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. In vivo studies verified that the RGD-modified DDS had the ability to prolong blood circulation (t_1/2 = 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.

中文翻译：

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配体修饰的红细胞膜包裹的金属有机骨架纳米粒子，用于靶向抗肿瘤治疗。

用于治疗肿瘤的全身化学疗法经常导致严重的全身性副作用并影响患者的依从性。尽管新兴的药物输送系统（DDS）技术可以将所需的货物输送到肿瘤部位，但由于靶向能力不足或药代动力学不足，DDS受到了限制。在这里，我们组装了一种新型的靶向DDS，用于精确的肿瘤治疗，方法是将靶向肿瘤的多肽环状RGD（cRGD）修饰的红细胞膜（eM-cRGD）掩盖在沸石咪唑酯骨架8（ZIF-8）纳米颗粒（NPs）上封装的阿霉素（DOX）。对于ZIF-8：DOX = 1：1的质量比，负载能力高达49％。纳米级靶向DDS通过增强的通透性和保留（EPR）效应促进了NP在肿瘤组织中的蓄积，NPs主动靶向配体，然后转移至内体。对pH敏感的载体在低pH下释放出更高的DOX水平，这与肿瘤微环境和肿瘤细胞内细胞器的水平相仿，从而增强了对癌细胞生长的抑制。在pH = 5.0的酸性条件下，在48小时内DOX @ ZIF-8 NP的DOX累积释放率达到82.8％，而在pH = 7.4的酸性条件下DOX从DOX @ ZIF-8 NP的DOX累积释放率仅达到24.92％。 。流式细胞术证实，免疫细胞对DDS的内在化作用约为未修饰DDS的内化作用的44.35％。在pH = 5.0的酸性条件下，在48小时内DOX @ ZIF-8 NP的DOX累积释放率达到82.8％，而在pH = 7.4的酸性条件下DOX从DOX @ ZIF-8 NP的DOX累积释放率仅达到24.92％。 。流式细胞术证实，免疫细胞对DDS的内在化作用约为未修饰DDS的内化作用的44.35％。在pH = 5.0的酸性条件下，在48小时内DOX @ ZIF-8 NP的DOX累积释放率达到82.8％，而在pH = 7.4的酸性条件下DOX从DOX @ ZIF-8 NP的DOX累积释放率仅达到24.92％。 。流式细胞术证实，免疫细胞对DDS的内在化作用约为未修饰DDS的内化作用的44.35％。体内研究证实，RGD修饰的DDS具有延长血液循环的能力（t _1/2 = 6.81 h），通过整联蛋白αvβ3受体介导的途径增强了肿瘤特异性NP的积累，对此进行了进一步评估在带有人宫颈癌（HeLa）细胞的小鼠中产生明显的抗肿瘤作用；抑瘤率高达85.46％。在相同条件下，未修饰的DDS的血液循环半衰期仅为3.22 h，游离DOX的抑瘤率为81.34％。而且，用载体修饰的RGD可以实现令人满意的化学治疗效果，同时使副作用最小化。总而言之，我们新颖的靶向DDS可能有助于开发用于肿瘤精密治疗的智能DDS。