Singh Kajal, Pathan Shahidkhan, Malhotra Mehak, Jayakannan Manickam, Balasubramanian Nagaraj
Department of Biology, Indian Institute of Science Education and Research (IISER) Pune, Dr. Homi Bhabha Road, Pune, Maharashtra 411008, India.
Department of Chemistry, Indian Institute of Science Education and Research (IISER) Pune, Dr. Homi Bhabha Road, Pune, Maharashtra 411008, India.
Biomacromolecules. 2025 Aug 11;26(8):4948-4966. doi: 10.1021/acs.biomac.5c00366. Epub 2025 Jul 28.
Targeting Aurora Kinase A (AURKA) to modulate RalA activation offers a promising strategy for tumor suppression in Ras-independent and Ras-dependent cancers. However, clinical use of the AURKA inhibitor MLN8237 (Alisertib) is limited by its hydrophobicity and poor water solubility. To overcome these limitations, here, we developed an enzyme-biodegradable unimolecular micelle (UMM) nanoparticle to deliver MLN8237 (NP) and evaluated its therapeutic efficacy in tumor xenograft models. NP selectively inhibited AURKA, downregulated pSer194 RalA, and suppressed anchorage-independent growth in SKOV3 (Ras-independent) and MIA PaCa-2 (Ras-dependent) cancer cells. Nanoparticles loaded with sulforhodamine B (NP) and IR780 (NP) confirmed enhanced cellular uptake and tumor localization, respectively. Improved solubility and bioavailability enabled low-dose parenteral delivery of MLN8237, achieving significant tumor regression compared to free drug. This correlated with inhibition of AURKA and RalA phosphorylation (pSer194RalA) in both tumors. Together, they highlight the therapeutic potential of NP in targeting AURKA-RalA crosstalk in tumor xenografts.
靶向极光激酶A（AURKA）以调节RalA激活，为非Ras依赖性和Ras依赖性癌症的肿瘤抑制提供了一种有前景的策略。然而，AURKA抑制剂MLN8237（Alisertib）的临床应用受到其疏水性和低水溶性的限制。为克服这些限制，我们在此开发了一种酶可生物降解的单分子胶束（UMM）纳米颗粒来递送MLN8237（NP），并在肿瘤异种移植模型中评估其治疗效果。NP选择性抑制AURKA，下调pSer194 RalA，并抑制SKOV3（非Ras依赖性）和MIA PaCa-2（Ras依赖性）癌细胞的非锚定依赖性生长。负载磺基罗丹明B（NP）和IR780（NP）的纳米颗粒分别证实了细胞摄取增强和肿瘤定位。改善的溶解性和生物利用度使得能够低剂量肠胃外递送MLN8237，与游离药物相比实现了显著的肿瘤消退。这与两种肿瘤中AURKA和RalA磷酸化（pSer194RalA）的抑制相关。总之，它们突出了NP在肿瘤异种移植中靶向AURKA-RalA串扰的治疗潜力。
