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

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.

Materials

NCTD (purity ≥ 98%) was obtained from Meilun Biotech-nology Co., Ltd. (Dalian, China). Triethylamine, Ethyl oleate and 1,2-Propylene glycol were purchased from Maclean’s Chemical Reagent Co., Ltd. (Shanghai, China). Polyoxy-ethylene hydrogenated castor oil was obtained from Jiangsu Haian Petrochemical Co., Ltd (Jiangsu, China). Chitosan was provided by Bomei Biotechnology Company (Anhui, China). 2,3-Dimethylmaleic anhydride was purchased by Dipper Biotechnology (Shanghai, China). Micro powder silica gel were gifts from Shanhe Pharmaceutical Excipients Co., Ltd. (Anhui, China). Ganoderma lucidum spore oil is a gift from Anhui Jinzhai Qiaokang Pharmaceutical Co., Ltd. (Anhui, China). Norcantharidin tablets were purchased from JinbuhuanLankao Pharmaceutical Co., Ltd. (Shang-hai, China). HT29 and CT-26 luc cells were purchased from Chinese national collection of authenticated cell cultures (Shanghai, China). McCoy’s 5A medium and Fetal bovine serum were purchased from HyClone Biologicals (USA). Trypsin Digest (0.25%) and thiazole blue solution were pur-chased from Biyuntian Biotechnology Co., Ltd. (Shanghai, China).

Liu, X., Fang, W., Lu, W. et al. Oral pH-Sensitive Solid Self-Microemulsion of Norcantharidin Wrapped in Colon-Coated Capsule for Selective Therapy of Colorectal Carcinoma. AAPS PharmSciTech 26, 67 (2025). https://doi.org/10.1208/s12249-025-03056-0