Key Laboratory of Functional Polymer Materials (Ministry of Education), College of Chemistry, Nankai University, Tianjin 300071, China.
Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China.
Eur J Pharm Biopharm. 2018 Jun;127:371-377. doi: 10.1016/j.ejpb.2018.02.035. Epub 2018 Feb 27.
Despite extensive investigations, the clinical translation of nanocarrier-based drug delivery systems (NDDS) for cancer therapy is hindered by inefficient delivery and poor tumor penetration. Conventional chemotherapy by administration of free small molecule anticancer drugs remains the standard of care for many cancers. Herein, other than for carrying and releasing drugs, small nanoparticles were used as a potentiator of conventional chemotherapy by co-administration with free chemotherapeutic agents. This strategy avoided the problems associated with drug loading and controlled release encountered in NDDS, and was also much simpler than NDDS. Negatively charged poly(amido amine)-2,3-dimethylmaleic monoamide (PAMAM-DMA) dendrimers were prepared, which possessed low toxicity and can be converted to positively charged PAMAM dendrimers responsive to tumor acidic pH. The in situ formed PAMAM in tumor tissue promoted cellular uptake of co-administered doxorubicin by increasing the cell membrane permeability, and subsequently enhanced the cytotoxicity of doxorubicin. The small size of the dendrimers was favorable for deep penetration in tumor. Co-injection of PAMAM-DMA with doxorubicin into nude mice bearing human tumors almost completely inhibited tumor growth, with a mean tumor weight reducing by 55.9% after the treatment compared with the treatment with doxorubicin alone.
尽管进行了广泛的研究，但基于纳米载体的药物输送系统（NDDS）在癌症治疗中的临床应用仍受到输送效率低和肿瘤穿透性差的阻碍。目前，许多癌症仍采用给予游离小分子抗癌药物的常规化疗作为标准治疗方法。在这里，除了携带和释放药物外，小纳米颗粒还被用作与游离化疗药物联合给药的常规化疗增强剂。该策略避免了 NDDS 中遇到的药物负载和控制释放问题，而且比 NDDS 简单得多。制备了带负电荷的聚（酰胺-胺）-2,3-二甲基马来酸单酰胺（PAMAM-DMA）树枝状大分子，其具有低毒性，并可转化为对肿瘤酸性 pH 有响应的带正电荷的 PAMAM 树枝状大分子。原位形成的 PAMAM 在肿瘤组织中促进了共给药阿霉素的细胞摄取，增加了细胞膜通透性，从而增强了阿霉素的细胞毒性。树枝状大分子的小尺寸有利于在肿瘤中深入渗透。将 PAMAM-DMA 与阿霉素共同注射到荷有人肿瘤的裸鼠中，几乎完全抑制了肿瘤生长，与单独使用阿霉素相比，治疗后肿瘤重量平均减少了 55.9%。
