Nanoparticle-mediated drug delivery to tumor vasculature suppresses metastasis

Abstract

Integrin ␣ ␤3 is found on a subset of tumor blood vessels where it is associated with angiogenesis and malignant tumor growth. We designed an ␣ ␤3-targeted nanoparticle (NP) encapsulating the cytotoxic drug doxorubicin (Dox) for targeted drug delivery to the ␣ ␤3-expressing tumor vasculature. We observed real-time targeting of this NP to tumor vessels and noted selective apoptosis in regions of the ␣ ␤3-expressing tumor vasculature. In clinically relevant pancreatic and renal cell orthotopic models of spontaneous metastasis, targeted delivery of Dox produced an antimetastatic effect. In fact, ␣ ␤3-mediated delivery of this drug to the tumor vasculature resulted in a 15-fold increase in antimetastatic activity without producing drug-associated weight loss as observed with systemic administration of the free drug. These findings reveal that NP-based delivery of cytotoxic drugs to the ␣ ␤3-positive tumor vasculature represents an approach for treating metastatic disease.antiangiogenic ͉ intravital microscopy ͉ pancreatic cancer ͉ renal cell carcinoma ͉ liposome A ngiogenesis contributes to tumor malignancy and is linked to a wide variety of inflammatory and ischemic diseases. Integrin ␣v␤3, an internalization receptor for a number of viruses (1, 2), was shown to be preferentially expressed on the angiogenic endothelium in malignant or diseased tissues (3, 4). These characteristics of integrin ␣v␤3 make it an attractive targeting molecule for molecular imaging and delivery of therapeutics for cancer. Previous studies have shown that ␣v␤3-targeted nanoparticles (NPs) coupled to contrast agents can readily image the tumor vasculature revealing ''hot spots'' of angiogenesis within the tumor (5, 6). Therapeutic studies using the ␣v integrin-targeting peptide, RGD-4C, demonstrated that this peptide effectively targeted doxorubicin (Dox) to the tumor neovasculature and enhanced efficacy in human breast cancer xenografts in mice (7). In another study, an ␣v␤3-targeted NP delivering a suicide gene to angiogenic blood vessels was capable of producing an anticancer response (8). Although integrin ␣v␤3 is a marker of angiogenic endothelium, histological analysis of breast cancer biopsy tissue revealed that ␣v␤3 was a primary marker of blood vessels within the most malignant tumors (4). In fact, a strong correlation was established between the percent of ␣v␤3-positive vessels within the tumor and disease progression (9).Here, we report the design and characterization of an ␣v␤3-targeted NP capable of delivering various pharmacological agents to the ␣v␤3-expressing tumor vasculature. Evidence is provided that an ␣v␤3-targeted NP carrying the cytotoxic drug Dox is capable of controlling the metastatic behavior of pancreatic and renal cell cancer in mice. Importantly, targeted delivery of Dox to the tumor vasculature provided a 15-fold increase in the efficacy of the drug while producing few, if any, side effects. Results Design of NPs Targeted to Angiogenic Endothelium.A schematic representation of the targeted NP (RGD-NP) (Fig. ...

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