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Localized Tumor Delivery of Radiosensitizers and Chemotherapeutics Using ‘INCeRT ’ Implants Jodi Belz 1 , Stacey Markovic 2 , Rajiv Kumar 1,3 , Mark Neidre 2 , Robert Cormack 3 , Mike Makrigiorgos 3 , Srinivas Sridhar 1,3 1 Nanomedicine Science and Technology Center, 2 ECE Department, Northeastern University, Boston, MA 02115 3 Department of Radiation Oncology, Dana Farber Cancer Institute, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA. BIOLOGICAL IN SITU IMAGE GUIDED RADIOTHERAPY Biologic in-situ image guided radiation therapy (BIS- IGRT) 1,2,3,4 offers the potential to deliver planned, localized and sustained delivery of chemotherapy agent, without systemic toxicities, as part of routine minimally invasive image guided radiation therapy procedures This new approach for localized chemoradiation therapy, involves fabrication of spacers routinely used during prostate brachytherapy with radiosensitizing drugs/dyes. Cormack, et. al., IJROBP, v.76, 615 (2010 ) These Implantable Nanoplatforms for Chemoradiation Therapy (INCeRT) utilizes the nanoparticles properties of sustained drug release along with one or more imaging modality. INCeRT SPACERS DESIGN PLGA Spacer with Encapsulated Silica nanoparticles with drug/dye Release of Silica NPs from spacer Release of drug/dye from NPs A DUAL RELEASE PLATFORM INCeRT-1 Encapsulated system INCeRT-2 Conjugated system Commercial Spacers INNOVATION AND ADVANTAGES Localized sustained delivery of chemotherapeutic drug vs. intermittent systemic administration INCeRT provides means of image guided chemoradiation therapy by estimating the drug distribution produced by optical imaging. Tailored release profiles of the encapsulated drug to achieve radiosensitization synchronized with the radioactive decay rate for different sources such as Cs-131, Pd-103 and I-125. Minimal additional inconvenience to the patient (uses current implant needles and procedures). The synergistic effect of radiosensitization and radiation therapy could lead to reduced radiation doses and improved survival. Supported by IGERT grant NSF-DGE- 0965843 and ARMY/ W81XWH-12-1-0154. and by Brigham and Women’s Hospital. Top view Lateral view NPs impression in flash frozen fractured sample CHARACTERIZATION OF INCeRT SPACERS 100 150 200 250 300 350 400 0 20 40 60 80 100 Intensity (a.u.) Size (nm) ORM E1 Gauss Fit 750 800 850 900 0.0 0.5 1.0 ORM 09 ORM 08 ORM 07 ORM 06 ORM 05 Wavelength (nm) Fluorescence Intensity(CPS) SEM images of the Spacers TEM of Silica NPs DLS Of Silica NPs Optical signature of Si NPs IN VIVO DIFFUSION STUDIES BY OPTICAL IMAGING Comparison between dye doped (left) and NPs doped spacers (right) Transmission image Fluorescence image (Fluorescent Image-Dark Count)/Exposure Time 0 200 400 600 800 1000 1200 1400 1600 1800 (Intrinsic Image-Dark Count)/Exposure Time 1000 2000 3000 4000 5000 6000 7000 8000 Normalized Image 0.05 0.1 0.15 0.2 0.25 0.3 0.35 Normalized Image Overlaid on White Light Image 0 2 4 6 8 10 12 14 16 0 1 2 3 4 5 6 7 8 9 10 11 Spacer Area Comparisons Time (days) Area (mm 2 ) Free Dye Spacers 30 nm NP Spacers 200 nm NP Spacers Size dependent diffusion profile IN VIVO DIFFUSION STUDY DESIGN IN VIVO THERAPEUTIC EFFICACY OF DTX SPACERS R² = 0.8424 R² = 0.9628 R² = 0.9297 R² = 0.6832 0 200 400 600 800 1000 1200 0 5 10 15 Tumor Volume (mm^3) Time (Days) Control 1 Control 2 Control 3 Control 4 R² = 0.8152 R² = 0.5076 R² = 0.3879 0 100 200 300 400 500 600 700 800 0 10 Tumor Volume (mm^3) Time (Days) Free DTX 1 Free DTX 2 Free DTX 3 R² = 0.8078 R² = 0.9069 R² = 0.951 0 200 400 600 800 1000 1200 1400 0 2 4 6 8 10 12 14 16 Tumor Volume (mm^3) Time (Days) DTX Spacer 1 DTX Spacer 2 DTX Spacer 3 Control : No spacers Free DTX: IV injection DTX spacers DTX Dose: single intravenous injection of ~12mg/kg body weight DTX spacer: 2 spacers 3mm long with total DTX ~12mg/kg body weight CONCLUSIONS Developed a nanoparticle-based platform for combined local chemo-radiation therapy. Fabricated INCeRT spacers with biocompatible and biodegradable polymer, PLGA impregnated with varying sized nanoparticles encapsulating imaging probe (Cy 7.5) and chemotherapeutic drug, docetaxel. We have also fabricated PLGA spacers impregnated with high Z (atomic number) gold nanoparticles (Hi-Z-CuRE) for effectively boosting the radiation dose locally. In-vivo optical imaging demonstrates that the INCeRT spacer has a size dependent release profile of Silica NPs. In-vivo measurements demonstrate that NP remain resident in the vicinity of the implanted eluting spacers with accumulation over times appropriate to improve brachytherapy’s therapeutic ratio. In-vivo DTX spacers were shown to inhibit growth and shrink the tumor for a number of days as the drug was released intratumorally with minimal visible adverse effects to the mice. The spacers were most effective in smaller tumors, where the size of the tumor shrank at the time of sacrifice. REFERENCES 1. Cormack, R.A., Sridhar, S., Suh, W.W., et al Int J Radiat Oncol Biol Phys 76:615-23, 2010.; 2. Nagesha, D.K., Tada, D.B., Stambaugh, C.K., et al Phys Med Biol, 55:6039-52, 2010. 3. Tada, D.B., Singh, S., Nagesha, D., et al Pharm Res, 27:1738-45, 2010. 4. Cormack, RA, Nguyen P, D’Amico AV, et al Proc. SPIE, V.7964, P.79640A Orlando 2011. Comparison of systemic IV injected DTX verses localized release of DTX INCeRT Spacer injected Intraturmorally (IT) in PC3 Subcutaneous Tumors grown on hind leg of Male Nude Mice. 1. IT DTX Spacer Injection 2. IV DTX Injection 3. No treatment 3 2 1 Harvested Tumors Systemic chemotherapy is often used with radiation therapy in the management of prostate cancer, but leads to severe systemic toxicities. We have introduced the fabrication of an Implantable Nanoplatform for Chemo-radiation Therapy (INCeRT) spacer that offers the potential to deliver planned, localized and sustained delivery of chemotherapy and imaging agent. This new modality of chemotherapy would be delivered as part of a routine minimally invasive image guided radiation therapy procedure in brachytherapy. Such image guided chemoradiation therapy replaces currently used inert spacers with no therapeutic impact, with drug eluting spacers that provide the same spatial benefit with the added localized chemotherapeutic. This new therapeutic modality requires characterization of the drug distribution produced by implantable drug eluters. This work presents imaging based means to measure and compare temporal and spatial properties of diffusion distributions around spacers loaded with multi-sized dye-doped nanoparticles or spacers loaded with free dye. The optimized spacer was loaded with chemotherapeutics and inserted intratumorally for efficacy of the localized chemotherapy versus the standard systemic dosing. The in vivo chemotherapy measurements demonstrate that local chemotherapy is not only feasible, but as effective as current treatment options. This new localized chemo-treatment shows great potential in increased tumor reduction with overall decreased systemic toxicity. ABSTRACT Graduate Interdisciplinary Topics PhD in Bioengineering Abstract ID# 230
