ABSTRACT
PURPOSE: To evaluate the ability of radiofrequency (RF)-triggered drug release from a multicomponent chain-shaped nanoparticle to inhibit the growth of an aggressive breast tumor. METHODS: A two-step solid phase chemistry was employed to synthesize doxorubicin-loaded nanochains, which were composed of three iron oxide nanospheres and one doxorubicin-loaded liposome assembled in a 100-nm-long linear nanochain. The nanochains were tested in the 4T1-LUC-GFP orthotopic mouse model, which is a highly aggressive breast cancer model. The 4T1-LUC-GFP cell line stably expresses firefly luciferase, which allowed the non-invasive in vivo imaging of tumor response to the treatment using bioluminescence imaging (BLI). RESULTS: Longitudinal BLI imaging showed that a single nanochain treatment followed by application of RF resulted in an at least 100-fold lower BLI signal compared to the groups treated with nanochains (without RF) or free doxorubicin followed by RF. A statistically significant increase in survival time of the nanochain-treated animals followed by RF (64.3 days) was observed when compared to the nanochain-treated group without RF (35.7 days), free doxorubicin-treated group followed by RF (38.5 days), and the untreated group (30.5 days; n=5 animals per group). CONCLUSIONS: These studies showed that the combination of RF and nanochains has the potential to effectively treat highly aggressive cancers and prolong survival.
Subject(s)
Antineoplastic Agents/administration & dosage , Antineoplastic Agents/therapeutic use , Breast Neoplasms/drug therapy , Mammary Neoplasms, Experimental/drug therapy , Nanoparticles/administration & dosage , Adjuvants, Pharmaceutic , Animals , Antibiotics, Antineoplastic/administration & dosage , Antibiotics, Antineoplastic/therapeutic use , Breast Neoplasms/pathology , Doxorubicin/administration & dosage , Doxorubicin/analogs & derivatives , Doxorubicin/therapeutic use , Female , Humans , Luminescence , Mammary Neoplasms, Experimental/pathology , Mice , Mice, Inbred BALB C , Nanoparticles/chemistry , Polyethylene Glycols/administration & dosage , Polyethylene Glycols/therapeutic use , Radio Waves , Survival Analysis , Tumor BurdenABSTRACT
While potent cytotoxic agents are available to oncologists, the clinical utility of these agents is limited due to their non-specific distribution in the body and toxicity to normal tissues leading to use of suboptimal doses for eradication of metastatic disease. Furthermore, treatment of micrometastases is impeded by several biobarriers, including their small size and high dispersion to organs, making them nearly inaccessible to drugs. To circumvent these limitations in treating metastatic disease, we developed a multicomponent, flexible chain-like nanoparticle (termed nanochain) that possesses a unique ability to gain access to and be deposited at micrometastatic sites. Moreover, coupling nanochain particles to radiofrequency (RF)-triggered cargo delivery facilitated widespread delivery of drug into hard-to-reach cancer cells. Collectively, these features synergistically facilitate effective treatment and ultimately eradication of micrometastatic disease using a low dose of a cytotoxic drug.
Subject(s)
Antineoplastic Agents/administration & dosage , Breast Neoplasms/drug therapy , Drug Delivery Systems/methods , Nanoparticles/chemistry , Neoplasm Micrometastasis/drug therapy , Animals , Antineoplastic Agents/therapeutic use , Breast/drug effects , Breast/pathology , Breast Neoplasms/pathology , Cell Line, Tumor , Female , Humans , Mice , Mice, Inbred BALB C , Neoplasm Micrometastasis/pathologyABSTRACT
While the enhanced permeability and retention effect may promote the preferential accumulation of nanoparticles into well-vascularized primary tumors, it is ineffective in the case of metastases hidden within a large population of normal cells. Due to their small size, high dispersion to organs, and low vascularization, metastatic tumors are less accessible to targeted nanoparticles. To tackle these challenges, we designed a nanoparticle for vascular targeting based on an α(v)ß(3) integrin-targeted nanochain particle composed of four iron oxide nanospheres chemically linked in a linear assembly. The chain-shaped nanoparticles enabled enhanced "sensing" of the tumor-associated remodeling of the vascular bed, offering increased likelihood of specific recognition of metastatic tumors. Compared to spherical nanoparticles, the chain-shaped nanoparticles resulted in superior targeting of α(v)ß(3) integrin due to geometrically enhanced multivalent docking. We performed multimodal in vivo imaging (fluorescence molecular tomography and magnetic resonance imaging) in a non-invasive and quantitative manner, which showed that the nanoparticles targeted metastases in the liver and lungs with high specificity in a highly aggressive breast tumor model in mice.