Nanoparticle-based approaches for doxorubicin delivery in hepatocellular carcinoma: Current strategies and emerging...

Globally, hepatocellular carcinoma (HCC) is one of the most common causes of cancer-related death, but HCC treatment with the chemotherapeutic doxorubicin is limited because of acquired drug resistance. In this review, we examined current knowledge on the specific molecular mechanisms of doxorubicin resistance in HCC, including overexpression of drug efflux (ABC family) transporters, aberrations of the drug target topoisomerase IIα (TOP2A), impairments in apoptosis (p53, FOXO3, Bcl-2 family members), oncogenic activation of pro-survival signaling pathways (NF-κB, PI3K/Akt, and MAPKs), instances of tumor heterogeneity with sirtuins, and cancer stem cells. Additionally, we investigate the role of non-coding RNAs, particularly microRNAs and long non-coding RNAs, in modulating sensitivity to and resistance to doxorubicin in HCC. In conclusion, nanomedicine will become crucial in overcoming the limitations of significant doxorubicin resistance in HCC, utilizing advanced mechanisms to modulate treatment with doxorubicin in this context. This review details various nanotechnology-based approaches to the delivery of doxorubicin, including passive targeting using the enhanced permeability and retention (EPR) effect, active targeting with specific ligands, and stimulus-responsive drug release in the tumor microenvironment (e.g., pH, redox potential). We focus on preclinical studies that utilized a variety of nanoparticle formulations for palliative care to patients with HCC, have investigated the use of liposomes, polymeric nanoparticles (e.g., PCL, chitosan), metallic particles (e.g., gold, silver, iron oxide), dendrimers, and metal-organic frameworks (MOFs), which have been loaded with doxorubicin or combined with other agents (e.g., cantharidin, berberine, isoginkgetin, ginger extract). The nanoparticle formulations enhanced drug delivery, increased drug accumulation per cell, reduced systemic toxicity, and overcame drug resistance mechanisms in HCC models.