Dextran-based doxorubicin nanocarriers with improved tumor penetration

Area of Science:

• Biomedical Engineering
• Nanotechnology
• Cancer Therapeutics

Background:

• Improved tumor penetration is crucial for effective anticancer drug delivery.
• Dextran-based nanocarriers offer potential for targeted drug delivery.
• Acid-labile linkages can control drug release within tumor microenvironments.

Purpose of the Study:

• To develop and evaluate dextran-based nanocarriers for enhanced doxorubicin delivery.
• To assess the efficacy and tumor penetration of aldehyde dextran-doxorubicin nanocarriers (ald-dex-dox).
• To investigate the cellular uptake mechanisms of ald-dex-dox nanocarriers.

Main Methods:

• Synthesis of aldehyde dextran nanocarriers with acid-labile doxorubicin linkage.
• In vitro efficacy testing using 2D cell monolayers (SK-N-BE(2)) and IC50 determination.
• Confocal microscopy and Fluorescence Lifetime Imaging Microscopy (FLIM) for cellular uptake and drug release studies.
• 3D tumor spheroid models to evaluate drug penetration and therapeutic efficacy.
• Investigation of glucose's role and endocytosis pathways in nanocarrier accumulation.

Main Results:

• Aldehyde dextran nanocarriers (ald-dex-dox) showed significant efficacy (IC50 ∼300 nM) against 2D cancer cells.
• Rapid cellular internalization of intact ald-dex-dox particles was observed, with doxorubicin release occurring within 4 hours.
• Nanocarrier accumulation increased in glucose-depleted conditions, suggesting glucose receptor involvement in endocytosis.
• In 3D tumor spheroids, ald-dex-dox demonstrated superior efficacy and complete tumor penetration, unlike free doxorubicin.

Conclusions:

• Aldehyde dextran nanocarriers are effective drug delivery systems for doxorubicin.
• The nanocarriers exhibit enhanced tumor penetration and efficacy in 3D models compared to the free drug.
• Ald-dex-dox represents a promising platform for treating solid tumors.