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Published on: June 13, 2014
Dual-target carboxymethylated mannan nanoparticles for enhanced pH-responsive monomethyl auristatin E delivery in
Huiwen Hou1, Didi Gao1, Na Lu2
1National Glycoengineering Research Center, Shandong University, Qingdao, 266237, Shandong, China; NMPA Key Laboratory for Quality Research and Evaluation of Carbohydrate-Based Medicine, Shandong University, Qingdao, 266237, China; Shandong Provincial Technology Innovation Center of Carbohydrate, Shandong University, Qingdao, 266237, China.
Abstract:
Hepatocellular carcinoma (HCC) is among the most prevalent and deadly cancers worldwide, with high recurrence and metastasis rates that significantly impact patient survival. Targeted therapy has emerged as a promising alternative to conventional treatments. This offers tumor-specific drug delivery while minimizing adverse systemic effects. In this study, we present folate acid (FA)-carboxymethylated mannan (CM)- monomethyl auristatin E (MMAE) conjugate (FA-CM-MMAE, FCMMM), an innovative glycosylated dual-target nanoparticle designed for the precise delivery of MMAE to HCC cells. These nanoparticles utilize FA and CM as their targeting ligands and exhibit pH-responsive drug release in acidic tumor microenvironments. This allows enhanced specificity and reduces off-target toxicity. In vitro studies have demonstrated that FCMMM nanoparticles selectively deliver MMAE to HepG2 cells via receptor-mediated pathways, alleviating MMAE-associated toxicity in normal cells. Furthermore, in vivo experiments in HCC-bearing mouse models have shown efficient tumor-specific accumulation of the drug, significant inhibition of tumor growth, and markedly lower levels of systemic toxicity than MMAE. This dual-targeting strategy integrates precise tissue targeting with controlled drug release. It addresses critical limitations of traditional HCC therapies such as nonspecific drug distribution, systemic toxicity, and drug resistance mechanisms. FCMMM shows potential as a next-generation nanoparticle platform for safer, more effective chemotherapeutic intervention in hepatic cancer.
Insights
A novel dual-target nanoparticle, folate acid (FA)-carboxymethylated mannan (CM)-monomethyl auristatin E (MMAE) conjugate (FCMMM), effectively targets hepatocellular carcinoma (HCC) cells. This innovative therapy enhances drug delivery, reduces toxicity, and inhibits tumor growth in preclinical models.
Area of Science:
- Oncology
- Nanomedicine
- Drug Delivery
Background:
- Hepatocellular carcinoma (HCC) presents significant global health challenges due to high mortality and recurrence rates.
- Conventional therapies for HCC often suffer from systemic toxicity and limited efficacy.
- Targeted drug delivery offers a promising strategy to improve treatment outcomes for HCC.
Purpose of the Study:
- To develop and evaluate an innovative glycosylated dual-target nanoparticle, FA-CM-MMAE (FCMMM), for precise delivery of monomethyl auristatin E (MMAE) to HCC cells.
- To assess the targeting specificity, pH-responsive drug release, and therapeutic efficacy of FCMMM in vitro and in vivo.
- To investigate the potential of FCMMM as a next-generation nanoplatform for safer and more effective HCC treatment.
Main Methods:
- Synthesis of folate acid (FA)-carboxymethylated mannan (CM)-monomethyl auristatin E (MMAE) conjugate (FCMMM) nanoparticles.
- In vitro evaluation of FCMMM targeting specificity and drug release in HepG2 cells (HCC cell line) and normal cells.
- In vivo assessment of FCMMM's tumor-specific accumulation, tumor growth inhibition, and systemic toxicity in HCC-bearing mouse models.
Main Results:
- FCMMM nanoparticles demonstrated selective delivery of MMAE to HepG2 cells via receptor-mediated pathways, minimizing toxicity to normal cells.
- In vivo studies showed efficient tumor-specific drug accumulation and significant inhibition of tumor growth in HCC mouse models.
- FCMMM exhibited markedly lower systemic toxicity compared to free MMAE, highlighting its safety profile.
Conclusions:
- The developed FCMMM nanoparticles represent a promising dual-targeting strategy for precise HCC therapy.
- This approach integrates targeted tissue delivery with controlled, pH-responsive drug release, addressing key limitations of current HCC treatments.
- FCMMM holds potential as an advanced nanotherapeutic platform for improving the safety and efficacy of chemotherapeutic interventions in hepatic cancer.
