Drug content on anticancer efficacy of self-assembling ketal-linked dextran-paclitaxel conjugates

Although polymer-drug conjugates (PDCs) show great promise as versatile drug delivery systems, no antitumor PDCs based on small-molecule drugs are currently on the market, partly because of the lack of validated design principles for PDCs. High drug content is thought to be essential for devising highly efficacious PDCs based on poorly soluble antitumor drugs, but this has not been well validated. Therefore, revisiting the relationship between drug content and PDC performance is vital. In this study, we synthesized four dextran-paclitaxel (PTX) conjugates (designated as DKPs) with different drug contents by linking dextran and PTX via an acid-responsive ketal, and we used the conjugates to construct self-assembled DKP nanoparticles (NPs) for antitumor therapy. We focused on how PTX content influenced the hydrolysis kinetics, cytotoxicity, cellular uptake and intracellular hydrolysis, pharmacokinetics, biodistribution, and antitumor efficacies of the DKP NPs. We found that DKP NPs with lower PTX content showed accelerated drug release and increased tumor accumulation, and consequently enhanced antitumor efficacy. In 4T1-Luc and Panc02-Luc cancer models, the NPs showed considerably improved therapeutic efficacy than the micellar formulation of PTX that is currently in clinical use. Our results indicate that DKP NPs with lower PTX content possess greater antitumor potential, and our findings offer new insights for the connection of drug content-formulation-bioactivity relationship in the rational design of PDC prodrugs.