School of Chemistry and Chemical Engineering, Shanghai Jiao Tong University, Shanghai 200240, China.
Institute of Molecular Medicine, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200217, China.
ACS Appl Mater Interfaces. 2024 Nov 6;16(44):59765-59776. doi: 10.1021/acsami.4c11064. Epub 2024 Oct 24.
The development and progression of tumors are characterized by intricate biological processes. Monotherapy not only struggles to achieve effective treatment but also tends to precipitate a series of issues, including multidrug resistance and limited antitumor effect. Consequently, it is imperative to adopt a synergistic multitherapy approach to enhance the efficacy of tumor treatment. The integration of chemotherapy drug with oligonucleotide drug for combinational treatment has shown significant promise in improving tumor therapeutic efficiency. However, the effective codelivery of oligonucleotide drugs and chemotherapy drugs faces substantial challenges such as poor stability of oligonucleotide drugs during the circulation time, limited tumor accumulation, and uncertain delivery ratios of different payloads. To overcome these obstacles, we have engineered cyclic Arg-Gly-Asp (cRGD)-modified red blood cell membrane (RBCm)-coated multidrug nanocomplexes, which were self-assembled from the Polo-like kinase 1 siRNA (siPlk1) and an irreversible tyrosine kinase inhibitor neratinib targeted to human epidermal growth factor receptor 2 (HER2) overexpressed in breast cancer. Through electrostatic and amphiphilic interactions between the positively charged neratinib and negatively charged siPlk1, we have successfully fabricated uniform multidrug nanoparticles. The cRGD-modified red blood cell membranes coated on the surface of the multidrug nanoparticles could enhance drug stability in circulation and tumor accumulation. This targeted combinational therapy significantly enhanced the antitumor efficiency in HER2-positive breast cancer and .
肿瘤的发生发展具有复杂的生物学过程。单一疗法不仅难以达到有效的治疗效果，而且容易引发一系列问题，包括多药耐药性和有限的抗肿瘤作用。因此，采用协同的多疗法来提高肿瘤治疗效果是势在必行的。将化疗药物与寡核苷酸药物结合进行联合治疗已显示出在提高肿瘤治疗效率方面的显著前景。然而，寡核苷酸药物和化疗药物的有效共递药面临许多挑战，例如寡核苷酸药物在循环时间内的稳定性差、肿瘤积累有限以及不同有效载荷的递药比例不确定。为了克服这些障碍，我们设计了环状精氨酸-甘氨酸-天冬氨酸（cRGD）修饰的红细胞膜（RBCm）包被的多药纳米复合物，该复合物由 Polo 样激酶 1 的 siRNA（siPlk1）和针对表皮生长因子受体 2（HER2）的不可逆酪氨酸激酶抑制剂奈拉替尼自组装而成，HER2 在乳腺癌中过表达。通过带正电荷的奈拉替尼和带负电荷的 siPlk1 之间的静电和两亲相互作用，我们成功地制备了均匀的多药纳米颗粒。多药纳米颗粒表面包覆的 cRGD 修饰的红细胞膜可以提高药物在循环中的稳定性和肿瘤积累。这种靶向联合治疗显著提高了 HER2 阳性乳腺癌的抗肿瘤效率。
