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Smart Brachytherapy Spacers for Combined Chemo-Radiation Therapy: Local Delivery of Nanoparticles, Chemotherapeutics, and Molecular Inhibitors for Cancer Treatment

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Smart Brachytherapy Spacers for Combined Chemo-Radiation Therapy: Local Delivery of Nanoparticles, Chemotherapeutics, and Molecular Inhibitors for Cancer Treatment Smart Brachytherapy Spacers for Combined Chemo-Radiation Therapy: Local delivery of nanoparticles, chemotherapeutics, and molecular inhibitors for cancer treatment A Dissertation Presented By Jodi Elizabeth Belz to The Department of Bioengineering in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the field of Bioengineering Northeastern University Boston, Massachusetts May 2017 ii ABSTRACT Prostate cancer remains the second leading cause of cancer related deaths in men with over 161,360 new cases and 26,730 associated deaths in the U.S. alone in 2017. While standardized screening has become routine and allowed for early stage detection, prostate cancer treatment options are scarce and often leave survivors with reduced quality of life due to off-target side effects. We have utilized technology in the standard clinical procedure Brachytherapy to deliver a new local chemotherapy implant with the standardized radiation treatment without the need for additional procedures. Brachytherapy uses plastic inert spacers to help clinicians place and separate the radioactive seeds. We have designed a biocompatible and biodegradable spacer that provides this spatial guidance, with the added therapeutic benefit of sustained chemotherapy and radiosensitization locally at the tumor site to sensitize the cancer throughout the course of brachytherapy rather than intermittent radiosensitization experienced with systemic chemotherapy administered every three weeks. These ‘smart brachytherapy spacers’ can be modified to tailor their release of docetaxel to coincide with varying half-lives of any radioactive seed used in brachytherapy. In this work, I have developed, characterized, and extensively tested a docetaxel loaded biodegradable implant for the treatment of prostate cancer. Our spacers were fabricated with a docetaxel loaded Poly(lactic-co-glycolic) acid cylindrical implant for intratumoral injection via an 18 gauge applicator needle for local, sustained therapy. Our spacers exhibit diffusion driven release in vitro over 75 days, designed to sensitize I-125 (t 1/2 = 60 days) brachytherapy seeds most commonly used for treatment of prostate cancer. The spacers were tested for therapeutic efficacy against clinically administered docetaxel iii and resulted in significant tumor inhibition and improved survival (median survival time (MST) of spacers 52 days versus 26 with IV DTX, p<0.01). Next the docetaxel spacer was combined with fractionated radiation therapy at reduced doses, to determine the radiosensitization and synergistic therapeutic response. Mice treated with local combined chemo-radiation resulted in significant survival improvement (MST 209 days vs. 120 in radiation therapy alone and 85 in spacers alone, p<0.01) and tumor inhibition, with 33% of mice cured. These results combined with a full toxicity study were completed and prove the therapeutic potential for successful clinical translation and impact. iv Acknowledgements I would like to first and foremost acknowledge my parents and siblings for their unconditional love and support. Mom and Dad, I have never gone a day unloved and for that I am forever grateful. This dissertation is dedicated to you. Thank you for always supporting me and encouraging me to be the best version of myself. I love you and you are my dearest inspirations. To my advisor, Dr. Srinivas Sridhar. I sincerely thank you. You have been patient, giving, and supportive. Working with you has awarded me more opportunities than most and I am grateful for all you have taught me. We have travelled across the world and back and genuinely thank you for everything you have done for me. To my second family, the Sridhar Lab. Paige and Rajiv, you have made this journey an unbelievable and worthwhile experience. I have learned so much from both of you. Thank you for your guidance, support, suggestions, and most importantly your laughter. You made every day more enjoyable and I will miss not working alongside you every day. You are not just colleagues, but true friends. Rita and Tim, the lab would not run without either of you so thank you for keeping us going. Noelle, Anne, Yuan, and Tej, you have been tremendous help in this work and I thank you for your contributions. I would like to thank our numerous collaborators both at Dana Farber Cancer Institute and Michigan State. Specifically, Robert Cormack for your large role, I appreciate all of your feedback as a member of my committee and of your enthusiasm and support on v this project. Your help has been instrumental in its success. I would also like to thank Ravina, Dolla, Aniruddha, and Houari who have sacrificed many weeks and weekends to help make sure my radiation treatments were completed on time. Karen Liby, you were a wonderful and kind collaborator who I hope to work with again in the future. Lastly, I would like to acknowledge the patients for whom we worked so hard for: those lost, surviving, and thriving. This past year, I received devastating news about a friend who lost their battle to prostate cancer. The implications of my work have never seemed so important. So I thank you and your families for sharing your battle and your continuous courage and fight. You are why I am so passionate about my work and you are the truest form of inspiration. vi LIST OF TABLES Table 1. TNM staging system for prostate cancer.........…………..……………………….8 Table 2. Commonly used radiation sources for brachytherapy ………………………......20 Table 3. Listed copolymer properties of PLGA available for purchase (Sigma)………... 59 Table 4 Design of preliminary in vivo LCRT experiment to determine appropriate dosing for synergistic therapeutic effects …………………...………………………………… 100 Table 5. Treatment plan for toxicity study showing time of sacrifice and number of animals per group ……………………………………………...……………………………….. 117 Table 6. Talazoparib implants decrease tumor size and extend survival in BRCA1-deficient mice………………………………………………………………………………..……140 vii LIST OF FIGURES Figure 1. Male Anatomy showing physiological location of prostate located below bladder, around urethra, and laterally to rectum.........………………………………...…………….4 Figure 2. Zonal depiction of the prostate. The prostate is divided into four regions, the central zone, transition zone, peripheral zone, and anterior fibromuscular stroma (AFS); ED: ejaculatory ducts, SV: seminal vesicles…………………………...............………….5 Figure 3. Gleason Grading System from 1 to 5, with grade 5 having the worst prognosis. The pathologist examines the biopsy sample of the prostate tissues microscopically, identifies any malignant areas, and assigns a score to each one. The first score is the predominant cancer type present, while the second number is the secondary pattern…... 10 Figure 4. Brachytherapy for prostate cancer using transrectal ultrasound guided imaging. Dozens of applicator needles are used to guide radioactive seeds into or near the tumor and placed using careful dose mapping of the tumor………………………………………… 15 Figure 5. Software imaging used to map out exact placement of applicator needles and brachytherapy seeds for complete dose mapping of the tumor while sparing radiation to healthy tissues prior to procedure……………………………………………………….. 21 Figure 6. Post-operative x-ray image showing permanent radiopaque brachytherapy seeds in prostate………………………………………………………………………………...22 Figure 7. Wientjes et al show spatial drug distribution in the prostate as a function of distance from the injection site after dogs were given intraprostatic infusions of doxorubicin (0.3m/150 AL over 150 minutes). Results show high drug concentrations are achievable, yet uneven distribution was attained…………………………………………23 Figure 8. Poly D,L-lactic-co-glycolic acid, where x and y represent the number of times each monomer repeats……………………………………………………………………24 Figure 9. PLGA hydrolysis results in lactic acid and glycolic acid oligomers…………..26 Figure 10. Taxanes stabilize microtubules, preventing mitosis, leading to eventual programmed cell death or apoptosis……………………………………………………...30 viii Figure 11. Paclitaxel and Docetaxel are structurally identical other than a difference in two functional groups which are highlighted in gray………………………………………….31 Figure 12. Size distribution of SiNP acquired from A) DLS. Data shows Gaussian distribution of silica nanoparticles with hydrodynamic diameter of ~36nm for SiNP encapsulating either Cy7.5, Cy5, or DTX and B) TEM image shows uniform silica nanoparticles with diameter of 30nm……………………………………………………..46 Figure 13. Stability of Silica Nanoparticles with docetaxel after fabrication, dialysis, and filtering showed no significant change in size during storage for 7 days in 4°C………...47 Figure 14. Release profile of docetaxel from silica nanoparticles in buffer (37°C, pH 7.4) over 6 days………………………………………………………………………………..48 Figure 15. PC3 cell viability after incubation with DTX loaded SiNP for 24, 48, and 72 hours. IC50 values are reported in molar concentration…………………………………..49 Figure 16. Confocal image of PC3 cellular uptake of Cy5 loaded silica nanoparticles (red) and RNA (blue) after 2 hr and 48 hr incubation…………………………………………50 Figure 17. Surviving fractions of empty SiNP, free docetaxel (DTX), and docetaxel loaded silica nanoparticles versus radiation at doses from 0-8 Gy using a small animal radiation research platform…………………………………………………………………………51 Figure 18. Schematic of INCeRT dual release platform with PLGA matrix embedded with Silica NPs loaded with chemotherapeutic or imaging moieties…………………………..54 Figure 19. Schematic
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