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

Abstract

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.

• Authors: Gina Song, David B Darr, Charlene M Santos, Mark Ross, Alain Valdivia, Jamie L Jordan, Bentley R Midkiff, Stephanie Cohen, Nana Nikolaishvili-Feinberg, C Ryan Miller, Teresa K Tarrant, Arlin B Rogers, Andrew C Dudley, Charles M Perou, William C Zamboni
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 20 Issue 23 Pg. 6083-95 (Dec 01 2014) ISSN: 1557-3265 [Electronic] United States
• PMID: 25231403 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: ©2014 American Association for Cancer Research.

Chemical References

• Chemokine CCL2
• Chemokine CCL5
• Vascular Endothelial Growth Factor A
• liposomal doxorubicin
• Polyethylene Glycols
• Doxorubicin
• Collagen

Topics

• Animals
• Breast Neoplasms (drug therapy, metabolism, mortality, pathology)
• Cell Line, Tumor
• Chemokine CCL2 (blood, metabolism)
• Chemokine CCL5 (blood, metabolism)
• Collagen (metabolism)
• Disease Models, Animal
• Doxorubicin (administration & dosage, analogs & derivatives, pharmacokinetics)
• Female
• Humans
• Mice
• Mice, Knockout
• Mice, Transgenic
• Nanoparticles (administration & dosage, metabolism)
• Neovascularization, Pathologic
• Polyethylene Glycols (administration & dosage, pharmacokinetics)
• Tumor Burden (drug effects)
• Tumor Microenvironment (drug effects)
• Vascular Endothelial Growth Factor A (metabolism)
• Xenograft Model Antitumor Assays