Ganguly Kuntal, Kulkarni Anandrao R, Aminabhavi Tejraj M
a Department of Pharmacology , Soniya Education Trust's College of Pharmacy , Dharwad , Karnataka , India and.
b Department of Pharmaceutics , All India Council for Technical Education , New Delhi , India.
Drug Deliv. 2016 Oct;23(8):2838-2851. doi: 10.3109/10717544.2015.1105324. Epub 2015 Nov 4.
Microspheres of chitosan (CS) cross-linked with polyethylene glycol (PEG) were prepared by emulsion-cross-linking followed by the solvent evaporation technique. The formulations were characterized and subjected to in vitro and in vivo tests to assess cell growth, changes in cell morphology, and activities by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay on human HT-29 colon cancer cell-lines.
In vivo activity was evaluated for dimethyl hydrazine-induced colorectal cancer in albino male Wistar rats. Biochemical and histological parameters were evaluated to understand their effectiveness for colon cancer therapy.
The 5-FU immediate release (IR) formulations suspended in SCMC produced an immediate cytotoxic effect, whereas microspheres inhibited proliferation of tumor cells to induce apoptosis over an extended time. Minimum inhibitory concentration (IC) values for both standard plain 5-FU and 5-FU-loaded microspheres were respectively 5.00 ± 0.004 µg/mL and 165 ± 1.9 µg/mL which showed the improved safety profile of the microsphere formulation. Tissue distribution showed high concentration of 5-FU in colon that was higher than IC value required to stop the growth or death of colon cancer cells from the colonic dysplasia in Duke's stage A. Significant reduction in tumor volume and multiplicity was observed with increased levels of liver enzymes in animals when treated with standard 5-FU formulation compared with 5-FU loaded microspheres. Elevated levels of serum albumin, creatinine, leukocytopenia, and thrombocytopenia were observed in animals for the standard 5-FU formulation.
The PEG cross-linked CS microspheres of this study slowly released 5-FU up to 24 h to colonic region and enhanced the antitumor activity.
采用乳化交联结合溶剂蒸发技术制备壳聚糖（CS）与聚乙二醇（PEG）交联的微球。对这些制剂进行表征，并进行体外和体内试验，以通过3-(4,5-二甲基噻唑-2-基)-2,5-二苯基四氮唑溴盐（MTT）法评估人HT-29结肠癌细胞系的细胞生长、细胞形态变化及活性。
评估对白化雄性Wistar大鼠二甲肼诱导的结直肠癌的体内活性。评估生化和组织学参数以了解其对结肠癌治疗的有效性。
悬浮于SCMC中的5-氟尿嘧啶速释（IR）制剂产生即刻细胞毒性作用，而微球在较长时间内抑制肿瘤细胞增殖以诱导凋亡。标准普通5-氟尿嘧啶和载5-氟尿嘧啶微球的最低抑菌浓度（IC）值分别为5.00±0.004μg/mL和165±1.9μg/mL，这表明微球制剂的安全性有所提高。组织分布显示结肠中5-氟尿嘧啶浓度较高，高于杜克A期结肠发育异常中阻止结肠癌细胞生长或死亡所需的IC值。与载5-氟尿嘧啶微球相比，用标准5-氟尿嘧啶制剂治疗的动物肝脏酶水平升高，肿瘤体积和数量显著减少。标准5-氟尿嘧啶制剂治疗的动物血清白蛋白、肌酐水平升高，出现白细胞减少和血小板减少。
本研究的PEG交联CS微球在长达24小时内向结肠区域缓慢释放5-氟尿嘧啶，并增强了抗肿瘤活性。
