Huang Xin, Zhou Hang, Jiao Rong, Liu Hanrui, Qin Changfu, Xu Lixin, Chen Yueyue
Beijing Key Laboratory of Environmental Toxicology, Department of Toxicology and Sanitary Chemistry, School of Public Health, Capital Medical University, Beijing 100069, PR China.
Department of Hernia and Abdominal Wall Surgery, Beijing Chao-Yang Hospital, Capital Medical University, Beijing 100043, PR China.
Langmuir. 2021 May 11;37(18):5475-5482. doi: 10.1021/acs.langmuir.0c03603. Epub 2021 Apr 29.
Supramolecular chemotherapy is a strategy that is currently used to improve the therapeutic efficacy of traditional chemotherapy while mitigating side effects. Heptaplatin, a platinum chemotherapeutic antitumor drug in colorectal tumors, is traditionally used in the clinic. However, its side effects and low efficiency in killing tumors remain unresolved. Herein, a facile supramolecular chemotherapy platform on account of the host-guest chemistry between cucurbit[7]uril and the commercially available heptaplatin was studied. At pH 7.4, heptaplatin showed a strong binding to the cucurbit[7]uril nanocarrier by H NMR, whose was (1.38 ± 0.06) × 10 M by isothermal titration calorimetry (ITC). At pH 6.0 in a tumor microenvironment, overexpressed spermine can exchange competitively heptaplatin from heptaplatin-CB[7]. This supramolecular complex achieved higher antitumor activity on colorectal tumor cells and lower cytotoxicity than the drug alone on colorectal normal cells. Furthermore, the antitumor mechanisms of supramolecular complex were investigated by apoptosis, cell cycle, and spermine synthase. It was found that heptaplatin-CB[7] consumed more colorectal tumorous intracellular spermine by the spermine synthase assay (413.85 ± 0.004 pg/mL); hepataplatin-CB[7] caused early apoptosis (87.73%) of colorectal tumor cells; heptaplatin-CB[7] induced an inhibitory response in the G phase of the tumor cell cycle. These findings demonstrated that heptaplatin-CB[7] had higher antitumor activity toward human colorectal tumor cells but lower cytotoxicity toward human colorectal normal cells. It is expected to promote the supramolecular chemotherapy and translational development of the nanocomplex into the clinical field.
超分子化疗是一种目前用于提高传统化疗疗效同时减轻副作用的策略。七铂是一种用于结直肠癌的铂类化疗抗肿瘤药物，传统上用于临床。然而，其副作用和杀瘤效率低的问题仍未得到解决。在此，基于葫芦[7]脲与市售七铂之间的主客体化学，研究了一种简便的超分子化疗平台。在pH 7.4时，通过核磁共振氢谱显示七铂与葫芦[7]脲纳米载体有强烈结合，通过等温滴定量热法（ITC）测得其结合常数为(1.38 ± 0.06) × 10 M。在肿瘤微环境的pH 6.0时，过表达的精胺可竞争性地将七铂从七铂 - 葫芦[7]脲中置换出来。这种超分子复合物对结直肠肿瘤细胞具有比单独药物更高的抗肿瘤活性，对结直肠正常细胞的细胞毒性更低。此外，通过凋亡、细胞周期和精胺合酶研究了超分子复合物的抗肿瘤机制。发现七铂 - 葫芦[7]脲通过精胺合酶测定消耗更多的结直肠肿瘤细胞内精胺（413.85 ± 0.004 pg/mL）；七铂 - 葫芦[7]脲导致结直肠肿瘤细胞早期凋亡（87.73%）；七铂 - 葫芦[7]脲在肿瘤细胞周期的G期诱导抑制反应。这些发现表明七铂 - 葫芦[7]脲对人结直肠肿瘤细胞具有更高的抗肿瘤活性，但对人结直肠正常细胞的细胞毒性更低。有望促进超分子化疗以及该纳米复合物向临床领域的转化发展。
