3-Carboxyphenylboronic acid functionalized polydopamine-coated cellulose nanocrystals as a pH-responsive nanocarrier for targeted curcumin delivery.

Targeted and stimuli-responsive drug delivery systems (DDS) hold significant potential for improving therapeutic efficacy and mitigating adverse effects in cancer treatment. Here, we developed a pH-responsive nanocarrier through a surface modification strategy, which enables active targeting of hepatocellular carcinoma (HCC) cells for the delivery of drug curcumin (Cur), a poorly water-soluble therapeutic agent. Briefly, a polydopamine (PDA) layer was first deposited onto the surface of cellulose nanocrystals (CNCs) via the self-polymerization of dopamine hydrochloride. Subsequently, 3-Carboxyphenylboronic acid (CA) was grafted onto the PDA-coated surface to obtain CNCs@PDA-CA. After that, Cur was loaded onto CNCs@PDA-CA by forming a boronate ester linkage with the boronic acid groups of CA, resulting in the final nanocomposite CNCs@PDA-CA-Cur with a drug loading capacity of 10.58 ± 1.32 %. This nanocarrier not only exhibited active targeting ability toward HCC cells, but also achieved controlled Cur release in response to the acidic tumor microenvironment. Specifically, CNCs@PDA-CA-Cur showed high pH-responsive ability that released 3.18-folds of Cur in acidic environments (pH = 5.4) more than in neutral environments (pH = 7.2). Furthermore, the nanocarrier demonstrated efficient active targeting to HCC cells, leading to elevated intracellular Cur accumulation and enhanced cytotoxicity in both 2D and 3D HCC models in vitro. Collectively, these results highlight the potential of the targeted and pH-responsive nanocarrier to improve the therapeutic delivery of poorly soluble drugs for HCC treatment.