Nucleolin-targeted silicon-based nanoparticles for enhanced chemo-sonodynamic therapy of diffuse large B-cell lymphoma.

in International journal of pharmaceutics by Yubo Wang, Yong Zhou, Jinling Wang, Lu Zhang, Chen Liu, Ding Guo, Yanlin Yu, Roumei Ye, Yun Wang, Bing Xu, Yiming Luo, Dengyue Chen

TLDR

  • The study develops a biocompatible nanomedicine delivery system for treating DLBCL by combining SDT with chemotherapy, demonstrating improved therapeutic efficacy and reduced systemic toxicity.

Abstract

The limited selectivity and high systemic toxicity of traditional chemotherapy hinder its efficacy in treating diffuse large B-cell lymphoma (DLBCL). The combination of sonodynamic therapy (SDT) with chemotherapy has emerged as a novel strategy for cancer treatment, aiming to improve therapeutic outcomes and reduce systemic toxicity. However, challenges such as elevated drug clearance rates and non-selecitivity remain to be resolved. This study has developed a biocompatible nanomedicine delivery system, PA-HM@DOX/ICG, employing hollow mesoporous silica nanoparticles (HMSNs) as the nanocarrier. The nanomedicine incorporates the chemotherapeutic agent doxorubicin (DOX) along with the sonosensitizer indocyanine green (ICG) within its encapsulation, and undergoes additional surface modification using lipid-nucleic acid conjugates (DSPE-PEG-AS1411) to facilitate active targeted delivery. In vitro cellular experiments have validated that PA-HM@DOX/ICG can specifically recognize and be internalized by SU-DHL-4 lymphoma cells due to the overexpression of nucleolin on their surface. The synergistic effects of DOX-induced DNA damage and reactive oxygen species (ROS) generated by ultrasound-activated ICG induce apoptosis in these cells. Furthermore, PA-HM@DOX/ICG displays minimal toxicity towards LO2 normal hepatocytes, indicating a favorable biosafety profile. In vivo animal studies have shown that PA-HM@DOX/ICG effectively accumulates in tumor sites in mice through both the enhanced permeability and retention (EPR) effect and nucleolin-mediated targeting. Under ultrasound irradiation, PA-HM@DOX/ICG significantly inhibits tumor growth. This study introduces a nanoplatform that integrates chemotherapy with sonodynamic therapy, offering a novel approach for the efficient treatment of DLBCL.

Overview

  • The study aims to develop a biocompatible nanomedicine delivery system for treating diffuse large B-cell lymphoma (DLBCL) by combining sonodynamic therapy (SDT) with chemotherapy.
  • The nanomedicine, PA-HM@DOX/ICG, uses hollow mesoporous silica nanoparticles (HMSNs) as the nanocarrier and incorporates doxorubicin (DOX) and indocyanine green (ICG) for synergistic effects.
  • The study evaluates the nanomedicine's in vitro and in vivo efficacy in treating SU-DHL-4 lymphoma cells and its biosafety profile in normal hepatocytes.

Comparative Analysis & Findings

  • In vitro experiments show that PA-HM@DOX/ICG specifically recognizes and internalizes SU-DHL-4 lymphoma cells through nucleolin-mediated targeting, inducing apoptosis with DOX-induced DNA damage and ROS generated by ultrasound-activated ICG.
  • In vivo studies demonstrate that PA-HM@DOX/ICG accumulates in tumor sites in mice through the EPR effect and nucleolin-mediated targeting, resulting in significant inhibition of tumor growth under ultrasound irradiation.
  • The nanomedicine displays minimal toxicity towards LO2 normal hepatocytes, confirming its favorable biosafety profile.

Implications and Future Directions

  • The study's findings suggest that PA-HM@DOX/ICG could be a novel approach for treating DLBCL, offering improved therapeutic efficacy and reduced systemic toxicity compared to traditional chemotherapy.
  • Future studies may focus on optimizing the nanomedicine's design and improving its biocompatibility, as well as exploring its potential application in other types of cancer.
  • The combination of SDT with chemotherapy could be expanded to treat other types of cancer, and further investigation into the mechanisms of sonodynamic therapy and the synergistic effects of chemotherapy may reveal new therapeutic opportunities.
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