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Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
Trends in Pharmacological Sciences (Impact Factor: 11.54). 03/2008; 29(2):57-61. DOI: 10.1016/
Source: PubMed


The development of antibody therapies for cancer is increasing rapidly, primarily owing to their specificity. Antibody distribution in tumors is often extremely uneven, however, leading to some malignant cells being exposed to saturating concentrations of antibody, whereas others are completely untargeted. This is detrimental because large regions of cells escape therapy, whereas other regions might be exposed to suboptimal concentrations that promote a selection of resistant mutants. The distribution of antibody depends on a variety of factors, including dose, affinity, antigens per cell and molecular size. Because these parameters are often known or easily estimated, a quick calculation based on simple modeling considerations can predict the uniformity of targeting within a tumor. Such analyses should enable experimental researchers to identify in a straightforward way the limitations in achieving evenly distributed antibody, and design and test improved antibody therapeutics more rationally.

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Available from: Greg M Thurber, Mar 27, 2014
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    • "Delivery of radiotoxic or chemotoxic “warheads” by antibodies or peptides, and administered by the IV method, is limited by high normal organ uptake and dose-limiting normal organ toxicities. Delivery barriers include tumor hydrostatic pressure [2], perivascular intratumoral concentration [3], [4], targets common to tumor and normal organs, and low tumor blood flow (relative to normal organs). The inability to efficiently target tumor masses is common to antibody and peptide conjugates, though these differ in size and pharmacokinetics. "
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    ABSTRACT: Here we introduce diffusion molecular retention (DMR) tumor targeting, a technique that employs PEG-fluorochrome shielded probes that, after a peritumoral (PT) injection, undergo slow vascular uptake and extensive interstitial diffusion, with tumor retention only through integrin molecular recognition. To demonstrate DMR, RGD (integrin binding) and RAD (control) probes were synthesized bearing DOTA (for (111) In(3+)), a NIR fluorochrome, and 5 kDa PEG that endows probes with a protein-like volume of 25 kDa and decreases non-specific interactions. With a GFP-BT-20 breast carcinoma model, tumor targeting by the DMR or IV methods was assessed by surface fluorescence, biodistribution of [(111)In] RGD and [(111)In] RAD probes, and whole animal SPECT. After a PT injection, both probes rapidly diffused through the normal and tumor interstitium, with retention of the RGD probe due to integrin interactions. With PT injection and the [(111)In] RGD probe, SPECT indicated a highly tumor specific uptake at 24 h post injection, with 352%ID/g tumor obtained by DMR (vs 4.14%ID/g by IV). The high efficiency molecular targeting of DMR employed low probe doses (e.g. 25 ng as RGD peptide), which minimizes toxicity risks and facilitates clinical translation. DMR applications include the delivery of fluorochromes for intraoperative tumor margin delineation, the delivery of radioisotopes (e.g. toxic, short range alpha emitters) for radiotherapy, or the delivery of photosensitizers to tumors accessible to light.
    PLoS ONE 03/2013; 8(3):e58290. DOI:10.1371/journal.pone.0058290 · 3.23 Impact Factor
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    • "Thus, we expect that much lower dose may be required than antibodies to FGFR1. Also, 3) the large size of antibodies results in poor tissue penetration [21], whereas R50E could more fully interrogate a tumor mass. And 4) Currently used target therapeutics (antibodies and kinase inhibitors) almost always induce resistance after a while. "
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    ABSTRACT: Fibroblast growth factor-1 (FGF1) and FGF2 play a critical role in angiogenesis, a formation of new blood vessels from existing blood vessels. Integrins are critically involved in FGF signaling through crosstalk. We previously reported that FGF1 directly binds to integrin αvβ3 and induces FGF receptor-1 (FGFR1)-FGF1-integrin αvβ3 ternary complex. We previously generated an integrin binding defective FGF1 mutant (Arg-50 to Glu, R50E). R50E is defective in inducing ternary complex formation, cell proliferation, and cell migration, and suppresses FGF signaling induced by WT FGF1 (a dominant-negative effect) These findings suggest that FGFR and αvβ3 crosstalk through direct integrin binding to FGF, and that R50E acts as an antagonist to FGFR. We studied if R50E suppresses tumorigenesis and angiogenesis. Here we describe that R50E suppressed tumor growth in vivo while WT FGF1 enhanced it using cancer cells that stably express WT FGF1 or R50E. Since R50E did not affect proliferation of cancer cells , we hypothesized that R50E suppressed tumorigenesis indirectly through suppressing angiogenesis. We thus studied the effect of R50E on angiogenesis in several angiogenesis models. We found that excess R50E suppressed FGF1-induced migration and tube formation of endothelial cells, FGF1-induced angiogenesis in matrigel plug assays, and the outgrowth of cells in aorta ring assays. Excess R50E suppressed FGF1-induced angiogenesis in chick embryo chorioallantoic membrane (CAM) assays. Interestingly, excess R50E suppressed FGF2-induced angiogenesis in CAM assays as well, suggesting that R50E may uniquely suppress signaling from other members of the FGF family. Taken together, our results suggest that R50E suppresses angiogenesis induced by FGF1 or FGF2, and thereby indirectly suppresses tumorigenesis, in addition to its possible direct effect on tumor cell proliferation We propose that R50E has potential as an anti-cancer and anti-angiogenesis therapeutic agent ("FGF1 decoy").
    PLoS ONE 02/2013; 8(2):e57927. DOI:10.1371/journal.pone.0057927 · 3.23 Impact Factor
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    • "The transport model was employed approximating the shape of the tumor spheroids as being strictly spherical. While the spheroids generated in this work were not perfect spheres, spherical coordinates have been utilized in several previous studies describing drug transport in tumor spheroids (Goodman et al. 2008; Thurber and Wittrup 2008), and have provided a reasonable shape estimate of the spheroids to describe drug penetration in this model. "
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    ABSTRACT: The mechanisms governing the efficient tumor spheroid penetration and transport by poly(amidoamine) (PAMAM) dendrimers displaying varying numbers of cyclic RGD targeting peptides (2, 3, 7, or 10) were evaluated in this work. The cell-free binding affinities and cellular internalization kinetics of PAMAM-RGD conjugates to malignant glioma cells were determined experimentally, and the results were incorporated into a mathematical model to predict the transport of these materials through a multicellular tumor spheroid. The theoretical analysis demonstrated that greater RGD crosslinking may improve transport through tumor spheroids due to their decreased integrin-binding affinity. This study provides evidence that altering the density of tumor-targeting ligands from a drug delivery platform is a feasible way to optimize the tumor-penetration efficiency of an anticancer agent, and provides insight into the physicochemical mechanisms governing the relative effectiveness of these conjugates.
    Biotechnology and Bioengineering 12/2011; 108(12):2999-3008. DOI:10.1002/bit.23255 · 4.13 Impact Factor
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