Targeting of Primary Breast Cancers and Metastases in a Transgenic Mouse Model Using Rationally Designed Multifunctional SPIONs

Abstract

Breast cancer remains one of the most prevalent and lethal malignancies in women. The inability to diagnose small volume metastases early has limited effective treatment of stage 4 breast cancer. Here we report the rational development and use of a multifunctional superparamagnetic iron oxide nanoparticle (SPION) for targeting metastatic breast cancer in a transgenic mouse model and imaging with magnetic resonance (MR). SPIONs coated with a copolymer of chitosan and polyethylene glycol (PEG) were labeled with a fluorescent dye for optical detection and conjugated with a monoclonal antibody against the neu receptor (NP-neu). SPIONs labeled with mouse IgG were used as a non-targeting control (NP-IgG). These SPIONs had desirable physiochemical properties for in vivo applications such as near neutral zeta potential and hydrodynamic size around 40 nm, and were highly stable in serum containing medium. Only NP-neu showed high uptake in neu expressing mouse mammary carcinoma (MMC) cells which was reversed by competing free neu antibody, indicating their specificity to the neu antigen. In vivo, NP-neu was able to tag primary breast tumors and significantly, only NP-neu bound to spontaneous liver, lung, and bone marrow metastases in a transgenic mouse model of metastatic breast cancer, highlighting the necessity of targeting for delivery to metastatic disease. The SPIONs provided significant contrast enhancement in MR images of primary breast tumors; thus, they have the potential for MRI detection of micrometastases, and provide an excellent platform for further development of an efficient metastatic breast cancer therapy.

Development of nanotheranostics against metastatic breast cancer — A focus on the biology & mechanistic approaches

“…Actively targeted nanoparticles composed of both SPIONs and fluorescent probes have been found to be successful in detecting tumor cells in metastatic breast cancer models (Yang et al, 2009;Kievit et al, 2012;Peirist et al, 2012;). Nanochain of iron oxide nanospheres tagged with cyclic RGD peptide (cRGDfC) and NIR fluorophore formulated by Peiris et al, were found to co-localize efficiently in the tumor endothelium and metastatic lesions in lung and liver (secondary sites) by targeting α v β 3 integrin, which was confirmed using MRI and fluorescence imaging (Peirist et al, 2012).…”

“…Nanochain of iron oxide nanospheres tagged with cyclic RGD peptide (cRGDfC) and NIR fluorophore formulated by Peiris et al, were found to co-localize efficiently in the tumor endothelium and metastatic lesions in lung and liver (secondary sites) by targeting α v β 3 integrin, which was confirmed using MRI and fluorescence imaging (Peirist et al, 2012). SPION (MRI) coated with chitosan-g-PEG copolymer tagged with Alexa Fluor 647 (Optical imaging) was found to be efficient in detecting spontaneous metastasis and facilitated in vivo MRI analysis and ex vivo fluorescence analysis in the detection of primary as well as micrometastatic lesions (Kievit et al, 2012).…”

Inhibition of primary and metastatic tumors in mice by E-selectin-targeted polymer–drug conjugates

“…Active targeting of tumor-specific surface receptors that are expressed or overexpressed uniquely on primary tumors was described previously using nanosized medicines (nanomedicines) for the treatment of primary tumors [4][5][6][7][8] and can also be applied for the treatment of metastases [9,10]. However, the genetic mutations that cancer cells undergo increase their resistance to chemotherapeutic agents [11] and, although nanomedicines can overcome some of the mechanisms responsible for this resistance [12], biological barriers such as the high interstitial pressure and the dense extracellular matrix within tumors [13] render their penetration into the tissue largely inefficient beyond the perivascular region [14][15][16].…”

Superparamagnetic iron oxide nanoparticle-based delivery systems for biotherapeutics

“…Recently, a wide range of carriers harnessed with targeting ligands or stimuli-responsive moieties that are responsive to external stimuli such as lights, ultrasounds, and magnetic fields have been developed for targeted delivery of biotherapeutics [10, 11]. Among these carriers, superparamagnetic iron oxide nanoparticle (SPION)-based delivery systems have drawn considerable attention because of their unique features such as biocompatibility and superparamagnetism that makes them detectable by MRI for monitoring treatment response and enables magnet-driven drug delivery and release [12-17]. …”