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Unimolecular Micelle for MLN8237 Delivery to Target AURKA-RalA Crosstalk for Ras-Driven Tumor Suppression in Mice

Kajal Singh1,2, Shahidkhan Pathan2, Mehak Malhotra2

  • 1Department of Biology, Indian Institute of Science Education and Research (IISER) Pune, Dr. Homi Bhabha Road, Pune, Maharashtra 411008, India.

Biomacromolecules
|July 28, 2025
PubMed

Insights

We developed a nanoparticle delivery system for the cancer drug MLN8237 (Alisertib), improving its solubility and efficacy. This novel nanoparticle formulation effectively suppressed tumor growth in preclinical models by targeting Aurora Kinase A (AURKA).

Area of Science:

  • Oncology
  • Nanomedicine
  • Biochemistry

Background:

  • Aurora Kinase A (AURKA) is a key target for cancer therapy, particularly in modulating RalA activation.
  • The clinical application of the AURKA inhibitor MLN8237 (Alisertib) is hindered by poor solubility and hydrophobicity.
  • Targeting AURKA-RalA crosstalk presents a promising strategy for both Ras-dependent and Ras-independent cancers.

Purpose of the Study:

  • To develop an enzyme-biodegradable unimolecular micelle (UMM) nanoparticle for improved MLN8237 delivery.
  • To evaluate the therapeutic efficacy of the MLN8237-loaded nanoparticle (NPMLN) in preclinical tumor xenograft models.
  • To assess the impact of NPMLN on AURKA inhibition and RalA phosphorylation in cancer cells and tumors.

Main Methods:

  • Development of an enzyme-biodegradable unimolecular micelle (UMM) nanoparticle for MLN8237 encapsulation (NPMLN).
  • In vitro evaluation of NPMLN in SKOV3 (Ras-independent) and MIA PaCa-2 (Ras-dependent) cancer cells for AURKA inhibition, pSer194 RalA downregulation, and anchorage-independent growth suppression.
  • In vivo assessment of NPMLN therapeutic efficacy, tumor localization (using NPIR780), and cellular uptake (using NPSRB) in tumor xenograft models.

Main Results:

  • NPMLN selectively inhibited AURKA and downregulated pSer194 RalA, suppressing cancer cell growth in vitro.
  • Nanoparticles demonstrated enhanced cellular uptake and tumor localization, facilitating effective drug delivery.
  • Parenteral administration of NPMLN at low doses resulted in significant tumor regression, superior to free MLN8237, with confirmed inhibition of AURKA and pSer194 RalA in tumors.

Conclusions:

  • The developed unimolecular micelle nanoparticle (NPMLN) effectively overcomes the solubility and bioavailability limitations of MLN8237.
  • NPMLN demonstrates significant therapeutic potential by targeting the AURKA-RalA pathway in preclinical cancer models.
  • This nanoparticle-based drug delivery system offers a promising approach for cancer treatment, enhancing the efficacy of AURKA inhibitors.

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