Elechalawar Chandra Kumar, Bhattacharya Dwaipayan, Ahmed Mohammed Tanveer, Gora Halley, Sridharan Kathyayani, Chaturbedy Piyush, Sinha Sarmistha Halder, Chandra Sekhar Jaggarapu Madhan Mohan, Narayan Kumar Pranav, Chakravarty Sumana, Eswaramoorthy Muthusamy, Kundu Tapas Kumar, Banerjee Rajkumar
Applied Biology Division, CSIR-Indian Institute of Chemical Technology Hyderabad 500 007 India
Academy of Scientific & Innovative Research (AcSIR) Taramani Chennai 600113 India.
Nanoscale Adv. 2019 Jul 24;1(9):3555-3567. doi: 10.1039/c9na00056a. eCollection 2019 Sep 11.
Glioblastoma multiforme (GBM), the highly invasive form of glioma, exhibits the highest mortality in patients with brain malignancies. Increasing glioma patients' survivability is challenging, as targeting only tumor-associated malignant cells would not reduce the overall aggressiveness of the tumor mass. This is due to the inadequacy in countering pro-proliferative, invasive and metastatic factors released by tumor-mass associated macrophages (TAMs). Hence, strategically, dual targeting both tumor cells and TAMs is necessary for effective glioma treatment and increased survivability. Conventional FR-targeting systems can easily target cancer cells that overtly express folate receptors (FRs). However, FRs are expressed only moderately in both glioma cells and in TAMs. Hence, it is more challenging to coordinate dual targeting of glioma cells and TAMs with lower levels of FR expression. A recently developed carbon nanosphere (CSP) with effective blood-brain barrier (BBB) penetrability was modified with a new folic acid-cationic lipid conjugate (F8) as a targeting ligand. The uniqueness of the cationic lipid-folate conjugate is that it stably associates with the negatively charged CSP surface at about >22 mol% surface concentration, a concentration at least 5-fold higher than what is achieved for conventional FR-targeting delivery systems. This enabled dual uptake of the CSP on TAMs and tumor cells FRs. A doxorubicin-associated FR-targeting formulation (CFD), in an orthotopic glioma model and in a glioma subcutaneous model, induced the maximum anticancer effect with enhanced average mice survivability twice that of untreated mice and without any systemic liver toxicity. Additionally, we observed a significant decrease of TAM-released pro-aggressive factors, TGF-β, STAT3, invasion and migration related sICAM-1, and other cytokines indicating anti-TAM activity of the CFD. Taken together, we principally devised, to the best of our knowledge, the first FR-targeting nano-delivery system for targeting brain-associated TAMs and tumor cells as an efficient glioma therapeutic.
多形性胶质母细胞瘤（GBM）是胶质瘤的高度侵袭性形式，在脑恶性肿瘤患者中死亡率最高。提高胶质瘤患者的生存率具有挑战性，因为仅靶向肿瘤相关的恶性细胞并不能降低肿瘤块的整体侵袭性。这是由于在对抗肿瘤块相关巨噬细胞（TAM）释放的促增殖、侵袭和转移因子方面存在不足。因此，从战略上讲，双重靶向肿瘤细胞和TAM对于有效的胶质瘤治疗和提高生存率是必要的。传统的FR靶向系统可以轻松靶向过度表达叶酸受体（FR）的癌细胞。然而，FR在胶质瘤细胞和TAM中仅适度表达。因此，协调对FR表达水平较低的胶质瘤细胞和TAM的双重靶向更具挑战性。一种最近开发的具有有效血脑屏障（BBB）穿透性的碳纳米球（CSP）用一种新的叶酸-阳离子脂质偶联物（F8）作为靶向配体进行了修饰。阳离子脂质-叶酸偶联物的独特之处在于，它在表面浓度约>22 mol%时与带负电荷的CSP表面稳定结合，该浓度比传统FR靶向递送系统所达到的浓度至少高5倍。这使得CSP能够在TAM和肿瘤细胞FR上双重摄取。一种与阿霉素相关的FR靶向制剂（CFD），在原位胶质瘤模型和胶质瘤皮下模型中，诱导了最大的抗癌效果，平均小鼠生存率提高了两倍，高于未治疗的小鼠，且没有任何全身性肝毒性。此外，我们观察到TAM释放的促侵袭因子、转化生长因子-β、信号转导和转录激活因子3、与侵袭和迁移相关的可溶性细胞间黏附分子-1以及其他细胞因子显著减少，表明CFD具有抗TAM活性。综上所述，据我们所知，我们主要设计了第一种用于靶向脑相关TAM和肿瘤细胞的FR靶向纳米递送系统，作为一种有效的胶质瘤治疗方法。
