The ultimate question to be addressed here is what range of filamentous shapes & flexibilities are 'nano' in the circulation and in permeating tumors or other porous tissues? Our worm-like 'Filomicelles' are made from amphiphilic PEG-based polymers similar to those in clinical use and similar to those used to make polymer vesicles, but our cylindrical Filomicelles already appear to possess surprisingly distinct and advantageous pharmacokinetic properties. While the biomaterials literature currently suggests that a particle radius much greater than approximately 100-200 nm leads to rapid clearance by phagocytes of the liver and spleen, we find that Filomicelles many microns long can """"""""worm"""""""" through the capillaries and circulate in vivo for a week or more - longer than any synthetic carrier yet reported. Mapping out the limits of this long circulation - length, diameter, flexibility, surface charge, drug retention, and ligand-targeting - is our pen-ultimate Aim in vivo. Long circulating Filomicelles should greatly increase the 'Area Under the Curve' for drug delivery, and we indeed already find that a single injection of PEG-polyester, 8 mu m-long Filomicelles loaded with the hydrophobic anti-mitotic drug taxol shrinks a solid tumor by almost half ... And this is found at a 'TAX' dose (in mg/kg) which is ineffective as free drug. Filomicelles also appear more potent than a single injection of polymer vesicles loaded with both TAX and Doxorubicin. Since our two types of polymer-based carriers are made from copolymers that differ in PEG fraction by only 5-10%, we can more directly compare effects of carrier morphology in delivery. For either system however, we do not yet know how much TAX is (i) released directly in the circulation, (ii) released gradually with sphere micelles from degrading carriers in circulation, or (iii) released from Filomicelles or vesicles that have permeated the tumor. Our ultimate Aim here is to address how the Filomicelles (vs polymer vesicles) might take advantage of the Enhanced Permeation and Retention ('EPR') effect in passive delivery to tumors - specifically lung tumors (with 80- 90% mortality in humans) in a xenograft model. The generality of the EPR effect with these carriers will be examined in limited studies of their permeation into non-cancerous 'porous' tissues such as damaged myocardium and dystrophic muscle. In parallel with the in vivo studies above, we propose to further the designs (with atomistic simulation), make, load, characterize (stability, release, etc.), and target novel block copolymer carriers. Targeted worm-like Filomicelles are already seen to cooperatively zip up on surfaces displaying suitable receptors, at least with model systems in vitro. Subsequent internalization by the cell can then lead to delivery of a large amount of drug all at once from a single micelle - enough to kill a single cell, in principle. In our initial Aims we seek to test this hypothesis of potency by first clarifying precepts of block copolymer self-assembly and shape stability, and then assessing copolymer degradation, cellular trafficking and transport. We propose a focused development of therapeutic ligands, including targeted apoptosis-inducers, as we ultimately seek a wider range of control and targeting (but passive first!) of copolymer assemblies for in vivo studies. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Biomedical Imaging and Bioengineering (NIBIB)
Type
Research Project (R01)
Project #
5R01EB007049-02
Application #
7287798
Study Section
Gene and Drug Delivery Systems Study Section (GDD)
Program Officer
Henderson, Lori
Project Start
2006-09-15
Project End
2010-06-30
Budget Start
2007-07-01
Budget End
2008-06-30
Support Year
2
Fiscal Year
2007
Total Cost
$347,541
Indirect Cost
Name
University of Pennsylvania
Department
Engineering (All Types)
Type
Schools of Engineering
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
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
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
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
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

Showing the most recent 10 out of 39 publications