Engineering Intramolecular Compactness in Water-Soluble Single-Chain Nanoparticles for Optimized Platinum Delivery.

Single-chain nanoparticles (SCNPs) have been extensively studied for various applications, including catalysis, drug delivery, antimicrobial agents, rheology modifiers, and in nanocomposites. For catalytic applications, the collapsed polymer chain was often cross-linked using a metal complex, which also served as the active catalytic site. Inspired by the successful formation of a metal complex containing SCNPs, we have adopted this system for the delivery of the anticancer drug cisplatin. However, to deliver cisplatin into cells across the cell membrane, an understanding of the detailed structure and compactness of SCNPs is essential. In this work, we synthesized a series of statistical copolymers based on polyethylene glycol methyl ether acrylate (PEGMEA) as water-soluble monomer, 2-carboxy ethyl acrylate (CEA) as the ligand for platinum drug conjugation, and a hydrophobic monomer (methyl acrylate (MA), butyl acrylate (BA), and benzyl acrylate (BzA)) to enhance the compactness of the SCNP. The library of polymers was conjugated with cisplatin, and the resulting SCNPs were characterized predominantly by size-exclusion chromatography (SEC) with viscosity detection and small-angle X-ray scattering (SAXS), as dynamic light scattering alone is insufficient to provide information about the SCNP formation. Increasing the amount of CEA and, therefore, the amount of cisplatin reduced viscosity and the radius of gyration (R g), thus increasing compaction. The same was achieved by incorporating hydrophobic comonomers with BA polymers showing the strongest collapse. The toxicity of these drug-loaded SCNPs was tested in the ovarian cancer cell line A2780, healthy lung cells MRC-5, and cisplatin-resistant ovarian cancer cells A2780cis, showing that greater SCNP collapse correlates with higher toxicity, but only in the absence of hydrophobic comonomers.