Development of Tumor Microenvironment-Responsive Nanoparticles with Enhanced Tissue Penetration

Area of Science:

• Nanomedicine and Drug Delivery
• Cancer Therapeutics
• Biotechnology

Background:

• Liposomes modified with pH-sensitive peptides (SAPSp-lipo) show promise for tumor delivery but require enhanced penetration into tumor cores.
• Current methods struggle to effectively deliver therapeutic agents deep within the complex tumor microenvironment.
• The internalizing RGD peptide (iRGD) is known for its tumor-penetrating capabilities, offering a potential strategy to improve liposome delivery.

Purpose of the Study:

• To develop and evaluate liposomes modified with iRGD-conjugated SAPSp (SAPSp-iRGD-lipo) for enhanced intratumoral penetration.
• To investigate the mechanism underlying the enhanced tumor penetration of SAPSp-iRGD-lipo.
• To assess the therapeutic efficacy of SAPSp-iRGD-lipo for delivering anticancer siRNA.

Main Methods:

• Synthesis of liposomes conjugated with iRGD-modified pH-sensitive peptides (SAPSp-iRGD-lipo).
• In vitro and in vivo evaluation of liposome penetration in spheroids and tumor tissues.
• Assessment of Neuropilin-1 involvement using inhibitors and localization studies.
• Analysis of F-actin dynamics and its role in tumor penetration.
• Evaluation of siRNA delivery and apoptosis induction in cancer cells under acidic conditions.

Main Results:

• SAPSp-iRGD-lipo demonstrated significantly deeper penetration into spheroids and tumor tissues compared to SAPSp-lipo.
• Enhanced penetration was mediated by Neuropilin-1 and involved actin depolymerization, not F-actin accumulation.
• The nanoparticles effectively delivered siRNA, inducing apoptosis in cancer cells under slightly acidic conditions.
• Localization studies confirmed Neuropilin-1-mediated penetration within tumors.

Conclusions:

• SAPSp-iRGD-modified nanoparticles represent a novel class of tumor-penetrable drug carriers.
• These nanoparticles exhibit microenvironment-responsive properties for efficient intratumoral delivery.
• The developed system holds potential for enhanced cancer therapy through improved drug targeting and efficacy.