Abstract 548: Multistage nanoparticle delivery system for deep penetration into solid tumor
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AbstractBackground: Through the enhanced permeation and retention (EPR) effect, current FDA-approved cancer nanotherapeutics accumulate preferentially around leaky regions of the tumor vasculature due to their large size – typically ∼100 nm in diameter. However, these extravasated large nanocarriers localize mostly at the tumor periphery and might not be able to effectively distribute throughout the tumor due to the dense collagen matrix in the tumor interstitum. The resulting heterogeneous distribution of therapeutic are likely responsible for the modest survival benefits of current nanomedicine.Methods: To overcome these physiological barriers to drug delivery in tumors, we have developed a multistage nanoparticle delivery system (QDGelNP) in which 100-nm nanoparticles “shrink” to 10-nm nanoparticles after they extravasate from the tumor vasculature and are exposed to the tumor microenvironment, allowing enhanced penetration into the tumor parenchyma. This “shrinkage” is preferentially triggered in the tumor by proteases, such as MMP-2, which are highly expressed and/or activated in the tumor microenvironment. These proteases degrade the cores of 100-nm gelatin nanoparticles, releasing smaller 10-nm nanoparticles from their surfaces. We used quantum dots (QD) as a model system for the 10-nm particles because their fluorescence can be monitored in vivo to test the validity of our approach.Results: In vivo blood circulation half-life measurement indicates that our QDGelNPs exhibited the long circulation half-life (22.0 ± 3.4 hours) necessary for the EPR effect. In vitro MMP-2 activation of QDGelNPs was characterized using gel filtration chromatography, fluorescence correlation spectroscopy, and collagen gel diffusion; these experiments revealed that the size change was efficient (50% activation in 1.5 hrs using 0.16 μM MMP-2) and effective in the enhancement of diffusive transport in dense collagen matrices (∼1 mm penetration in 12 hrs, D = ∼2.3 × 10−7 cm2s−1). To test whether tumor secreted MMP-2 can change the size of QDGelNPs in vivo, we intratumorally administered QDGelNPs into MMP-2 expressing tumors (HT-1080) grown in mouse dorsal skin chamber transparent window models and monitored interstitial distribution of QDs by intravital microscopy. At 6 hrs post-injection, the QDGelNPs penetrated up to ∼300μm into the surrounding tumor tissue (Deff = ∼2.2 × 10-8 cm2s−1), whereas 100-nm single-stage control nanoparticles were confined mostly at the injection site. These data confirmed our QDGelNPs’ capacity to penetrate the tumor's dense collagen matrix for delivery deep into solid tumors.Conclusion: We have successfully developed a multistage nanoparticle delivery system. Such delivery systems provide a promising approach to improving the delivery of anticancer agents into solid tumors and, as a result, reduction of the likelihood for tumor regression and enhancement of the drug's therapeutic efficacy.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 548. doi:10.1158/1538-7445.AM2011-548
