Abstract SY20-01: PET-guided and ultrasound-enhanced nanotherapy
Authors: Katherine W. Ferrara, Azadeh Kheirolomoom, Jai W. Seo, Shengping Qin, Hua Zhang, Lisa Even, Cecilie Rygh
Journal: Cancer Research (2011)

Abstract Nanoencapsulation has the potential to reduce systemic toxicity while increasing the accumulation of drugs within tumors. In order to optimize therapeutic efficacy, we employ imaging to assess target availability and particle pharmacokinetics. We report on advances in the application of imaging to optimize nanotherapeutics. First, micron-sized bubbles have long been employed in cardiology to assess perfusion, and are widely available in Europe for the assessment of tumor perfusion. Such microbubbles can quantitatively assess the response of the vasculature to therapeutics, even differentiating the effects of unique anti-angiogenic therapeutics. Recently, microbubbles targeted to vascular integrins and VEGF have demonstrated the potential to detect and characterize tumors and are poised to enter human trials. With targeted ultrasound agents, multiple vascular receptors can be queried at a single study date. We will demonstrate the use of an RGD-targeted microbubble to assess syngeneic mouse tumors in a repeatable and specific fashion. The accumulation of targeted microbubbles on tumor endothelium occurs within 1-2 minutes (1), facilitating the personalized choice of therapies. Further, we have labeled nanoparticles for imaging with positron emission tomography (PET) and have demonstrated the use of such particles to detect the transition from premalignant to malignant lesions in preclinical studies. Nanoparticles, including 4×4×14 nm albumin (2), 100-nm liposomes and micron-diameter microbubbles (3), have been labeled for nuclear imaging of the shell (4-6) and in parallel the core of the particle has been imaged to assess stability. In particular, the accumulation of radiolabelled albumin, as assessed by PET, increased in a sensitive and gradual fashion over a malignant transition. PET imaging of radiolabelled particles also shows the potential to identify small regions of multifocal or metastatic disease that might otherwise be missed and facilitates mapping the heterogeneity of accumulation of particles with a diameter on the order of 100 nm or more. Based on such data, we have created an image-guided pharmacokinetic model encompassing particle circulation and stability (7) and applied this model and associated labeling methods to provide head-to-head comparisons of the pharmacokinetics of various nanotechnologies. In preclinical studies, stable particles accumulate to ∼5-10% ID/g within 24 hours. In a syngeneic mouse model, such accumulation can be locally increased to ∼20% ID/g with the application of therapeutic ultrasound (8, 9). Finally, in order to capitalize on the potential of nanomedicine, our laboratory has been focused on the development of particles that minimize systemic toxicity. With this approach, drug scheduling can be optimized for therapeutic impact. For example, we have formed a precipitate complex between copper and doxorubicin within nanoparticles (9). The advantage of this approach is that the particles are loaded at neutral pH and the copper-doxorubicin complex remains intact until a low pH environment is encountered in a lysosome or tumor. We found that the cardiac toxicity of doxorubicin was not detectable with this approach, while the tumor efficacy was undiminished. After a 28-day course of therapy with copper-doxorubicin liposomes, augmented with ultrasound, syngeneic tumors regressed to a premalignant phenotype of ∼ (1 mm)3 or could not be detected. References 1. Anderson C, et al. (2011) Ultrasound molecular imaging of tumor angiogenesis with a novel αVβ3-integrin targeted microbubble contrast agent. Invest. Radiol. in press. 2. Rygh CB, et al. (2011) Longitudinal investigation of permeability and distribution of macromolecules in mouse malignant transformation using PET. Clinical Cancer Research. 3. Tartis MS, et al. (2008) Dynamic microPET imaging of ultrasound contrast agents and lipid delivery. J. Controlled Release 131(3):160-166. 4. Marik J, et al. (2007) Long-circulating liposomes radiolabeled with F-18 fluorodipalmitin (F-18 FDP). Nucl. Med. Biol. 34(2):165-171. 5. Seo JW, et al. (2010) Liposomal Cu-64 labeling method using bifunctional chelators: polyethylene glycol spacer and chelator effects. Bioconjug. Chem. 21(7):1206-1215. 6. Seo JW, Zhang H, Kukis D, Meares C, &amp; Ferrara K (2008) A novel method to label preformed liposomes with Cu-64 for Positron Emission Tomography (PET) imaging. Bioconjug. Chem. 19(12):2577-2584. 7. Qin S, et al. (2010) An imaging-driven model for liposomal stability and circulation. Mol. Pharm. 7(1):12-21. 8. Kheirolomoom A, et al. (2010) Enhanced in vivo bioluminescence imaging using liposomal luciferin delivery system. J. Controlled Release 141(2):128-136. 9. Kheirolomoom A, et al. (2010) Copper—doxorubicin as a nanoparticle cargo retains efficacy with minimal toxicity. Molecular Pharmaceutics 7(6):1948-1958. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr SY20-01. doi:10.1158/1538-7445.AM2011-SY20-01