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 In3+), 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 [111In] RGD and [111In] 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 [111In] 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.
Highlights
We introduce a technique termed diffusion molecular retention (DMR) tumor targeting which exploits recently developed PEGfluorochrome shielded probes [1] that, after a peritumoral (PT) injection, undergo extensive diffusion through the interstitium, with tumor retention only through molecular recognition
We employed three techniques to demonstrate that DMR is an efficient method of tumor targeting, compared to the relatively inefficient targeting obtained with IV administration
The higher efficiency of tumor targeting obtained with DMR, relative to the standard IV method, was evident by tumor surface fluorescence (Figure 5), with SPECT imaging (Figure 6) and biodistribution studies (Figure 6)
Summary
We introduce a technique termed diffusion molecular retention (DMR) tumor targeting which exploits recently developed PEGfluorochrome shielded probes [1] that, after a peritumoral (PT) injection, undergo extensive diffusion through the interstitium, with tumor retention only through molecular recognition. By exploiting a PT injection and interstitial diffusion, DMR bypasses the many delivery barriers to solid tumors. 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. Approved antibody drug conjugates (e.g. Myotarg, withdrawn, and Adcetris) are indicated for disseminated leukemias or lymphomas, though some designed to target solid tumors are in clinical trials [13]. Methods to improve the targeting include sequence alteration [14,15,16], multivalency to increase affinity [17,18,19,20], increasing hydrophilicity to decrease nonspecific organ uptake [21,22,23], and the co-injection of amino acids to limit renal uptake [24]
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