Ulcerative colitis(UC)is a type of inflammatory bowel disease characterized by inflammation,ulcers and irritation of the mucosal lining.Oral drug delivery in UC encounters challenges because of multifaceted barriers.D...Ulcerative colitis(UC)is a type of inflammatory bowel disease characterized by inflammation,ulcers and irritation of the mucosal lining.Oral drug delivery in UC encounters challenges because of multifaceted barriers.Dexamethasone-loaded galactosylated-PLGA/Eudragit S100/pullulan nanocargoes(Dexa-GP/ES/Pu NCs)have been developed with a dual stimuli-sensitive coating responsive to both colonic pH and microbiota,and an underneath galactosylated-PLGA core(GP).The galactose ligand of the GP preferentially binds to the macrophage galactose type-lectin-C(MGL-2)surface receptor.Therefore,both stimuli and ligand-mediated targeting facilitate nanocargoes to deliver Dexa specifically to the colon with enhanced macrophage uptake.Modified emulsion method coupled with a solvent evaporation coating technique was employed to prepare Dexa-GP/ES/Pu NCs.The nanocargoes were tested using in vitro,ex vivo techniques and dextran sodium sulfate(DSS)induced UC model.Prepared nanocargoes had desired physicochemical properties,drug release,cell uptake and cellular viability.Investigations using a DSS-colitis model showed high localization and mitigation of colitis with downregulation of NF-ĸB and COX-2,and restoration of clinical,histopathological,biochemical indices,antioxidant balance,microbial alterations,FTIR spectra,and epithelial junctions’integrity.Thus,Dexa-GP/ES/Pu NCs found to be biocompatible nanocargoes capable of delivering drugs to the inflamed colon with unique targeting properties for prolonged duration.展开更多
Galactosylated chitosan (GC) is synthesized and used to prepare IL-1Ra loaded GC nanoparticles by an electrospraying technique. Polyethylene oxide (PEO) is mixed with GC to enhance the electrospraying ability. The...Galactosylated chitosan (GC) is synthesized and used to prepare IL-1Ra loaded GC nanoparticles by an electrospraying technique. Polyethylene oxide (PEO) is mixed with GC to enhance the electrospraying ability. The effect of the spraying solution properties on particle formation is investigated. The IL-1Ra loaded nanoparticles with an average diameter of 530 nm and a regularly spherical shape are observed by the scanning electron microscopy (SEM). The amount of the IL-1Ra is measured by the enzyme-linked immunosorbent assay (ELISA) kit. The loading capacity of the nanoparticle is (1.52± 0.04)% (n = 3) and the encapsulation efficiency reaches (90. 36 ± 3.46) % (n = 3). For the evaluation of GC nanoparticles' hepatocytes targeting efficacy, hepatocytes and mesenchymal stem cells (MSCs) are incubated with FITC-labeled GC nanoparticles for 24 h as the experimental and control groups. Results of the fluorescence microscope show that the fluorescence signals observed in hepatocytes are significantly higher than in the MSCs, indicating that the developed GC nanoparticles have an obvious liver targeting property.展开更多
AIM: To observe the curative effect of galactosylated chitosan (GC)/5-fluorouracil (5-FU) nanoparticles in liver caner mice and its side effects. METHODS: The GC/5-FU nanoparticle is a nanomate- rial made by cou...AIM: To observe the curative effect of galactosylated chitosan (GC)/5-fluorouracil (5-FU) nanoparticles in liver caner mice and its side effects. METHODS: The GC/5-FU nanoparticle is a nanomate- rial made by coupling GC and 5-FU. The release experiment was performed in vitro. The orthotropic liver cancer mouse models were established and divided into control, GC, 5-FU and GC/5-FU groups. Mice in the control and GC group received an intravenous injection of 200 μL saline and GC, respectively. Mice in the 5-FU and GC/5-FU groups received 200 μL (containing 0.371 mg 5-FU) 5-FU and GC/5-FU, respectively. The tumor weight and survival time were observed. The cell cycle and apoptosis in tumor tissues were monitored by flow cytometry. The expression of p53, Bax, Bcl-2, caspase-3 and poly adenosine 50-diphosphate-ribose polymerase 1 (PARP-1) was detected by immunohistochemistry, reverse transcription-polymerase chain reaction and Western blot. The serum blood biochemical parameters and cytotoxic activity of natural killer (NK) cell and cy- totoxicity T lymphocyte (CTL) were measured. RESULTS: The GC/5-FU nanoparticle is a sustained release system. The drug loading was 6.12% ± 1.36%, the encapsulation efficiency was 81.82% ± 5.32%, and the Zeta potential was 10.34 ± 1.43 mV. The tu- mor weight in the GC/5-FU group (0.4361±0.1153 g vs 1.5801 ± 0.2821 g, P 〈 0.001) and the 5-FU (0.7932±0.1283 g vs 1.5801 ±0.2821 g, P 〈 0.001) was sig- nificantly lower than that in the control group; GC/5- FU treatment can significantly lower the tumor weight (0.4361± 0.1153 g vs 0.7932±0.1283 g, P 〈 0.001), and the longest median survival time was seen in the GC/5-FU group, compared with the control (12 d vs 30 d, P 〈 0.001), GC (13 d vs 30 d, P 〈 0.001) and 5-FU groups (17 d vs 30 d, P 〈 0.001). Flow cytom- etry revealed that compared with the control, GC/5- FU caused a higher rate of G0-G1 arrest (52.79% ± 13.42% vs 23.92%±9.09%, P = 0.014 ) and apopto- sis (2.55% ±1.10% vs 11.13% ±11.73%, P 〈 0.001) in hepatic cancer cells. Analysis of the apoptosis path- ways showed that GC/5-FU upregulated the expression of p53 at both the protein and the mRNA levels, which in turn lowered the ratio of Bcl-2lBax expression; this led to the release of cytochrome C into the cytosol from the mitochondria and the subsequent activation of caspase-3. Upregulation of caspase-3 expression de- creased the PARP-1 at both the mRNA and the protein levels, which contributed to apoptosis. 5-FU increased the levels of aspartate aminotransferase and alanine aminotransferase, and decreased the numbers of platelet, white blood cell and lymphocyte and cytotoxic activities of CTL and NK cells, however, there were no such side effects in the GC/5-FU group. CONCLUSION: GC/5-FU nanoparticles can significant- ly inhibit the growth of liver cancer in mice via the p53 apoptosis pathway, and relieve the side effects and im- munosuppression of 5-FU.展开更多
A novel galactosylated cholesterol with mono-galactoside moiety, (5-cholesten-3-yl)-4-oxo-4-[2-(lactobionylamido)ethylamido]butanoate 6 was synthesized. Its chemical structure was characterized by IR, ESI-MS, ^13C...A novel galactosylated cholesterol with mono-galactoside moiety, (5-cholesten-3-yl)-4-oxo-4-[2-(lactobionylamido)ethylamido]butanoate 6 was synthesized. Its chemical structure was characterized by IR, ESI-MS, ^13C NMR, ^1H NMR. Doxorubicin entrapped in the liposomes containing 10% mol/mol 6 was rapidly accumulated in liver and mainly uptake by parenchymal cells in mice.展开更多
AIM: To evaluate the usefulness of the functional hepatic resection rate (FHRR) calculated using 3D computed tomography (CT)/<sup>99m</sup>Tc-galactosyl-human serum albumin (GSA) single-photon emission com...AIM: To evaluate the usefulness of the functional hepatic resection rate (FHRR) calculated using 3D computed tomography (CT)/<sup>99m</sup>Tc-galactosyl-human serum albumin (GSA) single-photon emission computed tomography (SPECT) fusion imaging for surgical decision making.METHODS: We enrolled 57 patients who underwent bi- or trisectionectomy at our institution between October 2013 and March 2015. Of these, 26 patients presented with hepatocellular carcinoma, 12 with hilar cholangiocarcinoma, six with intrahepatic cholangiocarcinoma, four with liver metastasis, and nine with other diseases. All patients preoperatively underwent three-phase dynamic multidetector CT and <sup>99m</sup>Tc-GSA scintigraphy. We compared the parenchymal hepatic resection rate (PHRR) with the FHRR, which was defined as the resection volume counts per total liver volume counts on 3D CT/<sup>99m</sup>Tc-GSA SPECT fusion images.RESULTS: In total, 50 patients underwent bisectionectomy and seven underwent trisectionectomy. Biliary reconstruction was performed in 15 patients, including hepatopancreatoduodenectomy in two. FHRR and PHRR were 38.6 ± 19.9 and 44.5 ± 16.0, respectively; FHRR was strongly correlated with PHRR. The regression coefficient for FHRR on PHRR was 1.16 (P < 0.0001). The ratio of FHRR to PHRR for patients with preoperative therapies (transcatheter arterial chemoembolization, radiation, radiofrequency ablation, etc.), large tumors with a volume of > 1000 mL, and/or macroscopic vascular invasion was significantly smaller than that for patients without these factors (0.73 ± 0.19 vs 0.82 ± 0.18, P < 0.05). Postoperative hyperbilirubinemia was observed in six patients. Major morbidities (Clavien-Dindo grade ≥ 3) occurred in 17 patients (29.8%). There was no case of surgery-related death.CONCLUSION: Our results suggest that FHRR is an important deciding factor for major hepatectomy, because FHRR and PHRR may be discrepant owing to insufficient hepatic inflow and congestion in patients with preoperative therapies, macroscopic vascular invasion, and/or a tumor volume of > 1000 mL.展开更多
基金the Higher Education Commission of Pakistan for the provision of HEC Indigenous scholarship (PIN No. 315-12214-2BS3-132) for the research workthe provision of grant under HEC NRPU project No. 9272/Federal/NRPU/R&D/HEC/2017
文摘Ulcerative colitis(UC)is a type of inflammatory bowel disease characterized by inflammation,ulcers and irritation of the mucosal lining.Oral drug delivery in UC encounters challenges because of multifaceted barriers.Dexamethasone-loaded galactosylated-PLGA/Eudragit S100/pullulan nanocargoes(Dexa-GP/ES/Pu NCs)have been developed with a dual stimuli-sensitive coating responsive to both colonic pH and microbiota,and an underneath galactosylated-PLGA core(GP).The galactose ligand of the GP preferentially binds to the macrophage galactose type-lectin-C(MGL-2)surface receptor.Therefore,both stimuli and ligand-mediated targeting facilitate nanocargoes to deliver Dexa specifically to the colon with enhanced macrophage uptake.Modified emulsion method coupled with a solvent evaporation coating technique was employed to prepare Dexa-GP/ES/Pu NCs.The nanocargoes were tested using in vitro,ex vivo techniques and dextran sodium sulfate(DSS)induced UC model.Prepared nanocargoes had desired physicochemical properties,drug release,cell uptake and cellular viability.Investigations using a DSS-colitis model showed high localization and mitigation of colitis with downregulation of NF-ĸB and COX-2,and restoration of clinical,histopathological,biochemical indices,antioxidant balance,microbial alterations,FTIR spectra,and epithelial junctions’integrity.Thus,Dexa-GP/ES/Pu NCs found to be biocompatible nanocargoes capable of delivering drugs to the inflamed colon with unique targeting properties for prolonged duration.
基金The National Natural Science Foundation of China(No.30901431)the Natural Science Foundation of Jiangsu Province(No.BK2010242)
文摘Galactosylated chitosan (GC) is synthesized and used to prepare IL-1Ra loaded GC nanoparticles by an electrospraying technique. Polyethylene oxide (PEO) is mixed with GC to enhance the electrospraying ability. The effect of the spraying solution properties on particle formation is investigated. The IL-1Ra loaded nanoparticles with an average diameter of 530 nm and a regularly spherical shape are observed by the scanning electron microscopy (SEM). The amount of the IL-1Ra is measured by the enzyme-linked immunosorbent assay (ELISA) kit. The loading capacity of the nanoparticle is (1.52± 0.04)% (n = 3) and the encapsulation efficiency reaches (90. 36 ± 3.46) % (n = 3). For the evaluation of GC nanoparticles' hepatocytes targeting efficacy, hepatocytes and mesenchymal stem cells (MSCs) are incubated with FITC-labeled GC nanoparticles for 24 h as the experimental and control groups. Results of the fluorescence microscope show that the fluorescence signals observed in hepatocytes are significantly higher than in the MSCs, indicating that the developed GC nanoparticles have an obvious liver targeting property.
基金Supported by Natural Science Foundation of Shanghai,No.09ZR1424700 and 114119a4700Minhang District Natural Science Foundation of Shanghai,No. 2009MHZ085grants from Minhang District Public Health Bureau of Shanghai,No.2009MW28
文摘AIM: To observe the curative effect of galactosylated chitosan (GC)/5-fluorouracil (5-FU) nanoparticles in liver caner mice and its side effects. METHODS: The GC/5-FU nanoparticle is a nanomate- rial made by coupling GC and 5-FU. The release experiment was performed in vitro. The orthotropic liver cancer mouse models were established and divided into control, GC, 5-FU and GC/5-FU groups. Mice in the control and GC group received an intravenous injection of 200 μL saline and GC, respectively. Mice in the 5-FU and GC/5-FU groups received 200 μL (containing 0.371 mg 5-FU) 5-FU and GC/5-FU, respectively. The tumor weight and survival time were observed. The cell cycle and apoptosis in tumor tissues were monitored by flow cytometry. The expression of p53, Bax, Bcl-2, caspase-3 and poly adenosine 50-diphosphate-ribose polymerase 1 (PARP-1) was detected by immunohistochemistry, reverse transcription-polymerase chain reaction and Western blot. The serum blood biochemical parameters and cytotoxic activity of natural killer (NK) cell and cy- totoxicity T lymphocyte (CTL) were measured. RESULTS: The GC/5-FU nanoparticle is a sustained release system. The drug loading was 6.12% ± 1.36%, the encapsulation efficiency was 81.82% ± 5.32%, and the Zeta potential was 10.34 ± 1.43 mV. The tu- mor weight in the GC/5-FU group (0.4361±0.1153 g vs 1.5801 ± 0.2821 g, P 〈 0.001) and the 5-FU (0.7932±0.1283 g vs 1.5801 ±0.2821 g, P 〈 0.001) was sig- nificantly lower than that in the control group; GC/5- FU treatment can significantly lower the tumor weight (0.4361± 0.1153 g vs 0.7932±0.1283 g, P 〈 0.001), and the longest median survival time was seen in the GC/5-FU group, compared with the control (12 d vs 30 d, P 〈 0.001), GC (13 d vs 30 d, P 〈 0.001) and 5-FU groups (17 d vs 30 d, P 〈 0.001). Flow cytom- etry revealed that compared with the control, GC/5- FU caused a higher rate of G0-G1 arrest (52.79% ± 13.42% vs 23.92%±9.09%, P = 0.014 ) and apopto- sis (2.55% ±1.10% vs 11.13% ±11.73%, P 〈 0.001) in hepatic cancer cells. Analysis of the apoptosis path- ways showed that GC/5-FU upregulated the expression of p53 at both the protein and the mRNA levels, which in turn lowered the ratio of Bcl-2lBax expression; this led to the release of cytochrome C into the cytosol from the mitochondria and the subsequent activation of caspase-3. Upregulation of caspase-3 expression de- creased the PARP-1 at both the mRNA and the protein levels, which contributed to apoptosis. 5-FU increased the levels of aspartate aminotransferase and alanine aminotransferase, and decreased the numbers of platelet, white blood cell and lymphocyte and cytotoxic activities of CTL and NK cells, however, there were no such side effects in the GC/5-FU group. CONCLUSION: GC/5-FU nanoparticles can significant- ly inhibit the growth of liver cancer in mice via the p53 apoptosis pathway, and relieve the side effects and im- munosuppression of 5-FU.
文摘A novel galactosylated cholesterol with mono-galactoside moiety, (5-cholesten-3-yl)-4-oxo-4-[2-(lactobionylamido)ethylamido]butanoate 6 was synthesized. Its chemical structure was characterized by IR, ESI-MS, ^13C NMR, ^1H NMR. Doxorubicin entrapped in the liposomes containing 10% mol/mol 6 was rapidly accumulated in liver and mainly uptake by parenchymal cells in mice.
文摘AIM: To evaluate the usefulness of the functional hepatic resection rate (FHRR) calculated using 3D computed tomography (CT)/<sup>99m</sup>Tc-galactosyl-human serum albumin (GSA) single-photon emission computed tomography (SPECT) fusion imaging for surgical decision making.METHODS: We enrolled 57 patients who underwent bi- or trisectionectomy at our institution between October 2013 and March 2015. Of these, 26 patients presented with hepatocellular carcinoma, 12 with hilar cholangiocarcinoma, six with intrahepatic cholangiocarcinoma, four with liver metastasis, and nine with other diseases. All patients preoperatively underwent three-phase dynamic multidetector CT and <sup>99m</sup>Tc-GSA scintigraphy. We compared the parenchymal hepatic resection rate (PHRR) with the FHRR, which was defined as the resection volume counts per total liver volume counts on 3D CT/<sup>99m</sup>Tc-GSA SPECT fusion images.RESULTS: In total, 50 patients underwent bisectionectomy and seven underwent trisectionectomy. Biliary reconstruction was performed in 15 patients, including hepatopancreatoduodenectomy in two. FHRR and PHRR were 38.6 ± 19.9 and 44.5 ± 16.0, respectively; FHRR was strongly correlated with PHRR. The regression coefficient for FHRR on PHRR was 1.16 (P < 0.0001). The ratio of FHRR to PHRR for patients with preoperative therapies (transcatheter arterial chemoembolization, radiation, radiofrequency ablation, etc.), large tumors with a volume of > 1000 mL, and/or macroscopic vascular invasion was significantly smaller than that for patients without these factors (0.73 ± 0.19 vs 0.82 ± 0.18, P < 0.05). Postoperative hyperbilirubinemia was observed in six patients. Major morbidities (Clavien-Dindo grade ≥ 3) occurred in 17 patients (29.8%). There was no case of surgery-related death.CONCLUSION: Our results suggest that FHRR is an important deciding factor for major hepatectomy, because FHRR and PHRR may be discrepant owing to insufficient hepatic inflow and congestion in patients with preoperative therapies, macroscopic vascular invasion, and/or a tumor volume of > 1000 mL.