Repurposing Tamoxifen for Tumor Microenvironment Priming and Enhanced Tumor-Targeted Drug Delivery

Area of Science:

• Oncology
• Nanomedicine
• Tumor Microenvironment (TME) Research

Background:

• Dense stromal matrix in fibrotic tumors impedes drug delivery.
• Tamoxifen (TMX), an estrogen receptor modulator, can reprogram the tumor microenvironment (TME) and reduce desmoplasia.
• Repurposing TMX as a TME remodeling agent could enhance nanoparticle drug delivery.

Purpose of the Study:

• To investigate if TMX, in free and nano-formulated forms, can remodel the TME.
• To assess TMX's efficacy in improving tumor accumulation of nanoparticles in pancreatic ductal adenocarcinoma and triple-negative breast cancer models.
• To evaluate TMX's impact on key TME parameters like vascularization, perfusion, and collagen density.

Main Methods:

• Utilized PANC-1 and 4T1 mouse models for pancreatic and breast cancer, respectively.
• Administered free and nano-formulated TMX.
• Evaluated tumor accumulation of clinical-stage Cy7-labeled core-crosslinked polymeric micelles (CCPM) using in vivo imaging.
• Conducted histopathological immunofluorescence analysis of tumor tissues.

Main Results:

• Baseline CCPM accumulation was higher in PANC-1 tumors (16.7 % ID g⁻¹) than in 4T1 tumors (11.0 % ID g⁻¹).
• Neither free nor nano-formulated TMX significantly improved CCPM delivery in either tumor model.
• TMX treatment did not significantly alter vascularization, perfusion, macrophage infiltration, collagen density, or collagen fiber thickness.

Conclusions:

• TMX treatment does not prime the TME beneficially in PANC-1 and 4T1 mouse models.
• TMX does not enhance tumor-targeted drug delivery of nanoparticles in these models.
• Further research is needed to identify effective TME-modulating strategies for improved cancer nanomedicine delivery.