Chauhan Mahima, Shekhar Saurabh, Yadav Bhavna, Garg Vandana, Dutt Rohit, Mehata Abhishesh Kumar, Goswami Pooja, Koch Biplob, Muthu Madaswamy S, Singh Rahul Pratap
Department of Pharmacy, School of Medical and Allied Sciences, GD Goenka University, Gurugram 122103, India.
Guru Teg Bahadur Hospital, GTB Enclave, Dilshad Garden, New Delhi, Delhi 110095, India.
Biomater Adv. 2024 Jun;160:213833. doi: 10.1016/j.bioadv.2024.213833. Epub 2024 Mar 20.
Conventional chemotherapy and poor targeted delivery in brain cancer resulting to poor treatment and develop resistance to anticancer drugs. Meanwhile, it is quite challenging to diagnose/detection of brain tumor at early stage of cancer which resulting in severity of the disease. Despite extensive research, effective treatment with real-time imaging still remains completely unavailable, yet. In this study, two brain cancer cell specific moieties i.e., AS1411 aptamer and RGD are decorated on the surface of chitosan-PLGA nanoparticles to improve targeted co-delivery of docetaxel (DTX) and upconversion nanoparticles (UCNP) for effective brain tumor therapy and real-time imaging. The nanoparticles were developed by a slightly modified emulsion/solvent evaporation method. This investigation also translates the successful synthesis of TPGS-chitosan, TPGS-RGD and TPGS-AS1411 aptamer conjugates for making PLGA nanoparticle as a potential tool of the targeted co-delivery of DTX and UCNP to the brain cancer cells. The developed nanoparticles have shown an average particle size <200 nm, spherical in shape, high encapsulation of DTX and UCNP in the core of nanoparticles, and sustained release of DTX up to 72 h in phosphate buffer saline (pH 7.4). AS1411 aptamer and RGD functionalized theranostic chitosan-PLGA nanoparticles containing DTX and UCNP (DUCPN-RGD-AS1411) have achieved greater cellular uptake, 89-fold improved cytotoxicity, enhanced cancer cell arrest even at lower drug conc., improved bioavailability with higher mean residence time of DTX in systemic circulation and brain tissues. Moreover, DUCPN-RGD-AS1411 have greatly facilitated cellular internalization and higher accumulation of UCNP in brain tissues. Additionally, DUCPN-RGD-AS1411 demonstrated a significant suppression in tumor growth in brain-tumor bearing xenograft BALB/c nude mice with no impressive sign of toxicities. DUCPN-RGD-AS1411 has great potential to be utilized as an effective and safe theranostic tool for brain cancer and other life-threatening cancer therapies.
传统化疗以及脑癌中靶向递送不佳导致治疗效果差且产生抗癌药物耐药性。同时，在癌症早期诊断/检测脑肿瘤颇具挑战性，这导致疾病严重程度增加。尽管进行了广泛研究，但实时成像的有效治疗方法目前仍然完全无法实现。在本研究中，壳聚糖 - 聚乳酸 - 羟基乙酸共聚物（PLGA）纳米颗粒表面修饰了两种脑癌细胞特异性部分，即AS1411适配体和RGD，以改善多西他赛（DTX）和上转换纳米颗粒（UCNP）的靶向共递送，用于有效的脑肿瘤治疗和实时成像。纳米颗粒通过略微改良的乳液/溶剂蒸发法制备。本研究还成功合成了TPGS - 壳聚糖、TPGS - RGD和TPGS - AS1411适配体缀合物，以使PLGA纳米颗粒成为将DTX和UCNP靶向共递送至脑癌细胞的潜在工具。所制备的纳米颗粒平均粒径<200 nm，呈球形，DTX和UCNP在纳米颗粒核心中的包封率高，并且在磷酸盐缓冲盐水（pH 7.4）中DTX可持续释放长达72小时。含有DTX和UCNP的AS1411适配体和RGD功能化的治疗诊断用壳聚糖 - PLGA纳米颗粒（DUCPN - RGD - AS1411）实现了更高的细胞摄取、细胞毒性提高89倍、即使在较低药物浓度下也能增强癌细胞停滞、改善生物利用度以及DTX在体循环和脑组织中的平均驻留时间更长。此外，DUCPN - RGD - AS1411极大地促进了细胞内化以及UCNP在脑组织中的更高积累。此外，DUCPN - RGD - AS1411在携带脑肿瘤的异种移植BALB/c裸鼠中显示出对肿瘤生长的显著抑制，且没有明显的毒性迹象。DUCPN - RGD - AS1411有很大潜力被用作脑癌和其他危及生命的癌症治疗的有效且安全的治疗诊断工具。
