Wang Ting, Li Qianyao, Xu Rui, Zhao Zixuan, Sun Qi, Xu Xiaoding, Li Rong
The Second Affiliated Hospital, Department of Pharmacy, Hengyang Medical School, University of South China, Hengyang, China.
Guangzhou Key Laboratory of Medical Nanomaterials, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China.
Front Pharmacol. 2024 Jul 30;15:1437071. doi: 10.3389/fphar.2024.1437071. eCollection 2024.
Platinum-based chemotherapy has been widely used for clinical cancer treatment, but drug resistance is the main barrier to induce the poor prognosis of cancer patients. Long non-coding RNAs (lncRNAs) have been recognized as a type of new cancer therapeutic targets due to their important role in regulating cancer progression such as drug resistance. However, it is still challenged to effectively intervene the expression of lncRNAs as they are usually located at various subcellular organelles (, nucleus, mitochondrion, and endoplasmic reticulum). We herein developed an endosomal pH-responsive nanoparticle (NP) platform for small interfering RNA (siRNA) and cisplatin prodrug co-delivery and effective cisplatin-resistant hepatocellular carcinoma (HCC) therapy. This co-delivery nanoplatform is comprised of a hydrophilic polyethylene glycol (PEG) shell and a hydrophobic poly (2-(diisopropylamino)ethyl methacrylate) (PDPA) core, in which cisplatin prodrug and electrostatic complexes of nucleus-targeting amphiphilic peptide (NTPA) and siRNA are encapsulated. After intravenous injection and then uptake by tumor cells, the endosomal pH could trigger the dissociation of nanoplatform and enhance the endosomal escape of loaded cisplatin prodrug and NTPA/siRNA complexes via the "proton sponge" effect. Subsequently, the NTPA/siRNA complexes could specifically transport siRNA into the nucleus and efficiently reverse cisplatin resistance via silencing the expression of lncRNA metastasis-associated lung adenocarcinoma transcript 1 (lncMALAT1) mainly localized in the nucleus, ultimately inhibiting the growth of cisplatin-resistant HCC tumor.
铂类化疗已广泛应用于临床癌症治疗，但耐药性是导致癌症患者预后不良的主要障碍。长链非编码RNA（lncRNA）因其在调节癌症进展（如耐药性）中的重要作用而被视为一类新的癌症治疗靶点。然而，由于lncRNA通常位于各种亚细胞器（细胞核、线粒体和内质网）中，有效干预其表达仍然具有挑战性。我们在此开发了一种内体pH响应纳米颗粒（NP）平台，用于小干扰RNA（siRNA）和顺铂前药的共递送以及有效的顺铂耐药肝细胞癌（HCC）治疗。这种共递送纳米平台由亲水性聚乙二醇（PEG）外壳和疏水性聚（甲基丙烯酸2-（二异丙基氨基）乙酯）（PDPA）核心组成，其中包裹了顺铂前药以及核靶向两亲性肽（NTPA）与siRNA的静电复合物。静脉注射后，肿瘤细胞摄取纳米平台，内体pH可触发纳米平台解离，并通过“质子海绵”效应增强负载的顺铂前药和NTPA/siRNA复合物的内体逃逸。随后，NTPA/siRNA复合物可将siRNA特异性转运至细胞核，并通过沉默主要定位于细胞核的lncRNA转移相关肺腺癌转录本1（lncMALAT1）的表达有效逆转顺铂耐药性，最终抑制顺铂耐药HCC肿瘤的生长。
