Effects of tumor microenvironment heterogeneity on nanoparticle disposition and efficacy in breast cancer tumor models.

Journal Article (Journal Article)

PURPOSE: Tumor cells are surrounded by a complex microenvironment. The purpose of our study was to evaluate the role of heterogeneity of the tumor microenvironment in the variability of nanoparticle (NP) delivery and efficacy. EXPERIMENTAL DESIGNS: C3(1)-T-Antigen genetically engineered mouse model (C3-TAg) and T11/TP53(Null) orthotopic syngeneic murine transplant model (T11) representing human breast tumor subtypes basal-like and claudin-low, respectively, were evaluated. For the pharmacokinetic studies, non-liposomal doxorubicin (NL-doxo) or polyethylene glycol tagged (PEGylated) liposomal doxorubicin (PLD) was administered at 6 mg/kg i.v. x1. Area under the concentration versus time curve (AUC) of doxorubicin was calculated. Macrophages, collagen, and the amount of vasculature were assessed by IHC. Chemokines and cytokines were measured by multiplex immunochemistry. NL-doxo or PLD was administered at 6 mg/kg i.v. weekly x6 in efficacy studies. Analyses of intermediary tumor response and overall survival were performed. RESULTS: Plasma AUC of NL-doxo and PLD encapsulated and released doxorubicin was similar between two models. However, tumor sum total AUC of PLD was 2-fold greater in C3-TAg compared with T11 (P < 0.05). T11 tumors showed significantly higher expression of CC chemokine ligand (CCL) 2 and VEGF-a, greater vascular quantity, and decreased expression of VEGF-c compared with C3-TAg (P < 0.05). PLD was more efficacious compared with NL-doxo in both models. CONCLUSION: The tumor microenvironment and/or tumor cell features of breast cancer affected NP tumor delivery and efficacy, but not the small-molecule drug. Our findings reveal the role of the tumor microenvironment in variability of NP delivery and therapeutic outcomes.

Full Text

Duke Authors

Cited Authors

  • Song, G; Darr, DB; Santos, CM; Ross, M; Valdivia, A; Jordan, JL; Midkiff, BR; Cohen, S; Nikolaishvili-Feinberg, N; Miller, CR; Tarrant, TK; Rogers, AB; Dudley, AC; Perou, CM; Zamboni, WC

Published Date

  • December 1, 2014

Published In

Volume / Issue

  • 20 / 23

Start / End Page

  • 6083 - 6095

PubMed ID

  • 25231403

Pubmed Central ID

  • PMC4565518

Electronic International Standard Serial Number (EISSN)

  • 1557-3265

Digital Object Identifier (DOI)

  • 10.1158/1078-0432.CCR-14-0493

Language

  • eng

Conference Location

  • United States