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PDA-Based Glyconanomicelles for Hepatocellular Carcinoma Cells Active Targeting Via Mannose and Asialoglycoprotein
María Negrete1, Elena Romero-Ben2, Alicia Gutiérrez-Valencia1
1Hospital University "Virgen del Rocío"/CSIC/University of Seville, Institute of Biomedicine of Seville, Seville, Spain.
Abstract:
Hepatocellular carcinoma (HCC) is the sixth most common neoplasia and the fourth most common cause of cancer-related mortality worldwide. Sorafenib is the first-line molecular therapy for patients in an advanced stage of HCC. However, the recommended clinical dose of Sorafenib is associated with several complications, which derive from its lack of cell specificity and its very low water solubility. To circumvent these drawbacks, in the present study we developed two sugar-coated polydiacetylene-based nanomicelles-Sorafenib carriers targeting mannose and asialoglycoprotein receptors (MR and ASGPR, respectively). The strategies allowed the inducement of apoptosis and reduction of cell proliferation at a nanomolar, instead of micromolar, range in liver cancer cells. The study showed that, contrary to literature data, Sorafenib included into the pMicMan (Man = mannose) vector (targeting MR) is more efficient than pMicGal (Gal = galactose) (targeting ASGPR). Indeed, pMicMan increased the endosomal incorporation with an increased intracellular Sorafenib concentration that induced apoptosis and reduced cell proliferation at a low concentration range (10-20 nM).
Insights
New nanomicelles improve sorafenib treatment for liver cancer. These carriers target cancer cells, reducing side effects and increasing drug effectiveness at lower doses.
Area of Science:
- Biotechnology
- Nanomedicine
- Oncology
Background:
- Hepatocellular carcinoma (HCC) is a major global health concern, with sorafenib as a primary treatment for advanced stages.
- Current sorafenib therapy faces challenges due to low water solubility and lack of cell specificity, leading to complications.
- Targeted drug delivery systems are needed to enhance efficacy and reduce toxicity in HCC treatment.
Purpose of the Study:
- To develop novel polydiacetylene-based nanomicelles for targeted delivery of sorafenib in HCC.
- To evaluate the efficacy of nanomicelles targeting mannose receptors (MR) and asialoglycoprotein receptors (ASGPR).
- To compare the therapeutic potential of MR-targeting (pMicMan) versus ASGPR-targeting (pMicGal) nanomicelles.
Main Methods:
- Synthesis of sugar-coated polydiacetylene-based nanomicelles encapsulating sorafenib.
- Functionalization of nanomicelles to target mannose receptors (MR) and asialoglycoprotein receptors (ASGPR).
- In vitro assessment of nanomicelle-mediated sorafenib delivery, apoptosis induction, and cell proliferation inhibition in liver cancer cells.
Main Results:
- Both pMicMan and pMicGal nanomicelles demonstrated enhanced efficacy compared to free sorafenib.
- Contrary to expectations, pMicMan (targeting MR) showed superior performance over pMicGal (targeting ASGPR).
- pMicMan significantly increased intracellular sorafenib concentration, inducing apoptosis and reducing proliferation at nanomolar concentrations (10-20 nM).
Conclusions:
- Sugar-coated nanomicelles offer a promising strategy for targeted sorafenib delivery in HCC.
- The MR-targeting nanomicelle (pMicMan) is more effective than ASGPR-targeting (pMicGal) for enhancing sorafenib's therapeutic index.
- This approach enables potent anti-cancer effects at significantly lower, less toxic doses.
