoparticles for Pancreatic Cancer Treatment

“…Nano-drug delivery systems (NDDS), including biodegradable nanoparticles, liposomes, micelles, etc., have been utilized as a potent formulation strategy in various biomedical applications to improve therapeutic outcomes (Kou et al, 2018;Yao et al, 2018;Yao et al, 2020a;Moradi Kashkooli et al, 2020;Shao et al, 2020). NDDS could improve the stability and solubility of therapeutics, as well as optimize the in vivo behavior by prolonging circulation time, enhanced penetration and retention effect, and reduced side effects of drugs.…”