Multifunctional Microspheres Dual-Loaded with Doxorubicin and Sodium Bicarbonate Nanoparticles to Introduce Synergistic Trimodal Interventional Therapy

Abstract

Lactic acid in the tumor microenvironment is highly correlated with the prognosis of tumor chemoembolization, but there are limited clinical strategies to deal with it. To improve the efficacy, NaHCO3 nanoparticles are innovatively introduced into drug-loaded microspheres to neutralize lactic acid in the tumor microenvironment. Here we showed that multifunctional ethyl cellulose microspheres dual-loaded with doxorubicin (DOX) and NaHCO3 nanoparticles (DOX/NaHCO3-MS) presented excellent antitumor effects by improving the pH of the tumor microenvironment. The homeostasis of the tumor microenvironment was continuously disturbed due to the sustained release of NaHCO3 nanoparticles, which also led to a significant increase in tumor cell apoptosis (compared with the control and DOX-MS groups). We also showed that the administration of DOX/NaHCO3-MS via the hepatic artery in a rabbit model of VX2 orthotopic liver cancer resulted in optimal antitumor efficacy, and the area of tumor necrosis at the embolization site was significantly increased and the proliferation of tumor cells was significantly weakened. The designed DOX/NaHCO3-MS exhibited strong synergistic antitumor effects of embolization, chemotherapy, and tumor microenvironment improvement. The present microspheres provided a strategy for the enhancement of the chemoembolization of hepatocellular carcinoma, which could also be extended to other clinical embolization treatments for blood-rich solid tumors.

Recent Progress in Advanced Hydrogel‐Based Embolic Agents: From Rational Design Strategies to Improved Endovascular Embolization

“…The equilibrium state of the tumor microenvironment was broken and ultimately led to inhibit the growth of tumor cells. [211,212] Therefore, the hydrogels with pH-regulation properties are essential to be developed by incorporating pH neutralization reagents (e.g., calcium carbonate (CaCO 3 ), sodium bicarbonate (NaHCO 3 )). Moreover, it is desirable to perform a comprehensive investigation of the combination therapy of artery-blocking and tumor immune microenvironment enhancement to elucidate the possible therapeutic mechanism.…”

Homogenous multifunctional microspheres induce ferroptosis to promote the anti-hepatocarcinoma effect of chemoembolization

“…The VX2 tumor was propagated by the transplanted tumor of the rabbit model, which were left based on our previous research and stored in liquid nitrogen, and the orthotopic models of liver tumors were also established as our previously reports [ 18 , 41 ]. Briefly, 31 male New Zealand white rabbits (2–2.5 kg in weight) were prepared, and one was the donor rabbit and the other thirty were the intervention ones.…”

“…TACE was carried out on 2 week after tumor implantation, and the operation process refers to our previous research [ 41 ]. Briefly, the rabbits were anesthetized by 2% pentobarbital sodium (1 mL/Kg; Sigma-Aldrich, MO).…”

Smart nanoparticles and microbeads for interventional embolization therapy of liver cancer: state of the art

“…Drug-eluting embolic systems containing NaHCO 3 were designed for the rapid release of drugs by CO 2 gas generation in the slightly acidic TME while maintaining the particle structure for occlusion of tumor-feeding vessels [ 92 , 93 ]. It is expected that the developed TME-responsive gas-generating microspheres can be efficiently applied to TACE.…”