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Background/Objectives: To overcome the side effects of conventional cancer treatment, multifunctional nanoparticles with image-guidance properties are increasingly desired to obtain enhanced therapeutic efficacy without any toxicity of the treatment. Herein, we introduce the potential of Polydopamine Radioimmunotherapy with Image-guided Monitoring and Enhanced (drug) Release System (PRIMERS) to meet the challenges of currently used cancer therapy. Methods: The PDA nanobowls were synthesized using an emulsion-induced interfacial anisotropic assembly method followed by surface modification with high-Z material to obtained the final product PRIMERS. Results: The engineered multifunctional nanosystem “PRIMERS” could serve as fiducial markers with the potential for use in combination cancer therapy. By leveraging the advantages of the excellent surface functionalization capability of PDA, the anisotropic nanostructure (PDA nanobowls) has been successfully functionalized with gadolinium, which shows strong MRI contrast signal both in vitro in phantom and in vivo in animals. The results of anti-cancer drug loading and releasing efficiency of these functionalized nanobowls are presented. Moreover, the gadolinium-coated PDA nanobowls demonstrate the capacity for loading immunotherapy drugs (Anti-CD40) with activated release in acidic pH levels characteristic of the tumor microenvironment, with enhanced release following administration of radiation therapy in vitro. Conclusions: Overall, the results highlight the potential of this new technology for combining radiotherapy with activated image-guided drug delivery, which offers broad opportunities to overcome current challenges in cancer treatment.

Smart radiotherapy biomaterials (SRBs) include seed and liquid biomaterials designed to be employed as fiducial markers during radiotherapy while also delivering therapeutic drug payloads to enhance treatment outcomes. In this study, we investigate a novel Customizable Lyophilized Agent for Radiotherapy Imaging and TherapY (CLARITY) biomaterial, which can be loaded with immunoadjuvants (anti-CD40 monoclonal antibody or Caflanone (FBL-03G)) at the point of care. The CLARITY biomaterial was investigated in an animal model of pancreatic cancer using C57BL6 mice. Mice were imaged before and at different points of time post-treatment to evaluate the potential of CLARITY biomaterial to provide imaging contrast similar to fiducials. This study also used cadavers to assess CLARITY’s potential to provide imaging contrast in humans. Results showed imaging contrast from computed tomography (CT) and magnetic resonance imaging (MRI) modalities for up to 30 days post-treatment, demonstrating potential for use as fiducials. A significant increase in survival (***, p = 0.0006) was observed for mice treated with CLARITY biomaterial loaded with immunoadjuvant for up to 10 weeks post-treatment compared to those without treatment. These initial results demonstrate the potential of CLARITY biomaterial to serve as a smart multifunctional radiotherapy biomaterial and provide the impetus for further development and optimization as a point-of-care technology for combination radiotherapy and immunotherapy.

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.

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.

IntroductionFiducials 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.MethodsThis 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.ResultsResults 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.DiscussionThe 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.

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.

In efforts to overcome current challenges in cancer treatment, multifunctional nanoparticles are attracting growing interest, including nanoparticles made with polydopamine (PDA). PDA is a nature-inspired polymer with a dark brown color. It has excellent biocompatibility and is biodegradable, offering a range of extraordinary inherent advantages. These include excellent drug loading capability, photothermal conversion efficiency, and adhesive properties. Though the mechanism of dopamine polymerization remains unclear, PDA has demonstrated exceptional flexibility in engineering desired morphology and size, easy and straightforward functionalization, etc. Moreover, it offers enormous potential for designing multifunctional nanomaterials for innovative approaches in cancer treatment. The aim of this work is to review studies on PDA, where the potential to develop multifunctional nanomaterials with applications in photothermal therapy has been demonstrated. Future prospects of PDA for developing applications in enhancing radiotherapy and/or immunotherapy, including for image-guided drug delivery to boost therapeutic efficacy and minimal side effects, are presented.

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.

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.

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.

Radiation therapy induces immunogenic cell death, which can theoretically stimulate T cell priming and induction of tumor-specific memory T cell responses, serving as an in situ vaccine. In practice, this abscopal effect is rarely observed. We use two mouse models of pancreatic cancer to show that a single dose of stereotactic body radiation therapy (SBRT) synergizes with intratumoral injection of agonistic anti-CD40, resulting in regression of non-treated contralateral tumors and formation of long-term immunologic memory. Long-term survival was not observed when mice received multiple fractions of SBRT, or when TGFβ blockade was combined with SBRT. SBRT and anti-CD40 was so effective at augmenting T cell priming, that memory CD8 T cell responses to both tumor and self-antigens were induced, resulting in vitiligo in long-term survivors.

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.

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.

Nanotechnology has opened up a new, previously unimaginable world in cancer diagnosis and therapy, leading to the emergence of cancer nanomedicine and nanoparticle-aided radiotherapy. Smart nanomaterials (nanoparticle drones) can now be constructed with capability to precisely target cancer cells and be remotely activated with radiation to emit micrometer-range missile-like electrons to destroy the tumor cells. These nanoparticle drones can also be programmed to deliver therapeutic payloads to tumor sites to achieve optimal therapeutic efficacy. In this article, we examine the state-of-the-art and potential of nanoparticle drones in targeting lung cancer. Inhalation (INH) (air) versus traditional intravenous (“sea”) routes of navigating physiological barriers using such drones is assessed. Results and analysis suggest that INH route may offer more promise for targeting tumor cells with radiosensitizers and cannabinoids from the perspective of maximizing damage to lung tumors cells while minimizing any collateral damage or side effects.

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.

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. [ABSTRACT FROM AUTHOR]

Nanoparticle-aided radiation therapy is emerging as a promising modality to enhance radiotherapy via the radiosensitizing action of high atomic number (Z) nanoparticles. However, the delivery of sufficiently potent concentrations of such nanoparticles to the tumor remain a challenge. This study investigates the dose enhancement to lung tumors due to high-Z nanoparticles (NPs) administered via inhalation during external beam radiotherapy. Here NPs investigated include: cisplatin nanoparticles (CNPs), carboplatin nanoparticles (CBNPs), and gold nanoparticles (GNPs).Using Monte Carlo–generated megavoltage energy spectra, a previously employed analytic method was used to estimate dose enhancement to lung tumors due to radiation-induced photoelectrons from the NPs administered via inhalation route (IR) in comparison to intravenous (IV) administration. Previous studies have indicated about 5% of FDA-approved cisplatin concentrations reach the lung via IV. Meanwhile recent experimental studies indicate that 3.5–14.6 times higher concentrations of NPs can reach the lung by IR compared to IV. Taking these into account, the dose enhancement factor (DEF) defined as the ratio of the radiotherapy dose with and without nanoparticles was calculated for a range of NPs concentrations and tumor sizes. The DEF for IR was then compared with that for IV.For IR with 3.5 times higher concentrations than IV, and 2 cm diameter tumor, clinically significant DEF values of up to 1.19, 1.26, and 1.51 were obtained for CNPs, CBNPs and GNPs. In comparison values of 1.06, 1.08, and 1.15 were obtained via IV administration. For IR with 14.6 times higher concentrations, even higher DEF values were obtained e.g. 1.81 for CNPs. Results also showed that the DEF increased with increasing field size or decreasing tumor volume, as expected.The results of this work indicate that IR administration of targeted high-Z CNPs/CBNPs/GNPs could enable clinically significant DEF to lung tumors compared to IV administration during external beam radiotherapy. For FDA approved concentrations of CNPs or CBNPs considered, this could allow for additional dose enhancement to tumors via photoelectric mechanism during concomitant chemoradiotherapy. [ABSTRACT FROM AUTHOR]