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  • Priming of the Brain Tumor Microenvironment Enables Improved Nanomedicine Delivery

    Final Number:
    362

    Authors:
    Yuanxin Chen PhD; Wen Jiang; Yaqing Qie PhD; Xiujie Liu PhD; Christina von Roemeling MSc; Kevin Shih; Robert E. Wharen MD; Betty Y.S. Kim MD, PhD, FRCS(C)

    Study Design:
    Laboratory Investigation

    Subject Category:

    Meeting: Congress of Neurological Surgeons 2016 Annual Meeting

    Introduction: A major challenge in cancer nanotechnology is the efficient delivery of nanomedicines into solid tumors. Nanomedicine relies on a functional vascular network and minimal tissue resistance to achieve homogeneous transport and distribution in solid tumor via convection- and diffusion-based mechanisms. This is especially true for brain tumors, where the presence of specialized blood brain barrier further impedes transport of nanomedicine from the systemic circulation into the central nervous system. Unlike blood vessels within healthy tissues, tumor vessels are often morphologically pathologic and functionally impaired, due to an imbalance of pro- and anti-angiogenic growth factor production within the tumor microenvironment. Furthermore, within the tumor stroma, excessive and heterogeneous productions of collagen and other matrix proteins further restrict nanomedicine distribution.

    Methods: We characterized in real-time, perfusion and diffusion parameters of luminescent nanoparticles using syngeneic GL261 and the spontaneous RCAS-hPDGFb-HA/nestin–Tv-a; Ink4a/Arf-/- brain tumor model with multi-photon imaging, in vivo.

    Results: We demonstrate that tumor vasculature exhibits increased permeability and decreased perfusion capacity compared to normal vessels. As a result, transport of nanomedicine across the vessel wall into the tumor stroma is strongly dependent on particle size and surface polarity. Intratumoral mapping of nanomedicine distribution reveal that once gaining entry into tumors, nanoparticles often experience perivascular clumping and are unable to reach tumor tissue beyond 20µm from the nearest vessels. Finally, with therapeutic modulation of the tumor microenvironment using anti-VEGFr or anti-TGFß1 antibody treatments to remodel the tumor vasculature and collagen matrix, respectively, we show that tumors begin to exhibit improved tissue perfusion with improved delivery and distribution with nanomedicine into the tumor interstitium.

    Conclusions: The successful implementation of this combined therapeutic approach can have significant implications in developing effective targeted nanomedicines for brain tumors. These findings suggest that optimized delivery of nanomedicine for brain tumors maybe possible through the modulation of both the tumor vasculature and extracellular matrix.

    Patient Care: We propose to establish an optimal anti-angiogenic therapeutic regimen and modulation of the tumor microenvironment to improve drug delivery. This approach will not only result in lower systemic toxicity, but it will provide a paradigm shift in brain tumor therapy. Unlike conventional therapeutic strategies using high-doses of cytotoxic drugs to elicit maximum reduction of tumor burden, our vision is to specifically modulate tumor microenvironmental parameters, and utilize our bodies’ own immune system to keep brain tumors in remission. We envision that brain tumors can be effectively managed as a chronic disease in which our goal is to contain their disease activity via immune system modulation.

    Learning Objectives: 1. Priming of the tumor microenvironment to effectively deliver nanomedicines. 2. Limitations of nanoparticle delivery into solid tumors. 3. Novel strategies to enhance delivery and tumor clearance by modulating the tumor microenvironment

    References:

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