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BEST IN PHYSICS (THERAPY): Enhanced Drug Delivery by Nanoparticle and Radiation-Mediated Tumor Vascular Modulation

S Kunjachan1*, S Kotb1,2 , R Kumar1,3 , R Pola4 , M Pechar4 , F Gremse5 , R Taleei6 , F Trichard 2, V Motto-Ros2 , L Sancey7 , A Detappe1 , A Protti1 , I Shanmugam3 , T Ireland8 , T Etrych4 , S Sridhar1,3 , O Tillement2 , G Makrigiorgos1 , R Berbeco1 , (1) Brigham and Women's Hospital, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, (2) Insitut Lumiere Matiere, Villeurbanne, France (3) Northeastern University, Boston, MA, (4) Academy of Sciences of the Czech Republic, Prague, Czech Republic (5) University Hospital and Helmholtz Institute for Biomedical Engineering, Aachen, Germany, (6) University of Texas Southwestern Medical Center, Dallas, Texas, (7) Institute for Advanced Biosciences, Grenoble, Les Alpes, France, (8) Boston University, Boston, MA


(Tuesday, 7/31/2018) 1:45 PM - 3:45 PM

Room: Karl Dean Ballroom A1

Purpose: Effective drug delivery is restricted by the presence of complex pathophysiological barriers in solid tumors. In pancreatic adenocarcinoma (PDAC), the permeation and penetration of chemotherapeutics is limited, representing a substantial therapeutic challenge. In our previous work, we demonstrated that targeted nanoparticles (t-NP) can inflict vascular damage in pancreatic tumors when combined with radiation therapy (RT). Here, we present a strategy to selectively knock-down the tumor vascular barrier to enhance tumor-specific drug delivery in a human pancreatic tumor model.

Methods: Mice with subcutaneous human PDAC (Capan-1) tumors were divided into four cohorts: control, RT only, t-NP only and t-NP + RT. RGD-conjugated pegylated gold nanoparticles (t-NP) were injected at 24 hours before external beam radiation therapy (10 Gy). A short circulating MRI nanocontrast agent (Gad-NC, 2-3 nm) was administered 24 h post-RT to evaluate early vascular modulation and DCE-MRI was performed to evaluate changes in vascular dynamics. A long-circulating fluorescent nanocontrast agent (FL-NC, 10-12 nm) was used to evaluate accumulation over several days.

Results: We found that active disruption of the tumor vascular barrier using combined nanoparticle and radiation treatment led to improved tumor vascular permeability, resulting in substantial intratumor accumulation of both prototypical model nanodrugs: a short-circulating-nanocarrier with MR-sensitive gadolinium (8 kDa; t(1/2)≈1.5 h) and a long-circulating polymeric nanocarrier with fluorescence-sensitive dye (30 kDa; t(1/2)≈25 h). Functional changes in the vascular dynamics, measured by the relative changes in tumor permeability (Ktrans), flux rate (Kep) and extracellular interstitial volume (Ve) parameters, were consistent with the increase in drug delivery.

Conclusion: We have demonstrated selective tumor vascular modulation with targeted gold nanoparticles and external beam radiation therapy. The combination of radiation-induced anti-vascular and nanodrug-mediated anti-tumor treatment is attractive for tumors with a restrictive pathophysiology. This new concept represents a novel application of radiation therapy.

Funding Support, Disclosures, and Conflict of Interest: This work was supported, in part, by award number R21CA188833 from the National Institutes of Health and a JCRT Foundation Research Grant.


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