Escape from Cell Uptake: Drug-Free Cancer Therapeutics Regulated Hydrophobicity and Negative Charge

Self-aggregation and inducing cell membrane disruption in response to tumor microenvironment-stimuli is expected to be a promising approach for cancer treatment, but is limited by its insufficient stimuli-responsive cytotoxicity due to a lack of in-depth understanding of molecular characteristics, resulting in low selectivity of cell death induction. In this study, we focused on engineering polymer aggregation in detail to further improve tumor microenvironment-responsive cytotoxicity. PVA-U with grafting degrees (G.D.) of 3% (PVA-U3), 15% (PVA-U15), and 25% (PVA-U25) were synthesized and their aggregation properties cytotoxicity was evaluated. The difference in half maximal inhibitory concentration (IC50) values between pH 7.4 and pH 6.5 for PVA-U15 was 4.3-fold, which was greater than that of PVA-U25 at 2.8-fold, suggesting that tumor microenvironment-responsive cytotoxicity could be regulated by controlling G.D. of UDCA. Interestingly, PVA-U15 formed aggregates in the pericellular environment and adsorbed on the cell, effectively inducing cell death whereas PVA-U3 and PVA-U25 showed internalization in the cell. These results indicated that the balance of the surface charge and hydrophobicity could contribute to the adsorption on the cell membrane. These findings are expected to contribute to the development of membrane disruption strategies to control the aggregation properties and cell membrane interaction. Table of ContentsCancer therapeutics strategy targeting tumor microenvironment and cell adsorption of PVA-U with varying granting degree (G.D.). PVA-U is expected to aggregate and disrupt cell membrane in response to tumor microenvironment. PVA-U could regulate cell membrane adsorption by its negative charge and hydrophobicity due to controlling G.D. of UDCA, resulting in optimized tumor microenvironment selectivity. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=181 SRC="FIGDIR/small/671160v1_ufig1.gif" ALT="Figure 1"> View larger version (43K): org.highwire.dtl.DTLVardef@e8d4acorg.highwire.dtl.DTLVardef@1e27a1borg.highwire.dtl.DTLVardef@1beb5d8org.highwire.dtl.DTLVardef@1948d51_HPS_FORMAT_FIGEXP M_FIG C_FIG