4.7 Article

Hydrophobicity Regulates the Cellular Interaction of Cyanine5-Labeled Poly(3-hydroxypropionate)-Based Comb Polymers

期刊

BIOMACROMOLECULES
卷 23, 期 9, 页码 3560-3571

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AMER CHEMICAL SOC
DOI: 10.1021/acs.biomac.2c00303

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资金

  1. Monash Graduate Scholarship (MGS)
  2. ARC Future Fellowship from the Australian Research Council (ARC) [FT190100572]
  3. Postgraduate Publication Award (PPA)

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An in-depth understanding of the physicochemical properties of nanocarriers is crucial for the development of novel delivery systems. In this study, well-defined hydrophobic carboxylated poly(3-hydroxypropionate)-based comb polymers were synthesized and characterized. The study demonstrated the importance of hydrophobicity in tuning the cellular interactions of carboxylated polymers for future drug carrier design.
An in-depth understanding of the effect of physicochemical properties of nanocarriers on their cellular uptake and fate is crucial for the development of novel delivery systems. In this study, well-defined hydrophobic carboxylated poly(3-hydroxypropionate)-based comb polymers were synthesized. Two oligo(3-hydroxypropionate) (HPn) of different degrees of polymerization (DP; 5 and 9) bearing alpha-vinyl end-groups were obtained by an hydrogen transfer polymerization (HTP)-liquid/liquid extraction strategy. 2-Carboxyethyl acrylate (CEA), representing the DP 1 analogue of HPn, was also included in the study. (Macro)-monomers were polymerized via reversible addition-fragmenta-tion chain-transfer (RAFT) polymerization and fully characterized by H-1 NMR spectroscopy and size exclusion chromatography. All polymers were non-hemolytic and non-cytotoxic against NIH/3T3 cells. Detailed cellular association and uptake studies of Cy5-labeled polymers by flow cytometry and confocal laser scanning microscopy (CLSM) revealed that the carboxylated water-soluble PCEA, the polymer with the shortest side chain, efficiently targets mitochondria. However, increasing the side-chain DP led to a change in the intracellular fate. P(HP5) was trafficked to both mitochondria and lysosomes, while P(HP9) was exclusively found in lysosomes. Importantly, FLIM-FRET investigation of P(HP5) provided initial insight into the mitochondria subcompartment location of Cy5-labeled carboxylated polymers. Moreover, intracellular uptake mechanism studies were performed. Blocking scavenger receptors by dextran sulfate or cooling cells to 4 degrees C significantly affected the cell association of hydrophobic carboxylated polymers with an insignificant response to membrane-potential inhibitors. In contrast, water-soluble carboxylated polymers' cellular association was substantially inhibited in cells treated with compounds depleting the mitochondrial potential (Delta psi). Overall, this study highlights hydrophobicity as a valuable means to tune the cellular interaction of carboxylated polymers and thus will inform the design of future drug carriers based on Cy5-modified carboxylated polymers.

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