Assembly and Stability of Trastuzumab-Conjugated and Unmodified Poly(L-Histidine)-Poly(Ethylene Glycol) Micelles for Targeting HER2-positive Cells

Razvan Ghiarasim1, Gabriel Luta2, Mihail-Gabriel Dimofte2,3, Tore-Geir Iversen3, Mariana Pinteala1 and Alexandru Rotaru1*

1Centre of Advanced Research in Bionanoconjugates and Biopolymers, “Petru Poni” Institute of Macromolecular Chemistry, 41A Grigore Ghica Voda Alley, 700487 Iasi, Romania; ghiarasim.razvan@icmpp.ro (R.G.), pinteala@icmpp.ro (M.P.), rotaru.alexandru@icmpp.ro (A.R.)

2TRANSCEND Centre, Regional Institute of Oncology, 2-4 General Henri Mathias Berthelot Street, 700483 Iasi, Romania; gabriel.luta@iroiasi.ro (G.L.), mihail.dimofte@umfiasi.ro (M.-G.D.)

3Regional Institute of Oncology, 2-4 General Henri Mathias Berthelot Street, 700483 Iasi, Romania; mihail.dimofte@umfiasi.ro (M.-G.D.)

4Department of Molecular Cell Biology, Institute for Cancer Research, Oslo University Hospital, Oslo, 0379, Norway; t.g.iversen@ous-research.no (T.G.I.)

Short Description:

This manuscript explores the development and evaluation of poly(L-histidine)-poly(ethylene glycol) (PHis-PEG) micelles for targeted drug delivery to HER2-positive cancer cells. The study focuses on two types of micelles: trastuzumab-conjugated and unmodified PHis-PEG micelles. These micelles are designed to incorporate a fluorophore tag within their core and facilitate the surface attachment of the monoclonal antibody trastuzumab.

The research highlights the importance of micelle stability, particularly at concentrations below the critical micelle concentration (CMC), which is crucial for in vivo applications. The study demonstrates that the incorporation of hydrophobic molecules into the micelle core enhances stability below the CMC. However, it also notes that conjugation with trastuzumab can destabilize the micelles at the concentrations tested.

The stability of these micelles was further investigated in the presence of bovine serum albumin (BSA) to simulate the protein-rich environment of blood, providing insights into their behavior under physiological conditions. The findings indicate that unmodified micelles tend to disassemble over time, whereas trastuzumab-functionalized micelles loaded with hydrophobic molecules maintain strong stability.

Functionally, the trastuzumab-conjugated micelles showed substantial efficacy against HER2-overexpressing cell lines, underscoring their potential for targeted cancer therapy. This study advances the understanding of PHis-PEG micelles as pH-responsive drug delivery systems and highlights their promise for enhancing the targeted delivery of therapeutics in cancer treatment.

 

Manuscript is submitted to Journal of Molecular Liquids (manuscript number: MOLLIQ-D-24-03642).

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