Enhanced Tumor Targeting and Antitumor Activity of Methylated β-Cyclodextrin-Threaded Polyrotaxanes by Conjugating...

Area of Science:

• Biomaterials Science
• Nanotechnology
• Oncology

Background:

• Acid-degradable methylated β-cyclodextrins (Me-β-CDs)-threaded polyrotaxanes (Me-PRXs) induce autophagic cell death, showing potential as anticancer therapeutics, particularly in apoptosis-resistant cells.
• Integrin α_vβ₃ is overexpressed in tumors, making it a target for selective drug delivery.

Purpose of the Study:

• To design peptide-supermolecule conjugates for targeted delivery of Me-PRX to malignant tumors.
• To evaluate the efficacy and safety of Me-PRX conjugated with a tumor-targeting peptide.

Main Methods:

• Orthogonal post-modification of Me-PRX with cyclic Arg-Gly-Asp (cRGD) peptide via click chemistry.
• Surface Plasmon Resonance (SPR) to assess binding affinity of cRGD-Me-PRX to integrin α_vβ₃.
• In vitro studies using 4T1 cells to evaluate cellular internalization and antitumor activity.
• In vivo studies to assess tumor accumulation, antitumor effects, biocompatibility, and safety.

Main Results:

• cRGD-Me-PRX demonstrated strong binding to integrin α_vβ₃, unlike the non-targeted cRGE-Me-PRX.
• In vitro, cRGD-Me-PRX showed enhanced cellular uptake and antitumor activity in 4T1 cells compared to unmodified Me-PRX and cRGE-Me-PRX.
• In vivo, cRGD-Me-PRX effectively accumulated in tumors, exhibiting significant antitumor effects with excellent biocompatibility and safety.

Conclusions:

• Conjugation of cRGD peptide to Me-PRX enhances selectivity for integrin α_vβ₃-positive cancer cells.
• cRGD-Me-PRX represents a promising strategy for targeted anticancer therapy with improved efficacy and safety.