Mannosylated liposomes improve therapeutic effects of paclitaxel in colon cancer models.

Mannose receptor (MR) is a highly effective endocytic receptor. It is closely related to tumour immune escape and metastasis. We found that MR was highly expressed in some colon cancer cell lines such as CT26 and HCT116 cells. Therefore, MR might be a potential target in colon cancer therapy. In this study, we aimed to develop mannosylated liposomes containing anticancer drug paclitaxel and investigate the potential effects on targeted therapy for colon cancer. Mannosylated liposomes were prepared by film dispersion method. Characterisation, drug release behaviour, cytotoxicity, cellular uptake, anti-tumour efficacy and safety profiles of liposomes were investigated. The results showed that mannosylated liposomes had a higher CT26 cells uptake efficiency and tumour inhibition rate, which might be due to the target effect to MR. And no notable toxicity was observed. Taken together, these data demonstrated that mannosylated liposomes could target colon cancer and improve the efficacy of chemotherapy.

A Tenofovir-Loaded Glycyrrhetinic Acid-Modified Cationic Liposome for Targeted Therapy of Hepatitis B Virus.

Tenofovir (TFV), an acyclic nucleoside analog, exhibits potent anti-HBV activity. However, poor bioavailability, nephrotoxicity and bone toxicity limit its further clinical application. In this work, a novel tenofovir-loaded glycyrrhetinic acidmodified cationic liposome (TGCL) was prepared for targeted therapy of HBV. The TGCL had an average particle size of 107.39 ± 1.21 nm and an entrapment efficiency of 89.83 ± 2.70% with a positive zeta potential of 37.63 ± 1.22 mV. The results of in vitro indicated that the inhibitory effects on HBsAg, HBeAg and HBV cccDNA of TGCL in HepG2.2.15 cells were significantly better than that of free TFV and non-targeted cationic liposome. In the DHBV-infected duck model, TGCL showed remarkably suppression on DHBV DNA than that of free TFV. Overall, TGCL is a promising formulation of TFV for targeted therapy of HBV.

Cholesterol-modified Hydroxychloroquine-loaded Nanocarriers in Bleomycin-induced Pulmonary Fibrosis.

An increasing number of reports have suggested the use of hydroxychloroquine (HCQ) as an adjunct anti-cancer treatment to enhance the chemotherapeutic response, as well as for the treatment of several fibrotic skin diseases and cystic fibrosis. In this study, we synthesized a cholesterol-modified HCQ (Chol-HCQ) and hypothesized that a systemic delivery system with Chol-HCQ nanocarriers could be effective for the treatment of bleomycin-induced pulmonary fibrosis. Chol-HCQ significantly inhibits the proliferation of rat lung fibroblasts, regulates inflammation and ameliorates bleomycin-induced pulmonary fibrosis in rats. It regulates the expression of pro-inflammatory cytokines, such as TNF-α; reduces the infiltration of inflammatory neutrophils; and inhibits the phosphorylation of NF-κB. Chol-HCQ also reduces the expression of connective tissue growth factor (CTGF) and phosphorylation of extracellular regulated protein kinase (p-ERK) in rats with bleomycin-induced pulmonary fibrosis. Chol-HCQ nanocarriers reduce early pulmonary inflammation and inhibit the CTGF/ERK signalling pathway in bleomycin-induced pulmonary fibrosis. These results demonstrate that Chol-HCQ liposomes suppress pulmonary inflammation and reduce pulmonary fibrosis induced by bleomycin. The systemic administration safety of Chol-HCQ liposomes was confirmed after intravenous administration for 28 days in rats. The present study provides evidence that Chol-HCQ liposomes may be a potential therapeutic agent for inflammation associated with pulmonary fibrosis.

Cationic nanocarriers induce cell necrosis through impairment of Na(+)/K(+)-ATPase and cause subsequent inflammatory response.

Nanocarriers with positive surface charges are known for their toxicity which has limited their clinical applications. The mechanism underlying their toxicity, such as the induction of inflammatory response, remains largely unknown. In the present study we found that injection of cationic nanocarriers, including cationic liposomes, PEI, and chitosan, led to the rapid appearance of necrotic cells. Cell necrosis induced by cationic nanocarriers is dependent on their positive surface charges, but does not require RIP1 and Mlkl. Instead, intracellular Na(+) overload was found to accompany the cell death. Depletion of Na(+) in culture medium or pretreatment of cells with the Na(+)/K(+)-ATPase cation-binding site inhibitor ouabain, protected cells from cell necrosis. Moreover, treatment with cationic nanocarriers inhibited Na(+)/K(+)-ATPase activity both in vitro and in vivo. The computational simulation showed that cationic carriers could interact with cation-binding site of Na(+)/K(+)-ATPase. Mice pretreated with a small dose of ouabain showed improved survival after injection of a lethal dose of cationic nanocarriers. Further analyses suggest that cell necrosis induced by cationic nanocarriers and the resulting leakage of mitochondrial DNA could trigger severe inflammation in vivo, which is mediated by a pathway involving TLR9 and MyD88 signaling. Taken together, our results reveal a novel mechanism whereby cationic nanocarriers induce acute cell necrosis through the interaction with Na(+)/K(+)-ATPase, with the subsequent exposure of mitochondrial damage-associated molecular patterns as a key event that mediates the inflammatory responses. Our study has important implications for evaluating the biocompatibility of nanocarriers and designing better and safer ones for drug delivery.

Novel thermosensitive hydrogel for preventing formation of abdominal adhesions.

Adhesions can form after almost any type of abdominal surgery. Postoperative adhesions can be prevented by improved surgical techniques, such as reducing surgical trauma, preventing ischemia, and avoiding exposure of the peritoneal cavity to foreign materials. Although improved surgical techniques can potentially reduce formation of adhesions, they cannot be eliminated completely. Therefore, finding more effective methods to prevent postoperative adhesions is imperative. Recently, we found that a novel thermosensitive hydrogel, ie, poly(ε-caprolactone)-poly(ethylene glycol)-poly(ε-caprolactone) (PCEC) had the potential to prevent postoperative adhesions. Using the ring-opening polymerization method we prepared a PCEC copolymer which could be dissolved and assembled at 55°C into PCEC micelles with mean size of 25 nm. At body temperature, a solution containing PCEC micelles could convert into a hydrogel. The PCEC copolymer was biodegradable and had low toxicity in vitro and in vivo. We found that most animals in a hydrogel-treated group (n = 10) did not develop adhesions. In contrast, 10 untreated animals developed adhesions that could only be separated by sharp dissection (P < 0.001). The hydrogel could adhere to peritoneal wounds and degraded gradually over 7-9 days, transforming into a viscous fuid that was completely absorbed within 12 days. The injured parietal and visceral peritoneum remesothelialized over about seven and nine days, respectively. This study confirms that PCEC hydrogel has potential application in the prevention of postoperative adhesions.