Cancer Nanotherapeutics Research Articles

Nanoparticles in Oncology: The New Theragnostic Molecules

Cancer nanotherapeutics have shown promise in resolving some of the limitations of conventional drug delivery systems such as nonspecific biodistribution and targeting, lack of water solubility, low therapeutic indices, and poor oral bioavailability. Moreover, cancer nanotechnology has the potential of improving current approaches to cancer detection, diagnosis, and imaging. Recently, nanotechnology and molecular imaging have been combined to generate nanoparticles that simultaneously facilitate cancer therapy and diagnosis, the so called theragnostic nanoparticles. The aim of our review is to highlight recent developments within the context of the current knowledge of nanotechnology, to recall the experimental steps that have brought to the clinical development and application of nanoparticles, and explain the biological rationale for their use with oncologic patients. In particular, we summarize recent findings with respect to possible new applications for therapy and diagnosis, and their specific properties. Moreover, we report the more recent prospects in gene therapy, the possibility of using new drug delivery methods, the action of nanoparticles on the immune system and apoptosis, and the concrete possibility of detecting and characterizing circulating tumor cells or of developing new technologies in drug discovery.

Abstract 548: Multistage nanoparticle delivery system for deep penetration into solid tumor

Abstract Background: 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 ∼300 μm 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

Multistage nanoparticle delivery system for deep penetration into tumor tissue

Current Food and Drug Administration-approved cancer nanotherapeutics, which passively accumulate around leaky regions of the tumor vasculature because of an enhanced permeation and retention (EPR) effect, have provided only modest survival benefits. This suboptimal outcome is likely due to physiological barriers that hinder delivery of the nanotherapeutics throughout the tumor. Many of these nanotherapeutics are ≈ 100 nm in diameter and exhibit enhanced accumulation around the leaky regions of the tumor vasculature, but their large size hinders penetration into the dense collagen matrix. Therefore, we propose a multistage system in which 100-nm nanoparticles "shrink" to 10-nm nanoparticles after they extravasate from leaky regions of the tumor vasculature and are exposed to the tumor microenvironment. The shrunken nanoparticles can more readily diffuse throughout the tumor's interstitial space. This size change is triggered by proteases that are highly expressed in the tumor microenvironment such as MMP-2, which degrade the cores of 100-nm gelatin nanoparticles, releasing smaller 10-nm nanoparticles from their surface. We used quantum dots (QD) as a model system for the 10-nm particles because their fluorescence can be used to demonstrate the validity of our approach. In vitro MMP-2 activation of the multistage nanoparticles revealed that the size change was efficient and effective in the enhancement of diffusive transport. In vivo circulation half-life and intratumoral diffusion measurements indicate that our multistage nanoparticles exhibited both the long circulation half-life necessary for the EPR effect and the deep tumor penetration required for delivery into the tumor's dense collagen matrix.