School of Chinese Materia Medica, Guangzhou University of Chinese Medicine, Guangzhou 510006, China.
School of Pharmaceutical Sciences (Shenzhen), Sun Yat-sen University, Guangzhou 510275, China.
Mol Pharm. 2020 Sep 8;17(9):3328-3341. doi: 10.1021/acs.molpharmaceut.0c00421. Epub 2020 Aug 17.
Systemic chemotherapy for treating tumors often leads to serious systemic side effects and affects patient compliance. Although the emerging technology of drug delivery systems (DDSs) can deliver the required cargo to tumor sites, DDSs are limited due to insufficient targeting ability or deficient pharmacokinetics. Herein, we assembled a novel targeting DDS for precision tumor therapy by applying a tumor-targeting polypeptide cyclic RGD (cRGD)-modified erythrocyte membrane (eM-cRGD) cloaked on zeolitic imidazolate framework-8 (ZIF-8) nanoparticles (NPs) with encapsulated doxorubicin (DOX). For a mass ratio of ZIF-8:DOX = 1:1, the loading capacity was up to 49%. The nanoscale-sized targeting DDS promoted NP accumulation in tumor tissues via enhanced permeability and retention (EPR) effects, and the NPs actively targeted ligands and were then transferred to endosomes. The pH-sensitive carriers released higher DOX levels under the low pH mimicking that of a tumor microenvironment and tumor intracellular organelles, allowing enhanced inhibition of cancer cell growth. The cumulative release rate of DOX from DOX@ZIF-8 NPs reached 82.8% at 48 h in acidic conditions of pH = 5.0, while the cumulative release rate of DOX from the DOX@ZIF-8 NPs reached only 24.92% at pH = 7.4. The internalization of the DDS was approximately 44.35% that of the unmodified DDS by immune cells, as confirmed by flow cytometry. studies verified that the RGD-modified DDS had the ability to prolong blood circulation ( = 6.81 h), enhancing the tumor-specific accumulation of NPs by means of the integrin αvβ3 receptor-mediated pathway, which was further valuated in mice bearing human cervical cancer (HeLa) cells, and yielding a significant antitumor effect; the tumor inhibition rate was as high as 85.46%. Under the same conditions, the blood circulation half-life of the unmodified DDS was only 3.22 h, and the tumor inhibition rate of free DOX was 81.34%. Moreover, the RGD modified with a carrier could achieve a satisfactory chemotherapeutic effect while minimizing side effects. In summary, our novel targeting DDS could contribute to the development of intelligent DDSs for tumor precision therapy.
用于治疗肿瘤的全身化疗通常会导致严重的全身副作用，并影响患者的依从性。尽管新兴的药物传递系统（DDS）技术可以将所需的货物递送到肿瘤部位，但由于靶向能力不足或药代动力学缺陷，DDS 受到限制。在此，我们通过应用肿瘤靶向多肽环精氨酸-甘氨酸-天冬氨酸（cRGD）修饰的红细胞膜（eM-cRGD）包裹沸石咪唑酯骨架-8（ZIF-8）纳米粒子（NPs），构建了一种新型的靶向 DDS，用于精确肿瘤治疗，其中包裹阿霉素（DOX）。对于 ZIF-8:DOX 的质量比为 1:1，载药量高达 49%。纳米级靶向 DDS 通过增强的通透性和保留（EPR）效应促进 NP 在肿瘤组织中的积累，并且 NPs 主动靶向配体，然后被转移到内涵体。在模拟肿瘤微环境和肿瘤细胞内细胞器的低 pH 下，pH 敏感载体释放更高水平的 DOX，从而增强对癌细胞生长的抑制作用。在 pH = 5.0 的酸性条件下，DOX@ZIF-8 NPs 的 DOX 累积释放率在 48 h 时达到 82.8%，而在 pH = 7.4 时 DOX@ZIF-8 NPs 的 DOX 累积释放率仅为 24.92%。通过流式细胞术证实，免疫细胞内化 DDS 的量约为未修饰 DDS 的 44.35%。研究证实，RGD 修饰的 DDS 具有延长血液循环的能力（t1/2 = 6.81 h），通过整合素 αvβ3 受体介导的途径增强 NPs 的肿瘤特异性积累，在荷有人宫颈癌（HeLa）细胞的小鼠中进一步评估，产生了显著的抗肿瘤作用；肿瘤抑制率高达 85.46%。在相同条件下，未修饰 DDS 的血液循环半衰期仅为 3.22 h，游离 DOX 的肿瘤抑制率为 81.34%。此外，载体修饰的 RGD 可以实现令人满意的化疗效果，同时最大限度地减少副作用。总之，我们的新型靶向 DDS 可以为肿瘤精准治疗的智能 DDS 的发展做出贡献。
