Oral pH-Sensitive Solid Self-Microemulsion of Norcantharidin Wrapped in Colon-Coated Capsule for Selective Therapy of Colorectal Carcinoma

IF 3.4 4区 医学 Q2 PHARMACOLOGY & PHARMACY
Xia Liu, Wenyou Fang, Wenjie Lu, Mingchao Xu, Zijun Wu, Dan Su, Lingzhen Ding, Qing Zhang, Jinguang Ouyang, Tianming Wang, Lingfeng Sun, Song Gao, Hui Cheng, Rongfeng Hu
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Abstract

Due to the poor solubility, permeability, stability and tumor-targeting ability of norcantharidin (NCTD), currently commercially available NCTD formulations require patients to take the medicine more frequently. Moreover, the formulation of NCTD themselves have certain toxicity, thus showing unsatisfactory therapeutic outcomes and serious systemic side effects. Based on the specific acidic environment at the tumor site, in this study, the pH-sensitive NCTD solid self-microemulsion (NCTD@CS-DMMA SSME) was prepared by introducing 2,3-dimethylmaleic acid amide modified chitosan (CS-DMMA), and it was wrapped in colon-coated capsule to achieve stable and controlled drug release in the acidic environment of colonic tumors. After self-emulsification, it had a particle size of 75.88 ± 0.85 nm and carried a negative charge. Under the condition of pH 6.5, NCTD@CS-DMMA SSME exhibited first-order release kinetics characteristics. Moreover, the cumulative release under the condition of pH 6.5 was 2.04-fold higher than that under the condition of pH 7.4. The in situ intestinal absorption assay elucidated that the prepared formulation could effectively improve the absorption rate constant and apparent permeability coefficients of NCTD in colon tumor site. The antitumor effect in vivo and in vitro showed that it could not only improve the inhibition ability of tumor growth, migration and invasion in mice, but also increase the tumor-infiltrating T lymphocytes in mice with colon cancer, thus inhibiting tumor growth. In summary, the NCTD@CS-DMMA SSME can deliver drugs to the site of colon tumors and continuously release drugs, providing new insights into improving the treatment effectiveness of colon cancer.

Graphical Abstract

去甲斑蝥素包覆结肠包衣胶囊口服ph敏感固体自微乳选择性治疗结直肠癌
由于去甲花青素(NCTD)的溶解度、渗透性、稳定性和肿瘤靶向性较差,目前市售的NCTD制剂需要患者更频繁地服药。而且,NCTD的制剂本身具有一定的毒性,治疗效果不理想,全身性副作用严重。基于肿瘤部位特定的酸性环境,本研究引入2,3-二甲基马来酸酰胺修饰壳聚糖(CS-DMMA)制备了ph敏感型NCTD固体自微乳(NCTD@CS-DMMA SSME),并将其包裹在结肠包衣胶囊中,在结肠肿瘤的酸性环境中实现药物的稳定、可控释放。自乳化后,其粒径为75.88±0.85 nm,带负电荷。在pH 6.5条件下,NCTD@CS-DMMA SSME呈现一级释放动力学特征。pH 6.5条件下的累积释放量是pH 7.4条件下的2.04倍。原位肠吸收实验表明,该制剂可有效提高NCTD在结肠肿瘤部位的吸收速率常数和表观通透系数。体内和体外抗肿瘤作用表明,它不仅能提高小鼠肿瘤生长、迁移和侵袭的抑制能力,还能增加结肠癌小鼠的肿瘤浸润T淋巴细胞,从而抑制肿瘤生长。综上所述,NCTD@CS-DMMA SSME可以将药物输送到结肠肿瘤部位并持续释放药物,为提高结肠癌的治疗效果提供了新的见解。图形抽象
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来源期刊
AAPS PharmSciTech
AAPS PharmSciTech 医学-药学
CiteScore
6.80
自引率
3.00%
发文量
264
审稿时长
2.4 months
期刊介绍: AAPS PharmSciTech is a peer-reviewed, online-only journal committed to serving those pharmaceutical scientists and engineers interested in the research, development, and evaluation of pharmaceutical dosage forms and delivery systems, including drugs derived from biotechnology and the manufacturing science pertaining to the commercialization of such dosage forms. Because of its electronic nature, AAPS PharmSciTech aspires to utilize evolving electronic technology to enable faster and diverse mechanisms of information delivery to its readership. Submission of uninvited expert reviews and research articles are welcomed.
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