A Pectin-Based Delivery Nanoplatform with an Optimized Tradeoff between Active Targeting and Drug Loading for Hepatocellular Carcinoma Treatment

The presence of multivalent reactive groups in the structure of natural polysaccharides enables diverse modifications toward advanced nanomedicines with integrated functionalities for enhanced cancer therapy; therefore, a polysaccharide-based nanoplatform with an optimized trade-off between multifunctionalities for a maximized therapeutic efficiency has been always a long-term research interest, which, however, remains relatively unexplored. We report herein pectin-based delivery nanoplatforms with an optimized trade-off between active targeting and drug loading for chemo-immunotherapy of hepatocellular carcinoma (HCC). Specifically, the targeting moiety of pectin, galactose, is subjected to partial oxidization to an aldehyde function that enables the simultaneous modulation of active targeting properties and drug conjugation capacity by the degree of oxidation, affording pectin-based polymer prodrugs OP2-DOX, OP6-DOX, and OP10-DOX with three different degrees of oxidation. OP6-DOX nanoprodrugs (NPs) are subsequently screened to be the optimal nanoplatform in terms of the mean hydrodynamic size, colloidal stability, cellular uptake capacity, and in vitro cytotoxicity profiles. Most importantly, OP6-DOX NPs achieve a tumor inhibition rate (TIR) of 86.8%, which induces the efficient polarization of tumor-associated macrophages (TAMs) from M2 to M1 and natural killer (NK) cell recruitment in HCC tissues. Overall, the outcomes of this study could serve as an important theoretical guidance on the active targeting and drug loading trade-off modulation of polysaccharide-based nanoplatforms for cancer chemo-innate immunotherapy.