3D tumor tissue analogs and their orthotopic implants for understanding tumor-targeting of microenvironment-responsive nanosized chemotherapy and radiation.
An appropriate representation of the tumor microenvironment in tumor models can have a pronounced impact on directing combinatorial treatment strategies and cancer nanotherapeutics. The present study develops a novel 3D co-culture spheroid model (3D TNBC) incorporating tumor cells, endothelial cells and fibroblasts as color-coded murine tumor tissue analogs (TTA) to better represent the tumor milieu of triple negative breast cancer in vitro. Implantation of TTA orthotopically in nude mice, resulted in enhanced growth and aggressive metastasis to ectopic sites. Subsequently, the utility of the model is demonstrated for preferential targeting of irradiated tumor endothelial cells via radiation-induced stromal enrichment of galectin-1 using anginex conjugated nanoparticles (nanobins) carrying arsenic trioxide and cisplatin. Demonstration of a multimodal nanotherapeutic system and inclusion of the biological response to radiation using an in vitro/in vivo tumor model incorporating characteristics of tumor microenvironment presents an advance in preclinical evaluation of existing and novel cancer nanotherapies.


BACKGROUND
Existing in-vivo tumor models are established by implanting tumor cells into nude mice. Here, the authors described their approach 3D spheres containing tumor cells, enodothelial cells and fibroblasts. This would mimic tumor micro-environment more realistically. This interesting 3D model should reflect more accurately tumor response to various drugs and would enable the design of new treatment modalities.
Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, KY, USA.
Pallavi
P
Sethi
Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, KY, USA.
Amar
A
Jyoti
Chemistry of Life Processes Institute, Department of Chemistry, Northwestern University, Evanston, IL, USA.
Elden P
EP
Swindell
Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, KY, USA.
Ryan
R
Chan
Department of Radiation Medicine, University of Kentucky Chandler Hospital, Lexington, KY, USA.
Ulrich W
UW
Langner
Department of Radiation Medicine, University of Kentucky Chandler Hospital, Lexington, KY, USA.
Jonathan M
JM
Feddock
Division of Biomedical Informatics, University of Kentucky, Lexington, KY, USA.
Radhakrishnan
R
Nagarajan
Chemistry of Life Processes Institute, Department of Chemistry, Northwestern University, Evanston, IL, USA.
Thomas V
TV
O'Halloran
Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, KY, USA. Electronic address: m.upreti@uky.edu.
Meenakshi
M
Upreti
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000008:administration & dosage / Q000627:therapeutic use*; D001940:Breast / Q000187:drug effects / Q000473:pathology / Q000528:radiation effects; D002945:Cisplatin / Q000008:administration & dosage / Q000627:therapeutic use*; D018920:Coculture Techniques / Q000379:methods*; D004195:Disease Models, Animal; D016503:Drug Delivery Systems; D042783:Endothelial Cells / Q000187:drug effects / Q000473:pathology; D005260:Female; D005347:Fibroblasts / Q000187:drug effects / Q000473:pathology; D037483:Galectin 1 / Q000032:analysis; D051379:Mice; D008819:Mice, Nude; D053758:Nanoparticles / Q000737:chemistry; D010087:Oxides / Q000008:administration & dosage / Q000627:therapeutic use*; D018874:Spheroids, Cellular / Q000187:drug effects / Q000473:pathology; D064726:Triple Negative Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology / Q000532:radiotherapy*; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000473:pathology; D059016:Tumor Microenvironment / Q000187:drug effects / Q000528:radiation effects
D000970:Antineoplastic Agents; D001152:Arsenicals; D037483:Galectin 1; D010087:Oxides; D002945:Cisplatin; D000077237:Arsenic Trioxide
3 dimensional triple negative breast cancer (3D TNBC) model; 3D co-cultures; Galectin-1; Targeted nanoparticle; Tumor cell spheroids; Tumor microenvironment; Tumor tissue analogs (TTA)