Avoiding clearance to maximize dose - Shape, Flexibility, and a 'Marker of Self' Nanoparticles of many types - including the biodegradable and multifunctional polymer systems here - have been developed for delivery of therapeutics to tumors or other disease sites, and although some particles perform better than others, a large fraction of material is always cleared from the circulation by uptake into phagocytic cells - especially macrophages in the liver, spleen, and lymph nodes. Cleared particles do not deliver drug to a tumor, and targeting strategies (especially with intact Antibodies) have simply not solved this major in vivo problem. We are addressing the problem with two distinct strategies. Particle 'shape', particularly long wormlike 'filomicelles'self-assembled from block copolymers but inspired by filoviruses, has been found to delay clearance. Filomicelles persist in the circulation longer than any other particles [1], and thereby open the dosage window and shift the drug load toward the tumor [2]. 'Nano'in cross-section, filomicelles that are 8-10 mm long prove most effective. Such lengths approximate the diameter of blood cells, which have flexible and fluidic membranes, and so we hypothesize key roles for filomicelle flexibility and fragment ability - which will be addressed in Aim-1 with in vivo imaging coupled to drug/oligo delivery, i.e. multi-functionality. Secondly, a more broadly applicable strategy is hypothesized for persistent circulation based on exploiting 'Marker of Self'polypeptides found on blood cells - and all cells - in your body. Following up on our recent finding [3] that 'Marker of Self'polypeptides inhibit in vitro phagocytosis of micron-size polymer particles, Aim-2 will pursue initial results with nanoparticles that show 'Marker of Self'polypeptides can indeed inhibit clearance in vivo and that also demonstrate function of a 20 amino acid synthetic peptide. Our approach should also benefit the many efforts to target particles with intact Antibody that result in rapid and massive clearance. Finally, Aim-3 will test in mice with a 'humanized'immune system the hypothesis that actively preventing clearance of filomicelles and related nanocarriers by covalent anchorage of the smallest possible 'Marker of Self'polypeptide will open the dosage window on Maximum Tolerated Dose, enabling delivery of more drug (or oliogonucleotide) to a disease site such as a tumor or a dystrophic muscle and thereby treating the site(s) more effectively. (1) Y. Geng, P.
Dalh aim er, S. Cai, R. Tsai, M. Tewari, T. Minko, and D.E. Discher. Shape effects of filaments versus spherical particles in flow and drug delivery. Nature Nanotechnology 2: 249-255 (2007). , (2) D.A. Christian, S. Cai, O. Garbuzenko, T. Harada, A. Zajac, T. Minko and D.E. Discher. Flexible filaments for in vivo imaging and delivery: Persistent circulation of filomicelles opens the dosage window for sustained tumor shrinkage. ACS - Molecular Pharmaceutics 6: 1343-1352 (2009). (3) R. Tsai and D.E. Discher. Inhibition of 'Self'Engulfment through deactivation of Myosin-II at the Phagocytic Synapse between Human Cells Journal of Cell Biology 180: 989-1003 (2008). ** Cover Article and Editor's Highlight. ** 1

Public Health Relevance

A large fraction of drug injected into patients does not end up at the target site;off-target cytoxicity can also limit dose. We propose to maximize delivery of drugs to solid tumors and diseased muscle by reducing or eliminating the accumulation of drug-laden particles elsewhere in the body. Elongated assemblies will be shown - dependent on flexibility and fragment ability - to persist in the circulation and to deliver more therapeutic. 'Marker of Self'polypeptides that engage phagocyte receptors and turn off the phagocytes will be attached to multifunctional nanoparticles in order to maximize persistence in the circulation and thereby maximize dye and drug delivery of Antibody-laden particles. To maximize relevance to humans, we will test nanocarriers in 'humanized'NOD-SCID mice engrafted with human immune systems. We focus on lung cancer models because of the high mortality, and we also focus on muscle disease because of the high genetic frequency.

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National Institute of Biomedical Imaging and Bioengineering (NIBIB)
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Gene and Drug Delivery Systems Study Section (GDD)
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Tucker, Jessica
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University of Pennsylvania
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Nair, Praful R; Karthick, S A; Spinler, Kyle R et al. (2016) Filomicelles from aromatic diblock copolymers increase paclitaxel-induced tumor cell death and aneuploidy compared with aliphatic copolymers. Nanomedicine (Lond) 11:1551-69
Ivanovska, Irena L; Shin, Jae-Won; Swift, Joe et al. (2015) Stem cell mechanobiology: diverse lessons from bone marrow. Trends Cell Biol 25:523-32
Dasbiswas, K; Majkut, S; Discher, D E et al. (2015) Substrate stiffness-modulated registry phase correlations in cardiomyocytes map structural order to coherent beating. Nat Commun 6:6085
Shin, Jae-Won; Discher, Dennis E (2015) Blood and immune cell engineering: Cytoskeletal contractility and nuclear rheology impact cell lineage and localization: Biophysical regulation of hematopoietic differentiation and trafficking. Bioessays 37:633-42
Dingal, P C Dave P; Bradshaw, Andrew M; Cho, Sangkyun et al. (2015) Fractal heterogeneity in minimal matrix models of scars modulates stiff-niche stem-cell responses via nuclear exit of a mechanorepressor. Nat Mater 14:951-60
Spinler, Kyle R; Shin, Jae-Won; Lambert, Michele P et al. (2015) Myosin-II repression favors pre/proplatelets but shear activation generates platelets and fails in macrothrombocytopenia. Blood 125:525-33
Sosale, Nisha G; Rouhiparkouhi, Tahereh; Bradshaw, Andrew M et al. (2015) Cell rigidity and shape override CD47's ""self""-signaling in phagocytosis by hyperactivating myosin-II. Blood 125:542-52
Sosale, Nisha G; Spinler, Kyle R; Alvey, Cory et al. (2015) Macrophage engulfment of a cell or nanoparticle is regulated by unavoidable opsonization, a species-specific 'Marker of Self' CD47, and target physical properties. Curr Opin Immunol 35:107-12
Oltra, NĂºria Sancho; Nair, Praful; Discher, Dennis E (2014) From stealthy polymersomes and filomicelles to ""self"" Peptide-nanoparticles for cancer therapy. Annu Rev Chem Biomol Eng 5:281-99
Shin, Jae-Won; Buxboim, Amnon; Spinler, Kyle R et al. (2014) Contractile forces sustain and polarize hematopoiesis from stem and progenitor cells. Cell Stem Cell 14:81-93

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