State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Druggability of Biopharmaceuticals, Department of Pharmaceutics, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, China.
State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Druggability of Biopharmaceuticals, Department of Pharmaceutics, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, China.
Acta Biomater. 2018 Jul 15;75:398-412. doi: 10.1016/j.actbio.2018.05.050. Epub 2018 Jun 3.
Several obstacles are currently impeding the successful treatment of breast cancer, namely impaired drug accumulation into the tumor site, toxicity to normal cells and narrow therapeutic index of chemotherapy, multidrug resistance (MDR) and the metastatic spread of cancer cells through the blood and lymphatic vessels. In this regard, we designed a novel multifunctional nano-sized drug delivery system based on LyP-1 peptide-modified low-molecular-weight heparin-quercetin conjugate (PLQ). This nanosystem was developed for targeted co-delivery of multiple anticancer drugs to p32-overexpressing tumor cells and peritumoral lymphatic vessels, using LyP-1 peptide as active targeting ligand, with the aim to achieve a targeted combinatorial chemo/angiostatic therapy and MDR reversal. The cellular uptake of PLQ nanoparticles by p32-overexpressing breast cancer cells was significantly higher than nonfunctionalized nanoparticles. Besides, the anti-angiogenic activity of PLQ nanoparticles was proven by the effective inhibition of the bFGF-induced neovascularization in subcutaneous Matrigel plugs. More importantly, PLQ/GA nanoparticles with better targeting ability toward p32-positive tumors, displayed a high antitumor outcome by inhibition of tumor cells proliferation and angiogenesis. Immunohistochemistry and western blot assay showed that PLQ/GA nanoparticles significantly disrupted the lymphatic formation of tumor, and inhibited the P-glycoprotein (P-gp) expression in MCF-7 tumor cells, respectively. In conclusion, PLQ/GA nanoparticles provide a synergistic strategy for effective targeted co-delivery of chemotherapeutic and antiangiogenic agents and reversing MDR and metastasis in breast cancer.
Herein, we successfully developed a novel amphiphilic nanomaterial, LyP-1-LMWH-Qu (PLQ) conjugate, consisting of a tumor-targeting moiety LyP-1, a hydrophobic quercetin (a multidrug resistance [MDR]-reversing drug) inner core, and a hydrophilic low-molecular-weight heparin (an antiangiogenic agent) outer shell for encapsulating and delivering a hydrophobic chemotherapeutic agent (gambogic acid). This versatile nanoplatform with multiple targeted features, i.e., dual chemo/angiostatic effects, destruction ability of the peritumoral lymphatic vessels, and reversal of MDR, resulted in a significantly stronger antitumor efficacy and lower toxic side effect than those of nontargeted nanoparticles and the free drug solution. Therefore, this versatile nanosystem might provide a novel insight for the treatment and palliation of breast cancer by targeted co-delivery of chemo/antiangiogenic agents and reversing MDR and metastasis.
目前有几个障碍妨碍了乳腺癌的成功治疗，即药物在肿瘤部位的积累受到损害、对正常细胞的毒性以及化疗的治疗指数狭窄、多药耐药 (MDR) 和癌细胞通过血液和淋巴管的转移。在这方面，我们设计了一种基于 LyP-1 肽修饰的低分子量肝素-槲皮素缀合物 (PLQ) 的新型多功能纳米级药物递送系统。该纳米系统旨在通过 LyP-1 肽作为主动靶向配体，将多种抗癌药物靶向递送至 p32 过表达肿瘤细胞和肿瘤周围淋巴管，以实现靶向联合化疗/血管生成抑制和 MDR 逆转。PLQ 纳米颗粒被 p32 过表达的乳腺癌细胞摄取的细胞内摄取明显高于非功能化的纳米颗粒。此外，PLQ 纳米颗粒的抗血管生成活性通过有效抑制 bFGF 诱导的皮下 Matrigel 塞中的新血管生成得到证明。更重要的是，PLQ/GA 纳米颗粒对 p32 阳性肿瘤具有更好的靶向能力，通过抑制肿瘤细胞增殖和血管生成，表现出高抗肿瘤效果。免疫组织化学和 Western blot 分析表明，PLQ/GA 纳米颗粒显著破坏了肿瘤的淋巴管形成，并抑制了 MCF-7 肿瘤细胞中 P-糖蛋白 (P-gp) 的表达。总之，PLQ/GA 纳米颗粒为有效靶向共递化疗和抗血管生成药物以及逆转乳腺癌中的 MDR 和转移提供了协同策略。
在这里，我们成功开发了一种新型两亲性纳米材料，LyP-1-LMWH-Qu（PLQ）缀合物，由肿瘤靶向部分 LyP-1、疏水性槲皮素（一种多药耐药 [MDR]-逆转药物）内核和疏水性低分子量肝素（一种抗血管生成剂）外壳组成，用于封装和递送疏水性化疗药物（藤黄酸）。这种具有多种靶向特征的多功能纳米平台，即双重化疗/血管生成抑制作用、破坏肿瘤周围淋巴管的能力以及逆转 MDR，与非靶向纳米颗粒和游离药物溶液相比，显著增强了抗肿瘤疗效，降低了毒性副作用。因此，这种多功能纳米系统可能为通过靶向共递化疗/抗血管生成药物和逆转 MDR 和转移来治疗和缓解乳腺癌提供新的思路。
