A facile boronophenylalanine modified polydopamine dual drug-loaded nanoparticles for enhanced anti-tumor immune response in hepatocellular carcinoma comprehensive treatment.

Hepatocellular carcinoma (HCC) has an insidious onset and high malignancy. Most patients have progressed to intermediate and advanced stages by the time of diagnosis, and the long-term efficacy of traditional treatments is not satisfactory. Immunotherapy has shown great promise in the treatment of HCC in recent years; however, the low immunogenicity and severe immunosuppressive tumor microenvironment result in a low response rate to immunotherapy in HCC patients. Therefore, it is of great significance to improve the immunogenicity of HCC and thus enhance its sensitivity to immunotherapy. Here, we prepared the boronophenylalanine-modified dual drug-loaded polydopamine nanoparticles by a facile method. This system used boronophenylalanine-modified polydopamine nanoparticles as a delivery vehicle and photothermal material for the chemotherapeutic drug doxorubicin and the immune agonist CpG oligodeoxynucleotides (CpG-ODN), with both active targeting and lysosomal escape functions. The cancer cells are rapidly killed by photothermal treatment, and then chemotherapy is used to further kill cancer cells that are inadequately treated by photothermal treatment. The combination of photothermal-chemotherapy synergistically induces the release of relevant antigens from tumor cells, thus initiating anti-tumor immunity; and then cooperates with CpG-ODN to trigger a powerful anti-tumor immune memory effect, potently and durably inhibiting HCC recurrence.

Intratumoral Injection of Norcantharidin-Loaded Poly(D,L-lactide)-b-Poly(ethylene glycol)-b-Poly(D,L-lactide) Thermosensitive Hydrogel for the Treatment of Primary Hepatocellular Carcinoma.

In this study we employed self-designed PDLLA-PEG-PDLLA (PLEL) thermosensitive hydrogel to blend with norcantharidin (NCTD), a hydrophilic chemotherapeutic drug possessing curative effect on primary hepatocellular carcinoma (HCC) and adverse effects, then utilized the composite in HCC interstitial chemotherapy. PLEL copolymer was synthesized by ring-opening polymerization, NCTD-loaded PLEL hydrogel was prepared in a simple and reasonable way. The addition of NCTD had no significant effect on the temperature-dependent rheological properties of PLEL hydrogel. The pH values of NCTD-loaded gel solutions (13 wt%) and free NCTD solutions with three drug concentrations of 0.4 mg/mL, 0.8 mg/mL and 1.2 mg/mL under different storage conditions met the pH requirement of small-volume injection. There was no significant difference among the drug release behaviors of NCTD-loaded gels with drug concentrations of 0.4 mg/mL, 0.8 mg/mL and 1.2 mg/mL, they fitted first-order dynamics, exhibited significantly slower drug release than free drug solutions and the release was mainly based on drug diffusion. Drug-loaded gel solution (13 wt%) could evenly distribute throughout tumor tissue before converting into gel after being intratumorally injected and was able to significantly prolong retention time of the drug in tumor compared to free drug solution. The sustained-release performance of NCTD-loaded gel (13 wt%) was confirmed from the perspective of pharmacodynamics in vitro. The in vivo evaluation demonstrated that intratumoral injection of NCTD-loaded PLEL gel (13 wt%) was capable of improving curative effect of the drug and reducing its toxicity.