Characterization of Isolated Extracts from Justicia Plant Leaves used as Remedy for Anemia.

Indigenous populations use plants as an important healthcare resource or remedy for different diseases. Here, isolated extracts from Justicia (family Acanthanceae) plant leaves used in Africa as remedy for anemia are characterized by different methods to assess composition and potential nutritional or therapeutic value. Extracts from Justicia leaves were obtained by aqueous extraction, with further isolation by centrifuging and high-performance liquid chromatography. Extracts and isolated compounds were characterized by ultraviolet-visible (UV-Vis) spectroscopy and inductively coupled plasma mass spectrometry (ICP-MS). Hemoglobin activity was assessed using different hemoglobin assays (Cayman Chemical, and Sigma-Aldrich), as well as ELISA. In addition, the safety of the isolated samples was assessed in vitro and in vivo in mice. ICP-MS study results revealed many essential metabolites found in blood plasma. The UV-Vis spectroscopy results highlighted the presence of hemoglobin, with assays showing levels over 4 times higher than that of similar mass of lyophilized human hemoglobin. Meanwhile, in vivo studies showed faster recovery from anemia in mice administered with the isolated extracts compared to untreated mice. Moreover, in vitro and in vivo studies highlighted safety of the extracts. This study reveals the presence of high levels of elements essential for blood health in the isolated extracts from Justicia plant leaves. The findings inspire further research with the potential applications in food fortification, and as remedy for blood disorders like anemia, which disproportionally affects cancer patients, pregnant women, and populations in low- and middle-income countries.

Identification of microRNA-98 as a therapeutic target inhibiting prostate cancer growth and a biomarker induced by vitamin D.

The anti-tumor effect of vitamin D has been well recognized but its translational application is hindered by side effects induced by supra-physiological concentration of vitamin D required for cancer treatment. Thus, exploring the vitamin D tumor suppressive functional mechanism can facilitate improvement of its clinical application. We screened miRNA profiles in response to vitamin D and found that a tumor suppressive miRNA, miR-98, is transcriptionally induced by 1α,25-dihydroxyvitamin D(3) (1,25-VD) in LNCaP. Mechanistic dissection revealed that 1,25-VD-induced miR-98 is mediated through both a direct mechanism, enhancing the VDR binding response element in the promoter region of miR-98, and an indirect mechanism, down-regulating LIN-28 expression. Knockdown of miR-98 led to a reduction of 1,25-VD anti-growth effect and overexpression of miR-98 suppressed the LNCaP cells growth via inducing G2/M arrest. And CCNJ, a protein controlling cell mitosis, is down-regulated by miR-98 via targeting 3'-untranslated region of CCNJ. Interestingly, miR-98 levels in blood are increased upon 1,25-VD treatment in mice suggesting the biomarker potential of miR-98 in predicting 1,25-VD response. Together, the finding that growth inhibitive miR-98 is induced by 1,25-VD provides a potential therapeutic target for prostate cancer and a potential biomarker for 1,25-VD anti-tumor action.

Democratizing FLASH Radiotherapy.

FLASH radiotherapy (RT) is emerging as a potentially revolutionary advancement in cancer treatment, offering the potential to deliver RT at ultra-high dose rates (>40 Gy/s) while significantly reducing damage to healthy tissues. Democratizing FLASH RT by making this cutting-edge approach more accessible and affordable for healthcare systems worldwide would have a substantial impact in global health. Here, we review recent developments in FLASH RT and present perspective on further developments that could facilitate the democratizing of FLASH RT. These include upgrading and validating current technologies that can deliver and measure the FLASH radiation dose with high accuracy and precision, establishing a deeper mechanistic understanding of the FLASH effect, and optimizing dose delivery conditions and parameters for different types of tumors and normal tissues, such as the dose rate, dose fractionation, and beam quality for high efficacy. Furthermore, we examine the potential for democratizing FLASH radioimmunotherapy leveraging evidence that FLASH RT can make the tumor microenvironment more immunogenic, and parallel developments in nanomedicine or use of smart radiotherapy biomaterials for combining RT and immunotherapy. We conclude that the democratization of FLASH radiotherapy represents a major opportunity for concerted cross-disciplinary research collaborations with potential for tremendous impact in reducing radiotherapy disparities and extending the cancer moonshot globally.

Injectable Oxygen Microparticles Boost Radiation-Mediated In Situ Vaccination and Systemic Antitumor Immune Responses.

PURPOSE: The aim of this work was to determine whether intratumoral injections of a liquid oxygen solution are effective at boosting radiation-induced abscopal effects. METHODS AND MATERIALS: A liquid oxygen solution, comprising slow-release polymer-shelled oxygen microparticles, was fabricated and injected intratumorally to locally elevate tumor oxygen levels before and after treatment with radiation therapy. Changes in tumor volume were monitored. In a subset of studies, CD8-positive cells were depleted and the experiments were repeated. Histologic analyses of the tumor tissues were performed to quantify the concentration of infiltrating immune cells. RESULTS: Daily intratumoral injections of oxygen-filled microparticles significantly retarded primary and secondary tumor growth, boosted infiltration of cytotoxic T cells, and improved overall survival when used as an adjuvant to radiation therapy. The findings also demonstrated that efficacy requires both radiation and oxygen, suggesting that they act synergistically to enhance in situ vaccination and systemic antitumor immune responses. CONCLUSIONS: This study demonstrated the potential advantages of intratumoral injections of a liquid oxygen solution as a strategy to boost radiation-induced abscopal effects, and the findings warrant future efforts toward clinical translation of the injectable liquid oxygen solution.

Smart Radiotherapy Biomaterials for Image-Guided In Situ Cancer Vaccination.

Recent studies have highlighted the potential of smart radiotherapy biomaterials (SRBs) for combining radiotherapy and immunotherapy. These SRBs include smart fiducial markers and smart nanoparticles made with high atomic number materials that can provide requisite image contrast during radiotherapy, increase tumor immunogenicity, and provide sustained local delivery of immunotherapy. Here, we review the state-of-the-art in this area of research, the challenges and opportunities, with a focus on in situ vaccination to expand the role of radiotherapy in the treatment of both local and metastatic disease. A roadmap for clinical translation is outlined with a focus on specific cancers where such an approach is readily translatable or will have the highest impact. The potential of FLASH radiotherapy to synergize with SRBs is discussed including prospects for using SRBs in place of currently used inert radiotherapy biomaterials such as fiducial markers, or spacers. While the bulk of this review focuses on the last decade, in some cases, relevant foundational work extends as far back as the last two and half decades.

Pre-Clinical Investigations of the Pharmacodynamics of Immunogenic Smart Radiotherapy Biomaterials (iSRB).

The use of an immunogenic smart radiotherapy biomaterial (iSRB) for the delivery of anti-CD40 is effective in treating different cancers in animal models. This study further characterizes the use of iSRBs to evaluate any associated toxicity in healthy C57BL6 mice. iSRBs were fabricated using a poly-lactic-co-glycolic-acid (PLGA) polymer mixed with titanium dioxide (TiO2) nanoparticles incorporated into its matrix. Animal studies included investigations of freely injected anti-CD40, anti-CD40-loaded iSRBs, unloaded iSRBs and control (healthy) animal cohorts. Mice were euthanized at pre-determined time points post-treatment to evaluate the serum chemistry pertaining to kidney and liver toxicity and cell blood count parameters, as well as pathology reports on organs of interest. Results showed comparable liver and kidney function in all cohorts. The results indicate that using iSRBs with or without anti-CD40 does not result in any significant toxicity compared to healthy untreated animals. The findings provide a useful reference for further studies aimed at optimizing the therapeutic efficacy and safety of iSRBs and further clinical translation work.

Suppression of prostate cancer cell rolling and adhesion to endothelium by 1α,25-dihydroxyvitamin D3.

Adhesion of circulating prostate cancer (PCa) cells to the microvascular endothelium is a critical step during cancer metastasis. To study PCa cell rolling and adhesion behavior, we developed a dynamic flow-based microtube system to mimic the microvascular environment. We found that PCa cell rolling capacity is mediated by E-selectin and can be enhanced by stromal cell-derived factor-1 under different wall shear stresses. Using this device, we tested if the chemopreventive agent, vitamin D, could interfere with PCa cell adhesion. We found that 1α,25-dihydroxyvitamin D(3) (1,25-VD), the bioactive form of vitamin D, reduced PCa cell rolling numbers and increased rolling velocities resulting in a significant decreased number of PCa cells adhering to the microtube. The inhibitory effects of 1,25-VD on PCa cell heterotypic adhesion were further confirmed using microvascular endothelial cells in a static condition. Furthermore, we demonstrated that 1,25-VD can increase E-cadherin expression in PCa cells and promote the homotypic cell-cell aggregation, which can then hinder PCa cell adhesion to the endothelium. Blocking E-cadherin with a neutralizing antibody can reverse 1,25-VD-mediated suppression of PCa cell adhesion to the endothelium. Taken together, our data revealed that 1,25-VD promoted PCa cell aggregation by increasing E-cadherin expression, thus interfering with circulating PCa cell adhesion to microvascular endothelial cells and potentially reducing their metastatic potential.

A liquid immunogenic fiducial eluter for image-guided radiotherapy.

Introduction: Fiducials are routinely used to provide image-guidance during radiotherapy. Here, a new nanoparticle-based liquid immunogenic fiducial is investigated for its potential to provide image-guidance, while also enhancing treatment outcomes. Methods: This fiducial, liquid immunogenic fiducial eluter (LIFE) biomaterial, is formulated with natural biodegradable polymers, chitosan and sodium alginate with radio-sensitizing nanoparticles, and immunoadjuvant like anti-CD40 monoclonal antibody. Once administered intra-tumorally, this liquid smart radiotherapy biomaterial congeals within the calcium rich tumor microenvironment. The potential use of LIFE biomaterial for providing image guidance in magnetic resonance imaging (MRI) and computed tomography (CT) was investigated over different time period in a pre-clinical tumored mouse model. Results: Results showed that the LIFE biomaterial can provide both MRI contrast and CT imaging contrast over 3-weeks, with gradual decrease of the contrast over time, as the LIFE biomaterial biodegrades. Results also showed the LIFE biomaterial significantly slowed tumor growth and prolonged mice survival (p < 0.0001) over time. Discussion: The results highlight the potential use of the LIFE biomaterial as a multi-functional smart radiotherapy biomaterial that could be developed and optimized for hypo-fractionated radiotherapy applications and combining radiotherapy with immunoadjuvants.

Phytoradiotherapy to enhance cancer treatment outcomes with cannabidiol, bitter melon juice, and plant hemoglobin.

Despite technological advances in radiation therapy for cancer treatment, many patient populations still experience mediocre survival percentages, local control, and quality of life. Additionally, much of the world lacks access to expensive, modern treatment options. The need for innovative, cost-effective solutions that can improve patient treatment outcomes is essential. Phytomedicines have been shown to induce apoptotic tumor cell death, diminish tumor progression, reduce cancer incidence, alleviate harmful hypoxic conditions, and more. While an ample amount of research is available that characterizes many phytomedicines as having anti-cancer properties that increase tumor cell killing/control and mitigate the harmful side effects of radiation damage, little work has been done to investigate the synergistic effect of phytoradiotherapy: combining radiation treatment with phytomedicines. In this study, a protocol for testing the radiosensitizing effects of phytomedicines was validated and used to investigate the well-known plant based medicine cannabidiol (CBD) and the lesser-known medicinal fruit Bitter Melon. Additionally, based on its high concentration of plant hemoglobin which has been shown to abate hypoxia, the African-indigenous Justicia plant was tested in pancreatic adenocarcinoma mouse models. The studies reveal that these phytomedicines can effectively enhance tumor cell killing, minimize tumor growth, and prolong mice survival. There is certainly the need for additional research in this regard, however, phytoradiotherapy: the use of phytomedicines to enhance radiation therapy treatment outcomes, continues to show potential as a promising, innovative way to improve cancer care.

Image-Based Quantification of Gold Nanoparticle Uptake and Localization in 3D Tumor Models to Inform Radiosensitization Schedule.

Gold nanoparticles (GNPs) have shown particular promise as radiosensitizing agents and as complementary drug delivery agents to improve therapeutic index in cancer treatment. Optimal implementation, however, depends critically on the localization of GNPs at the time of irradiation, which, in turn, depends on their size, shape, and chemical functionalization, as well as organism-level pharmacokinetics and interactions with the tumor microenvironment. Here, we use in vitro 3D cultures of A549 lung carcinoma cells, which recapitulate interaction with extracellular matrix (ECM) components, combined with quantitative fluorescence imaging to study how time-dependent localization of ultrasmall GNPs in tumors and ECM impacts the degree of damage enhancement to tumor cells. Confocal imaging of fluorescence-labeled GNPs in 3D culture reveals that nanoparticles are initially embedded in ECM and only gradually accumulate in cancer cells over multiple days. Furthermore, the timing of GNP redistribution from ECM to cellular compartments directly impacts efficacy, with major damage enhancement when irradiation is performed after GNPs have accumulated significantly in 3D tumor nodules. These results underscore the importance of the timing and scheduling in treatment planning to ensure optimal radiosensitization, as well as the necessity of studying these effects in model systems that recapitulate elements of tumor microenvironment interaction.

Boosting the Abscopal Effect Using Immunogenic Biomaterials With Varying Radiation Therapy Field Sizes.

PURPOSE: Persistent immunosuppression in the tumor microenvironment is a major limitation to boosting the abscopal effect, whereby radiation therapy at 1 site can lead to regression of tumors at distant sites. Here, we investigate the use of radiation and immunogenic biomaterials (IBM) targeting only the gross tumor volume/subvolume for boosting the abscopal effect in immunologically cold tumors. METHODS AND MATERIALS: To evaluate the abscopal effect, 2 syngeneic contralateral tumors were implanted in each mouse, where only 1 tumor was treated. IBM was administered to the treated tumor with 1 fraction of radiation and results were compared, including as a function of different radiation therapy field sizes. The IBM was designed similar to fiducial markers using immunogenic polymer components loaded with anti-CD40 agonist. Tumor volumes of both treated and untreated tumors were measured over time, along with survival and corresponding immune cell responses. RESULTS: Results showed that radiation with IBM administered to the gross tumor subvolume can effectively boost abscopal responses in both pancreatic and prostate cancers, significantly increasing survival (P < .0001 and P < .001, respectively). Results also showed equal or superior abscopal responses when using field sizes smaller than the gross tumor volume compared with irradiating the whole tumor volume. These results were buttressed by observation of higher infiltration of cytotoxic CD8+ T-lymphocytes in the treated tumors (P < .0001) and untreated tumors (P < .0001) for prostate cancer. Significantly higher infiltration was also observed in treated tumors (P < .0001) and untreated tumors P < .01) for pancreatic cancer. Moreover, the immune responses were accompanied by a positive shift of proinflammatory cytokines in both prostate and pancreatic tumors. CONCLUSIONS: The approach targeting gross tumor subvolumes with radiation and IBM offers opportunity for boosting the abscopal effect while significantly minimizing healthy tissue toxicity. This approach proffers a radioimmunotherapy dose-painting strategy that can be developed for overcoming current barriers of immunosuppression especially for immunologically cold tumors.

A Risk Exchange: Health and Mobility in the Context of Climate and Environmental Change in Bangladesh-A Qualitative Study.

BACKGROUND: Climate change influences patterns of human mobility and health outcomes. While much of the climate change and migration discourse is invested in quantitative predictions and debates about whether migration is adaptive or maladaptive, less attention has been paid to the voices of the people moving in the context of climate change with a focus on their health and wellbeing. This qualitative research aims to amplify the voices of migrants themselves to add nuance to dominant migration narratives and to shed light on the real-life challenges migrants face in meeting their health needs in the context of climate change. METHODS: We conducted 58 semi-structured in-depth interviews with migrants purposefully selected for having moved from rural Bhola, southern Bangladesh to an urban slum in Dhaka, Bangladesh. Transcripts were analysed using thematic analysis under the philosophical underpinnings of phenomenology. Coding was conducted using NVivo Pro 12. FINDINGS: We identified two overarching themes in the thematic analysis: Firstly, we identified the theme "A risk exchange: Exchanging climate change and health risks at origin and destination". Rather than describing a "net positive" or "net negative" outcome in terms of migration in the context of climate change, migrants described an exchange of hazards, exposures, and vulnerabilities at origin with those at destination, which challenged their capacity to adapt. This theme included several sub-themes-income and employment factors, changing food environment, shelter and water sanitation and hygiene (WaSH) conditions, and social capital. The second overarching theme was "A changing health and healthcare environment". This theme also included several sub-themes-changing physical and mental health status and a changing healthcare environment encompassing quality of care and barriers to accessing healthcare. Migrants described physical and mental health concerns and connected these experiences with their new environment. These two overarching themes were prevalent across the dataset, although each participant experienced and expressed them uniquely. CONCLUSION: Migrants who move in the context of climate change face a range of diverse health risks at the origin, en route, and at the destination. Migrating individuals, households, and communities undertake a risk exchange when they decide to move, which has diverse positive and negative consequences for their health and wellbeing. Along with changing health determinants is a changing healthcare environment where migrants face different choices, barriers, and quality of care. A more migrant-centric perspective as described in this paper could strengthen migration, climate, and health governance. Policymakers, urban planners, city corporations, and health practitioners should integrate the risk exchange into practice and policies.

Optimizing In Situ Vaccination During Radiotherapy.

Effective in situ cancer vaccines require both a means of tumor cell death and a source of adjuvant to activate local dendritic cells. Studies have shown that the use of radiotherapy (RT) to induce tumor cell death and anti-CD40 to activate dendritic cells can result in in situ vaccination in animal models. Here, investigations are carried out on potential strategies to enhance such in situ vaccination. Strategies investigated include the use of smart immunogenic biomaterials (IBM) loaded with anti-CD40 in different tumor types including immunologically cold tumors like pancreatic and prostate tumors. The use of downstream checkpoint inhibitors to further boost such in situ vaccination is also examined. Results indicate that the use of IBM to deliver the anti-CD40 significantly enhances the effectiveness of in situ vaccination with anti-CD40 compared with direct injection in pancreatic and prostate cancers (p < 0.001 and p < 0.0001, respectively). This finding is consistent with significant increase in infiltration of antigen-presenting cells in the treated tumor, and significant increase in the infiltration of CD8+ cytotoxic T lymphocyte into distant untreated tumors. Moreover, in situ vaccination with IBM is consistently observed across different tumor types. Meanwhile, the addition of downstream immune checkpoint inhibitors further enhances overall survival when using the IBM approach. Overall, the findings highlight potential avenues for enhancing in situ vaccination when combining radiotherapy with anti-CD40.

Phytoradiotherapy: An Integrative Approach to Cancer Treatment by Combining Radiotherapy With Phytomedicines.

Radiotherapy (RT) is an effective method of cancer treatment, but like any other method of cancer treatment, there are inherent limitations. While technological advances and a growing understanding of its biological effects have improved its results dramatically, the use of RT is still limited to certain patient populations and by normal tissue toxicities. The harmful side effects of treating patients with radiation can offset its therapy benefits, limiting its use in certain cases. Phyto, or plant-based, medicines offer a way to add to radiation treatment, while also protecting patients from its toxic side effects. Phytomedicines such as cannabinoids (CBD) and bitter melon extract have demonstrated therapeutic properties, including the ability to activate apoptotic death in cancer cells, diminish tumor progression, and generally decrease the incidence of several cancer types. In addition, herbal drugs have been shown to be powerful antioxidants with the ability to decrease toxicity of RT without the adverse side effects found in synthetic drugs. Furthermore, a number of phytomedicines have been shown to mitigate hypoxic conditions within the tumor microenvironment, creating a more radiosensitive disease and preventing tumorigenesis. The purpose of this article is to examine the merits and demerits of employing phytomedicines during RT. Results from studies that have tested the effects of combining radiotherapy with supplemental herbal treatment are discussed along with perspectives on where additional research is needed to advance "Phytoradiotherapy". Overall, experimental evidence points to the fact that phytomedicines have significant potential to enhance RT, with need for cross-disciplinary collaborations to establish optimal dosing combinations with evidence-base for clinical translation.

Single Radiotherapy Fraction with Local Anti-CD40 Therapy Generates Effective Abscopal Responses in Mouse Models of Cervical Cancer.

Current treatment options for advanced cervical cancer are limited, especially for patients in poor-resource settings, with a 17% 5-year overall survival rate. Here, we report results in animal models of advanced cervical cancer, showing that anti-CD40 therapy can effectively boost the abscopal effect, whereby radiotherapy of a tumor at one site can engender therapeutically significant responses in tumors at distant untreated sites. In this study, two subcutaneous cervical cancer tumors representing one primary and one metastatic tumor were generated in each animal. Only the primary tumor was treated and the responses of both tumors were monitored. The study was repeated as a function of different treatment parameters, including radiotherapy dose and dosing schedule of immunoadjuvant anti-CD40. The results consistently suggest that one fraction dose of radiotherapy with a single dose of agonistic anti-CD40 can generate highly effective abscopal responses, with a significant increase in animal survival (p = 0.0004). Overall, 60% of the mice treated with this combination showed long term survival with complete tumor regression, where tumors of mice in other cohorts continued to grow. Moreover, re-challenged responders to the treatment developed vitiligo, suggesting developed immune memory for this cancer. The findings offer a potential new therapy approach, which could be further investigated and developed for the treatment of advanced cervical cancer, with major potential impact, especially in resource-poor settings.

Corrigendum: Flavonoid Derivative of Cannabis Demonstrates Therapeutic Potential in Preclinical Models of Metastatic Pancreatic Cancer.

[This corrects the article DOI: 10.3389/fonc.2019.00660.].

Increased carcinoembryonic antigen expression on the surface of lung cancer cells using gold nanoparticles during radiotherapy.

PURPOSE: Tumor-associated antigens are a promising target of immunotherapy approaches for cancer treatments but rely on sufficient expression of the target antigen. This study investigates the expression of the carcinoembryonic antigen (CEA) on the surface of irradiated lung cancer cells in vitro using gold nanoparticles as radio-enhancer. METHODS: Human lung carcinoma cells A549 were irradiated and expression of CEA on the cell surface measured by flow cytometry 3 h, 24 h, and 72 h after irradiation to doses of 2 Gy, 6 Gy, 10 Gy, and 20 Gy in the presence or absence of 0.1 mg/ml or 0.5 mg/ml gold nanoparticles. CEA expression was measured as median fluorescent intensity and percentage of CEA-positive cells. RESULTS: An increase in CEA expression was observed with both increasing radiation dose and time. There was doubling in median fluorescent intensity 24 h after 20 Gy irradiation and 72 h after 6 Gy irradiation. Use of gold nanoparticles resulted in additional significant increase in CEA expression. Change in cell morphology included swelling of cells and increased internal complexity in accordance with change in CEA expression. CONCLUSIONS: This study showed an increase in CEA expression on human lung carcinoma cells following irradiation. Increase in expression was observed with increasing radiation dose and in a time dependent manner up to 72 h post irradiation. The results further showed that gold nanoparticles can significantly increase CEA expression following radiotherapy.

Imaging and Characterization of Sustained Gadolinium Nanoparticle Release from Next Generation Radiotherapy Biomaterial.

Smart radiotherapy biomaterials (SRBs) present a new opportunity to enhance image-guided radiotherapy while replacing routinely used inert radiotherapy biomaterials like fiducials. In this study the potential of SRBs loaded with gadolinium-based nanoparticles (GdNPs) is investigated for magnetic resonance imaging (MRI) contrast. GdNP release from SRB is quantified and modelled for accurate prediction. SRBs were manufactured similar to fiducials, with a cylindrical shell consisting of poly(lactic-co-glycolic) acid (PLGA) and a core loaded with GdNPs. Magnetic resonance imaging (MRI) contrast was investigated at 7T in vitro (in agar) and in vivo in subcutaneous tumors grown with the LLC1 lung cancer cell line in C57/BL6 mice. GdNPs were quantified in-phantom and in tumor and their release was modelled by the Weibull distribution. Gd concentration was linearly fitted to the R1 relaxation rate with a detection limit of 0.004 mmol/L and high confidence level (R2 = 0.9843). GdNP loaded SRBs in tumor were clearly visible up to at least 14 days post-implantation. Signal decrease during this time showed GdNP release in vivo, which was calculated as 3.86 ± 0.34 µg GdNPs release into the tumor. This study demonstrates potential and feasibility for SRBs with MRI-contrast, and sensitive GdNP quantification and release from SRBs in a preclinical animal model. The feasibility of monitoring nanoparticle (NP) concentration during treatment, allowing dynamic quantitative treatment planning, is also discussed.

Author Correction: Selective Priming of Tumor Blood Vessels by Radiation Therapy Enhances Nanodrug Delivery.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Flavonoid Derivative of Cannabis Demonstrates Therapeutic Potential in Preclinical Models of Metastatic Pancreatic Cancer.

Pancreatic cancer is particularly refractory to modern therapies, with a 5-year survival rate for patients at a dismal 8%. One of the significant barriers to effective treatment is the immunosuppressive pancreatic tumor microenvironment and development of resistance to treatment. New treatment options to increase both the survival and quality of life of patients are urgently needed. This study reports on a new non-cannabinoid, non-psychoactive derivative of cannabis, termed FBL-03G, with the potential to treat pancreatic cancer. In vitro results show major increase in apoptosis and consequential decrease in survival for two pancreatic cancer models- Panc-02 and KPC pancreatic cancer cells treated with varying concentrations of FBL-03G and radiotherapy. Meanwhile, in vivo results demonstrate therapeutic efficacy in delaying both local and metastatic tumor progression in animal models with pancreatic cancer when using FBL-03G sustainably delivered from smart radiotherapy biomaterials. Repeated experiments also showed significant (P < 0.0001) increase in survival for animals with pancreatic cancer compared to control cohorts. The findings demonstrate the potential for this new cannabis derivative in the treatment of both localized and advanced pancreatic cancer, providing impetus for further studies toward clinical translation.