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The Tumor Microenvironment02:17

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Every normal cell or tissue is embedded in a complex local environment called stroma, consisting of different cell types, a basal membrane, and blood vessels. As normal cells mutate and develop into cancer cells, their local environment also changes to allow cancer progression. The tumor microenvironment (TME) consists of a complex cellular matrix of stromal cells and the developing tumor. The cross-talk between cancer cells and surrounding stromal cells is critical to disrupt normal tissue...
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Novel liposomes conjugated with iRGD peptides (SAPSp-iRGD-lipo) show enhanced tumor penetration and delivery. This nanoparticle system utilizes Neuropilin-1 and actin depolymerization for deeper tumor core access and therapeutic siRNA delivery.

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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.