Neeharika Sinha

Targeted radiotherapy enhancement during electronic brachytherapy of accelerated partial breast irradiation (APBI) using controlled release of gold nanoparticles

Several studies have demonstrated low rates of local recurrence with brachytherapy-based accelerated partial breast irradiation (APBI). However, long-term outcomes on toxicity (e.g. telangiectasia) and cosmesis remain a major concern. The purpose of this study is to investigate the dosimetric feasibility of using targeted non-toxic radiosensitizing gold nanoparticles (GNPs) for localized dose enhancement to the planning target volume (PTV) during electronic brachytherapy APBI while reducing normal tissue toxicity. We propose to incorporate GNPs into a micrometer-thick polymer film on the surface of routinely used lumpectomy balloon applicators and provide subsequent treatment using a 50 kVp Xoft device. An experimentally determined diffusion coefficient was used to determine space-time customizable distribution of GNPs for feasible in-vivo concentrations of 7 mg/g and 43 mg/g. An analytical approach from previously published work was employed to estimate the dose enhancement due to GNPs as a function of distance up to 1 cm from the lumpectomy cavity surface. Clinically significant dose enhancement values of at least 1.2, due to 2 nm GNPs, were found at 1 cm away from the lumpectomy cavity wall when using electronic brachytherapy APBI. Higher customizable dose enhancement was also achieved at other distances as a function of nanoparticle size. Our preliminary results suggest that significant dose enhancement can be achieved to residual tumor cells targeted with GNPs during APBI with electronic brachytherapy.

Potential of using cerium oxide nanoparticles for protecting healthy tissue during accelerated partial breast irradiation (APBI)

The purpose of this study is to investigate the feasibility of using cerium oxide nanoparticles (CONPs) as radical scavengers during accelerated partial breast irradiation (APBI) to protect normal tissue. We hypothesize that CONPs can be slowly released from the routinely used APBI balloon applicators-via a degradable coating-and protect the normal tissue on the border of the lumpectomy cavity over the duration of APBI. To assess the feasibility of this approach, we analytically calculated the initial concentration of CONPs required to protect normal breast tissue from reactive oxygen species (ROS) and the time required for the particles to diffuse to various distances from the lumpectomy wall. Given that cerium has a high atomic number, we took into account the possible inadvertent dose enhancement that could occur due to the photoelectric interactions with radiotherapy photons. To protect against a typical MammoSite treatment fraction of 3.4Gy, 5ng·g(-1) of CONPs is required to scavenge hydroxyl radicals and hydrogen peroxide. Using 2nm sized NPs, with an initial concentration of 1mg·g(-1), we found that 2-10days of diffusion is required to obtain desired concentrations of CONPs in regions 1-2cm away from the lumpectomy wall. The resultant dose enhancement factor (DEF) is less than 1.01 under such conditions. Our results predict that CONPs can be employed for radioprotection during APBI using a new design in which balloon applicators are coated with the NPs for sustained/controlled in-situ release from within the lumpectomy cavity.

Enhancing radiotherapy for lung cancer using immunoadjuvants delivered in situ from new design radiotherapy biomaterials: a preclinical study.

Studies show that radiotherapy of a primary tumor in combination with immunoadjuvants (IA) can result in increased survival or immune-mediated regression of metastasis outside the radiation field, a phenomenon known as abscopal effect. However, toxicities due to repeated systematic administration of IA have been shown to be a major obstacle in clinical trials. To minimize the toxicities and prime a more potent immune response, Ngwa et al have proposed that inert radiotherapy biomaterials such as fiducials could be upgraded to multifunctional ones loaded with IA for in situ delivery directly into the tumor sub-volume at no additional inconvenience to patients. In this preliminary study, the potential of such an approach is investigated for lung cancer using anti-CD40 antibody. First the benefit of using the anti-CD40 delivered in situ to enhance radiotherapy was tested in mice with subcutaneous tumors generated with the Lewis Lung cancer cell line LL/2 (LLC-1). The tumors were implanted on both flanks of the mice to simulate metastasis. Tumors on one flank were treated with and without anti-CD40 and the survival benefits compared. An experimentally determined in vivo diffusion coefficient for nanoparticles was then employed to estimate the time for achieving intratumoral distribution of the needed minimal concentrations of anti-CD40 nanoparticles if released from a multifuntional radiotherapy biomaterials. The studies show that the use of anti-CD40 significantly enhanced radiotherapy effect, slowing the growth of the treated and untreated tumors, and increasing survival. Meanwhile our calculations indicate that for a 2-4 cm tumor and 7 mg g-1 IA concentrations, it would take 4.4-17.4 d, respectively, following burst release, for the required concentration of IA nanoparticles to accumulate throughout the tumor during image-guided radiotherapy. The distribution of IA could be customized as a function of loading concentrations or nanoparticle size to fit current Stereotactic Body Radiotherapy schedules. Overall, the preliminary results support ongoing work in developing multifunctional radiotherapy biomaterials for in situ delivery of immunoadjuvants such as anti-CD40 to leverage the abscopal effect, while minimizing systemic toxicities. The potential of extending such an approach to other cancer types is discussed.

Enhancing the Therapeutic Efficacy of Cancer Treatment With Cannabinoids

Over the years, many in vitro and in vivo studies have shown the antineoplastic effects of cannabinoids (CBDs), with reports advocating for investigations of combination therapy approaches that could better leverage these effects in clinical translation. This study explores the potential of combination approaches employing CBDs with radiotherapy (RT) or smart biomaterials toward enhancing therapeutic efficacy during treatment of pancreatic and lung cancers. In in vitro studies, clonogenic assay results showed greater effective tumor cell killing, when combining CBDs and RT. Meanwhile, in vivo study results revealed major increase in survival when employing smart biomaterials for sustained delivery of CBDs to tumor cells. The significance of these findings, considerations for further research, and viable roadmap to clinical translation are discussed.

Priming the Abscopal Effect Using Multifunctional Smart Radiotherapy Biomaterials Loaded with Immunoadjuvants

In this study, we investigate the use of multifunctional smart radiotherapy biomaterials (SRBs) loaded with immunoadjuvants for boosting the abscopal effect of local radiotherapy (RT). SRBs were designed similar to currently used inert RT biomaterials, incorporating a biodegradable polymer with reservoir for loading payloads of the immunoadjuvant anti-CD40 monoclonal antibody. Lung (LLC1) tumors were generated both on the right and left flank of each mouse, with the left tumor representing metastasis. The mice were randomized and divided into eight cohorts with four cohorts receiving image-guided RT (IGRT) at 5 Gy and another similar four cohorts at 0 Gy. IGRT and Computed Tomography (CT) imaging were performed using a small animal radiation research platform (SARRP). Tumor volume measurements for both flank tumors and animal survival was assessed over 25 weeks. Tumor volume measurements showed significantly enhanced inhibition in growth for the right flank tumors of mice in the cohort treated with SRBs loaded with CD40 mAbs and IGRT. Results also suggest that the use of polymeric SRBs with CD40 mAbs without RT could generate an immune response, consistent with previous studies showing such response when using anti-CD40. Overall, 60% of mice treated with SRBs showed complete tumor regression during the observation period, compared to 10% for cohorts administered with anti-CD40 mAbs, but no SRB. Complete tumor regression was not observed in any other cohorts. The findings justify more studies varying RT doses and quantifying the immune-cell populations involved when using SRBs. Such SRBs could be developed to replace currently used RT biomaterials, allowing not only for geometric accuracy during RT, but also for extending RT to the treatment of metastatic lesions.

MO-FG-BRA-04: Leveraging the Abscopal Effect Via New Design Radiotherapy Biomaterials Loaded with Immune Checkpoint Inhibitors

Purpose: Studies show that stereotactic body radiation therapy (SBRT) of a primary tumor in combination with immune checkpoint inhibitors (ICI) could Result in an immune-mediated regression of metastasis outside the radiation field, a phenomenon known as abscopal effect. However toxicities due to repeated systematic administration of ICI have been shown to be a major obstacle in clinical trials. Towards overcoming these toxicity limitations, we investigate a potential new approach whereby the ICI are administered via sustained in-situ release from radiotherapy (RT) biomaterials (e.g. fiducials) coated with a polymer containing the ICI. Methods: New design RT biomaterials were prepared by coating commercially available spacers/fiducials with a biocompatible polymer (PLGA) film containing fluorescent nanoparticles of size needed to load the ICI. The release of the nanoparticles was investigated in-vitro. Meanwhile, an experimentally determined in- vivo nanoparticle diffusion coefficient was employed in analytic calculations based on Fick’s second law to estimate the time for achieving the concentrations of ICI in the tumor draining lymph node (TDLN) that are needed to engender the abscopal effect during SBRT. The ICI investigated here was anti-CTLA-4 antibody (ipilimumab) at approved FDA concentrations. Results: Our in -vitro study results showed that RT biomaterials could be designed to achieve burst release of nanoparticles within one day. Meanwhile, our calculations indicate that for a 2 to 4 cm tumor it would take 4–22 days, respectively, following burst release, for the required concentration of ICI nanoparticles to accumulate in the TDLN during SBRT. Conclusion: Current investigations combining RT and immunotherapy involve repeated intravenous administration of ICI leading to significant systemic toxicities. Our preliminary results highlight a potential new approach for sustained in-situ release of the ICI from new design RT biomaterials. These results provide impetus for more studies to leverage the powerful abscopal effect, while minimizing systemic toxicities through the new approach.

SU-E-T-750: Three Dimensional in Silico Study of Brachytherapy Application with In-Situ Dose-Painting Administered Via Gold-Nanoparticle Eluters

Purpose: Brachytherapy Application with in-situ Dose-painting Administered via Gold-Nanoparticle Eluters (BANDAGE) has been proposed as a new therapeutic strategy for radiation boosting of high-risk prostate tumor subvolume while minimizing dose to neighboring organs-at-risk. In a previous study the one-dimensional dose-painting with gold nanoparticles (GNP) released from GNP-loaded brachytherapy spacers was investigated. The current study investigates BANDAGE in three-dimensions. Methods: To simulate GNPs transport in prostrate tumors, a three dimensional, cylindrically symmetric transport model was generated using a finite element method (FEM). A mathematical model of Gold nanoparticle (GNPs) transport provides a useful strategy to optimize potential treatment planning for BANDAGE. Here, treatment of tumors with a radius of 2.5 cm was simulated in 3-D. This simulation phase considered one gold based cylindrical spacer (GBS of size 5mm × 0.8 mm) introduced at the center of the spherical tumor with initial concentration of 100 mg/g or 508 mol/m3 of GNP. Finite element mesh is used to stimulate the GNP transport. Gold concentrations within the tumor were obtained using a 3-D FEM solution implemented by COMSOL. Results: The analysis shows the spread of the GNPs through-out the tumor with the increase of concentration towards the periphery with time. The analysis also shows the concentration profiles and corresponding dose enhancement factors (dose boost factor) as a function of GNP size. Conclusion: This study demonstrates the use of computational modeling and optimal parameter estimation to predict local GNPs from central implant as a function of x, y and z axis . Such a study provides a useful reference for ongoing translational studies for the BANDAGE approach

WE‐G‐BRE‐09: Targeted Radiotherapy Enhancement During Accelerated Partial Breast Irradiation (ABPI) Using Controlled Release of Gold Nanoparticles (GNPs)

PURPOSE Several studies have demonstrated low rates of local recurrence with brachytherapy-based accelerated partial breast irradiation (APBI). However, long-term outcomes on toxicity (e.g. telangiectasia), and cosmesis remain a major concern. The purpose of this study is to investigate the dosimetric feasibility of using targeted non-toxic radiosensitizing gold nanoparticles (GNPs) for localized dose enhancement to the planning target volume (PTV) during APBI while reducing dose to normal tissue. METHODS Two approaches for administering the GNPs were considered. In one approach, GNPs are assumed to be incorporated in a micrometer-thick polymer film on the surface of routinely used mammosite balloon applicators, for sustained controlled in-situ release, and subsequent treatment using 50-kVp Xoft devices. In case two, GNPs are administered directly into the lumpectomy cavity e.g. via injection or using fiducials coated with the GNP-loaded polymer film. Recent studies have validated the use of fiducials for reducing the PTV margin during APBI with 6 MV beams. An experimentally determined diffusion coefficient was used to determine space-time customizable distribution of GNPs for feasible in-vivo concentrations of 43 mg/g. An analytic calculational approach from previously published work was employed to estimate the dose enhancement due to GNPs (2 and 10 nm) as a function of distance up to 1 cm from lumpectomy cavity. RESULTS Dose enhancement due to GNP was found to be about 130% for 50-kVp x-rays, and 110% for 6-MV external beam radiotherapy, 1 cm away from the lumpectomy cavity wall. Higher customizable dose enhancement could be achieved at other distances as a function of nanoparticle size. CONCLUSION Our preliminary results suggest that significant dose enhancement can be achieved to residual tumor cells targeted with GNPs during APBI with electronic brachytherapy or external beam therapy. The findings provide a useful basis for developing nanoparticle-aided APBI, with potential to significantly reduce normal tissue/skin toxicity.

SU-E-T-333: Towards Customizable Radiotherapy Enhancement (CuRE) for Prostate Cancer Using Cisplatin Nanoparticles

PURPOSE Replacing routinely used brachytherapy spacers with multifunctional ones loaded with cisplatin nanoparticles (CNP), which can be released into the tumor after implantation, could enable customizable radiation boosting to the prostate tumor in addition to chemotherapy effect. This study investigates the feasibility of customizing the intra-tumor biodistribution and corresponding dose enhancement (DEF) over time for the released CNP as a function of nanoparticle size. METHODS Dose enhancement factors (DEF) due to photon-induced emission of photo-/Auger electrons from CNPs were calculated as a function of concentration using previously published analytical calculation method. An experimentally determined diffusion coefficient (D) for 10 nm nanoparticles in mouse tumor model was employed to estimate D for other sizes using the Stoke- Einstein equation. The error function diffusion model in the experimental study was applied to generate the intra-tumor concentration profile for a burst release of CNPs from the spacer over time. The corresponding DEF profiles were then determined for brachytherapy using Pd-103 and I-125 sources. RESULTS As expected, the generated profiles showed greater DEF over time for smaller CNP sizes at sample distances from the spacer. For example, for a centrally located spacer, clinically significant DEF (> 20%) could be achieved near the tumor periphery (ca. 0.85 cm distance from the spacer for average PCa tumor size) after 20, and 100 days, respectively for CNPs sizes of 2 nm, and 10 nm, using I-125. Meanwhile for Pd-103, clinically significant DEF could be achieved at the same position after 22 and 108 days, respectively, for same size particles. CONCLUSION Our preliminary results demonstrate the feasibility of customizing dose enhancement to prostate tumors as a function of spacer location, brachytherapy source type or size of CNPs released from multifunctional spacers. Such an approach could enable customizable radiation boosting to tumor sub-volumes, while minimizing dose to healthy tissues.

SU‐E‐T‐586: Brachytherapy Application with in Situ Dose‐Painting Administered Via Gold‐Nanoparticle Eluters (BANDAGE) for Prostate Cancer (PCa)

PURPOSE A potential new therapeutic strategy to help prevent prostate cancer (PCa) recurrence involves loading routinely used brachytherapy spacers with non-toxic/biocompatible radiosensitizing gold nanoparticles (GNPs), which can be sustainably released in situ for radiation boosting of high-risk tumor subvolume. In this study, we investigated the intra-tumor biodistribution and corresponding dose enhancement (DEF) over time for the released GNPs, as a function of nanoparticle size. METHODS An experimentally determined diffusion coefficient (D) for 10 nm nanoparticles in mouse PCa tumor model from previous studies was employed to estimate D for other sizes using the Stoke-Einstein equation. The error function diffusion model in the experimental study was applied to generate the intratumor concentration profile for released GNPs from the spacer over time. The corresponding DEF profiles were then determined based on previously published results of DEF versus concentration when GNPs are employed during Pd-103 and I-125 brachytherapy. RESULTS As expected, the generated profiles showed greater DEF over time for smaller GNPs sizes at sample distances from the spacer. For example, for a centrally located spacer, clinically significant DEF (> 20%) could be achieved near the tumor periphery (for average PCa tumor size of about 2 cm diameter) after 14, and 65 days, respectively for GNPs sizes 2 nm, and 10 nm, when treating with I-125. Meanwhile for Pd-103, clinically significant DEF could be achieved at the same position after 13, and 57 days, respectively, for 2 nm and 10 nm nanoparticles. CONCLUSION Our preliminary results verify that intra-tumor dose enhancement or sub-volume boosting profiles can be customized by varying the sizes of nanoparticle released or eluted from nanoparticle-loaded brachytherapy spacers. These results provide a useful reference for further studies towards development of Brachytherapy Application with in situ Dose-painting Administered via Gold-nanoparticle Eluters (BANDAGE) for prostate cancer.