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Additional file 1: Fig. S1. Synthetic route of A DSPE-PEG2000-modified quercetin (DQ) and B GCA-modified COS (GCOS). Fig. S2. MALDI-TOF spectrum of chitosan oligosaccharide (COS) and GCOS. Fig. S3. DSC scanning results of A cholesterol. B PTX. C PTX-CHOL complex. Fig. S4. Cell cytotoxic evaluation of PTX@GCA-NPs. Cell viability of Caco-2 cells after incubated with A PTX@GCA-NPs for 4 h and B Blank GCA-NPs for 24 h. Data is presented as mean ± SEM, n = 6. Fig. S5. Changes of TEER value compared after Caco-2 cell monolayers were incubated with PTX@GCA-NPs and PTX@NPs, respectively. Data is presented as mean ± SEM, n =3. Fig. S6. FRET phenomenon validation. FRET signal of A DiO/DiR@GCA-NPs dispersed with deionized water and acetone. B FRET efficiency of DiO/DiI@GCA-NPs mixed with acetone and deionized water. C DiO/DiI@GCA-NPs, DiO@GCA-NPs, DiI@GCA-NPs. (Excitation wavelength at 480 nm and detection at 500 – 600 nm). Fig. S7. Relative tumor volume of LL2 bearing mice. Date is presented as mean ± SEM, n = 6. Fig. S8. Apoptosis rate analysis of TUNEL assay. Data is presented as mean ± SEM, n = 3, ***P < 0.001, **P < 0.01, *P < 0.05. Fig. S9. In vivo safety evaluation of LL2 bearing mice after dosing for 12 days. A Body weights. B Histological images of heart, liver, spleen, lung and kidney dyed with H&E staining. Date is presented as mean ± SEM, n = 6. (magnification: 200 ×). Table S1. Physicochemical properties of nanoparticles. Data is presented as mean ± SEM, n =3. Table S2. FRET efficiency of DiO/DiI@GCA-NPs and DiO@GCA-NPs + DiI@GCA-NPs mixture in BP side after incubated with Caco-2 cell monolayers. Data is presented as mean ± SD, n = 3. Table S3. Pharmacokinetic parameters following intravenous injection of Taxol and oral gavage of Taxol, PTX@NPs, PTX@GCA-NPs, PTX@GCA-NPs + TCA and PTX@GCA-NPs + CHE refer to the rats was orally administered with TCA and subcutaneous injected with CHE before oral PTX@GCA-NPs, respectively. (PTX: 10 mg/kg, TCA: 50 mg/kg, CHE: 3.6 mg/kg). Data is presented as mean ± SEM, n = 3.

Background Keloids represent benign fibroproliferative tumors which result from elevated expression of inflammation. Paclitaxel (PTX) was an effective chemotherapeutic agent and has been reported to have anti-fibrotic effects, but the strong hydrophobicity brings a challenge for its clinical application. Purpose The objective of this study was to improve the water solubility of PTX and investigate its anti-keloid effects. Methods We prepared a PTX-cholesterol-loaded liposomes (PTXL) by thin film evaporation fashion and characterized their physicochemical properties. We also investigated the effects of PTX on proliferation, invasion and fibrosis of keloid fibroblasts in vitro and in vivo. Results The prepared PTXL have a spherical appearance, a particle size of 101.43 nm and a zeta potential of −41.63 mV. PTXL possessed a high drug entrapment efficiency of 95.63% and exhibited a good stability within 30 days. The drugs in PTXL were released in a slow and sustained mode. The PTXL could be effectively uptaken into human keloids fibroblast (HKFs) in a time-dependent manner. In vitro, PTXL showed better ability on inhibiting cell proliferation, migration and invasion, and effectively on promoting apoptosis and arresting cell cycle in G2/M phase compared to PTX. Meanwhile, in vivo studies indicated that the PTXL had better performance on inhibiting the keloids growth compared to the PTX in keloid-bearing BALB/c nude mice model. Finally, we found PTX treatment suppressed the production of tumor necrosis factor alpah (TNF-α), interleukin 6 (IL-6) and transforming growth factor beta (TGF-β) and inhibited the expression of alpha smooth muscle actin (α-SMA) and collagen I in HKFs. The activation of protein kinase B (AKT)/glycogen synthase kinase 3 beta (GSK3β) signaling pathway also blocked by PTX in cultured HKFs and keloid tissues. LY294002, a PI3K (phosphatidylinositol 3-kinase)/AKT inhibitor, also suppressed the expression of TNF-α, IL-6 and TGF-β, and simultaneously, reduced the production of α-SMA and collagen I in HKFs. The inhibition of AKT/GSK3β signaling pathway contribute to inhibit the generation of fibrogenic cytokines by PTXL on ameliorating fibrosis progress in keloids. Conclusion Our results suggested that the developed PTXL would become a promising therapeutic agent in the field of anti-keloid therapy.

Minhu Cui,1,2 Mingji Jin,2 Mingfeng Han,2 Yingda Zang,2 Chuangjun Li,2 Dongming Zhang,2 Wei Huang,2 Zhonggao Gao,2 Xuezhe Yin3 1Department of Gastroenterology, Yanbian University Hospital, Yanji 133000, Jilin, People’s Republic of China; 2State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, People’s Republic of China; 3Department of Respiratory Medicine, Yanbian University Hospital, Yanji 133000, Jilin, People’s Republic of ChinaCorrespondence: Zhonggao GaoState Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, People’s Republic of ChinaTel/Fax +86 10-63028096Email zggao@imm.ac.cnXuezhe YinDepartment of Respiratory Medicine, Yanbian University Hospital, Yanji 133000, Jilin, People’s Republic of ChinaTel/Fax +86-433-2817019Email yinxz1234@163.comBackground: LA67 is a derivative of triptolide that exhibits strong antitumor activity. This derivative has a better safety profile than triptolide, but is limited by poor aqueous solubility.Aim and Methods: To improve solubility and further increase therapeutic efficacy, we prepared LA67-loaded polymeric micelles (LA67-PMs) using a film hydration method. The physicochemical properties of LA67-PMs were investigated, and the antitumor activity of this formulation against Colon26 (C26) cancer cell line was evaluated in vitro and in vivo with LA67 as a control.Results: Polymeric micelles containing LA67 had a particle size of 17.88 nm and a drug entrapment efficiency of 94.84%. This formulation dispersed completely in aqueous solution and exhibited slow, sustained release of LA67. Cellular uptake assay showed that LA67-PMs delivered LA67 to cancer cells with greater efficiency than free LA67, which resulted in increased LA67 accumulation in cancer cells. Cell counting kit 8 (CCK-8) assay showed that blank polymeric micelles (PMs) exhibited low toxicity and LA67-PMs exerted pronounced anti-proliferation effects against C26 cells. Furthermore, LA67-PMs induced apoptosis and repressed migration more effectively than free LA67. In vivo evaluation of antitumor activity showed that LA67-PMs inhibited tumor growth and distant organ metastasis to a greater extent than LA67, which resulted in improved survival rate. The potential mechanisms of these effects may have been induction of apoptosis, inhibition of cell proliferation, and neovascularization.Conclusion: Our study showed that LA67-PMs may be a promising formulation for treatment of colon cancer.Keywords: triptolide derivatives, polymeric micelles, small size, tumor therapy