Combined Chemo Research Articles

Abstract 5554: Breast cancer with different chemosensitivity has distinct influence on the immune microenvironment

Abstract Triple Negative Breast Cancer (TNBC) is a BC subgroup with the least favorable outcome and limited therapeutic options. Chemotherapy has long been the standard treatment, but resistance often develops. In recent years, various immunotherapy approaches have diversified, including combinations of chemo and immunotherapies. Increased understanding on how the difference in chemosensitivity affects the immune cells is of importance for further development of chemo-immunotherapies for TNBC. In this project we investigate how TNBC with distinct chemosensitivity modulate the immune microenvironment. Specifically, we explore the influence of the secretome, derived from the chemoresistant versus the sensitive BC cells, on macrophages (MØs) and T-cells. We have disclosed the chemosensitivity-dependent differences in the secretome, which were associated with diverse effects on MØ recruitment, polarization, and activation. Currently we investigate the secretome influence on interferon (IFN)-activated MØ. IFN stimuli is known to trigger tumoricidal activities in MØ, and we are setting up a co-culture assay, where such MØ functions could be explored in vitro. To study the secretome influence on T-cells, we employ T cell receptor (TCR)-engineered T cells that become activated in the presence of target cells. The preliminary results indicate that activation of the TCR T-cells was reduced in the presence of the “chemoresistant” secretome, suggesting its immunosuppressive influence. Work is in progress to validate this observation using other TCR T cells and functional markers of active T cells. Citation Format: Eleni Skourti, Kotryna Seip, Eivind V. Egeland, Shakila Jabeen, Nadia Mensali, Inger Øynebråten, Siri Juell, Else M. Inderberg, Olav Engebråten, Alexandre B. Corthay, Gunhild M. Mælandsmo, Lina Prasmickaite. Breast cancer with different chemosensitivity has distinct influence on the immune microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5554.

Evidence for tactile 3D shape discrimination by octopus.

Octopuses integrate visual, chemical and tactile sensory information while foraging and feeding in complex marine habitats. The respective roles of these modes are of interest ecologically, neurobiologically, and for development of engineered soft robotic arms. While vision guides their foraging path, benthic octopuses primarily search "blindly" with their arms to find visually hidden prey amidst rocks, crevices and coral heads. Each octopus arm is lined with hundreds of suckers that possess a combination of chemo- and mechanoreceptors to distinguish prey. Contact chemoreception has been demonstrated in lab tests, but mechanotactile sensing is less well characterized. We designed a non-invasive live animal behavioral assay that isolated mechanosensory capabilities of Octopus bimaculoides arms and suckers to discriminate among five resin 3D-printed prey and non-prey shapes (all with identical chemical signatures). Each shape was introduced inside a rock dome and was only accessible to the octopus' arms. Octopuses' responses were variable. Young octopuses discriminated the crab prey shape from the control, whereas older octopuses did not. These experiments suggest that mechanotactile sensing of 3D shapes may aid in prey discrimination; however, (i) chemo-tactile information may be prioritized over mechanotactile information in prey discrimination, and (ii) mechanosensory capability may decline with age.

The Effect of chemo- and radiotherapy on tumor necrosis in soft tissue sarcoma– does it influence prognosis?

BackgroundSoft tissue sarcomas (STSs) are a heterogeneous group of tumors. Wide surgical resection is standard, often combined with neoadjuvant chemotherapy, radiotherapy, or both. Studies have shown the predictive value of tumor necrosis in bone sarcoma (BS); however, the role of necrosis in STS after neoadjuvant therapies is still unclear. This study aimed to investigate the role of chemo- and radiotherapy in the formation of tumor necrosis and to evaluate the influence of tumor necrosis on overall survival and local recurrence-free survival. Data from BS patients and patients who did not receive neoadjuvant therapy were compared.MethodsA total of 779 patients with STS or BS were treated surgically. In all patients, tumor-specific factors such as type, size, or grading and the type of adjuvant therapy were documented. Local recurrence (LR), the diagnosis of metastatic disease, and survival during follow-up were evaluated.ResultsA total of 565 patients with STS and 214 with BS were investigated. In STS, 24.1% G1 lesions, 34.1% G2 lesions, and 41.8% G3 lesions were observed. Two hundred twenty-four of the patients with STS and neoadjuvant therapy had either radiotherapy (RTx) (n = 80), chemotherapy (CTx) (n = 93), or both (n = 51). Three hundred forty-one had no neoadjuvant therapy at all. In STS, tumor necrosis after neoadjuvant treatment was significantly higher (53.5%) than in patients without neoadjuvant therapy (15.7%) (p < 0.001). Patients with combined neoadjuvant chemo-/radiotherapy had substantially higher tumor necrosis than those with radiotherapy alone (p = 0.032). There was no difference in tumor necrosis in patients with combined chemo-/radiotherapy and chemotherapy alone (p = 0.4). The mean overall survival for patients with STS was 34.7 months. Tumor necrosis did not influence survival in a subgroup of G2/3 patients. In STS with no neoadjuvant therapy and grading of G2/3, the correlation between necrosis and overall survival was significant (p = 0.0248). There was no significant correlation between local recurrence (LR) and necrosis.ConclusionSTS shows a broad spectrum of necrosis even without neoadjuvant chemo- or radiotherapy. After CTx or/and RTx necrosis is enhanced and is significantly pronounced with a combination of both. There is a trend toward higher necrosis with CTx than with RTx. Grading substantially influences the necrosis rate, but necrosis in soft-tissue sarcoma following neoadjuvant therapy does not correlate with better survival or a lower local recurrence rate, as in bone sarcomas.

Intelligent responsive copper-diethyldithiocarbamate-based multifunctional nanomedicine for photothermal-augmented synergistic cancer therapy.

The design of multifunctional nanomedicine through the combination of multimodal treatments to achieve the optimal antitumor effect is essential for cancer therapy. Herein, we design and develop a multifunctional theranostic nanoplatform using an iron ion-doxorubicin (DOX) nanoscale coordination polymer (Fe/DOX NCP) as a shell coating on the surface of polyvinyl pyrrolidone (PVP) stabilized copper-diethyldithiocarbamate nanoparticles (Cu(DDC)2 NPs) for combined tumor chemo-/photothermal/chemodynamic therapy. The obtained Cu(DDC)2@Fe/DOX NPs display pH/laser dual-responsive degradation behavior and also exhibit favorable photothermal performance. Under 808 nm laser irradiation, Cu(DDC)2@Fe/DOX NPs can convert light into heat, which not only kills tumor cells via hyperthermia in photothermal therapy (PTT), but also accelerates the degradation of Fe/DOX NCPs to release Fe3+ and DOX. The liberated Fe3+ can be used to catalyze hydrogen peroxide via the Fenton reaction to produce highly toxic hydroxyl radicals (˙OH) in chemodynamic therapy (CDT). The released DOX and the exposed Cu(DDC)2 can cause significant cell death in combined chemotherapy via a superimposed effect. In vitro and in vivo results prove that Cu(DDC)2@Fe/DOX NPs with laser irradiation present remarkable anticancer performances in hyperthermia-enhanced chemo-/CDT. Therefore, this study provides a new strategy for highly efficient synergistic cancer therapy.

β-Glycosidase sensitive oral nanoparticles for combined photothermal and chemo treatment of colorectal cancer.

Colorectal cancer is one of the most common malignant tumors in the world, and its treatment strategies mainly include surgical resection, chemotherapy, adjuvant radiotherapy, and immunotherapy. Among them, chemotherapy inevitably produces systemic toxicity due to the lack of tumor targeting properties and drug resistance caused by long-term medication frequently occurs, immensely constraining the efficacy of chemotherapy alone. To solve the above-mentioned problems, rhamnolipid was used to encapsulate the chemotherapeutic drug 5-FU and photothermal agent bismuthene nanosheets (BiNS), chitosan was applied as the shell of the nanoparticle, and BiNS@RHL-CS/5-FU NPs for oral administration was successfully prepared. When transported in the stomach and small intestine, the double protection of rhamnolipid and chitosan shell prevented the early release of BiNS and 5-FU. When transported to the colon, β-glycosidase existing in the microenvironment along with elevated pH degraded the chitosan shell, and the reduction in particle size was beneficial for tumor tissue to uptake nanoparticles, thus greatly improving the tumor targeting ability of 5-FU and reducing the systemic toxicity. Due to the presence of BiNS, 1.0 W cm-2 808 nm laser irradiation significantly increased the temperature of the tumor site, not only killing tumor cells directly but also promoting cell uptake and penetration of nanoparticles in the tumor tissue, accelerating the release of 5-FU and improving the sensitivity of tumor cells to chemotherapy, eventually solving the shortcomings of traditional chemotherapy alone. Excellent anti-tumor efficacy has been achieved in both in vitro and in vivo experiments.

Photocrosslinked Co-Assembled Amino Acid Nanoparticles for Controlled Chemo/Photothermal Combined Anticancer Therapy.

Nanostructures formed from the self-assembly of amino acids are promising materials in many fields, especially for biomedical applications. However, their low stability resulting from the weak noncovalent interactions between the amino acid building blocks limits their use. In this work, nanoparticles co-assembled by fluorenylmethoxycarbonyl (Fmoc)-protected tyrosine (Fmoc-Tyr-OH) and tryptophan (Fmoc-Trp-OH) are crosslinked by ultraviolet (UV) light irradiation. Two methods are investigated to induce the dimerization of tyrosine, irradiating at 254nm or at 365nm in the presence of riboflavin as a photo-initiator. For the crosslinking performed at 254nm, both Fmoc-Tyr-OH and Fmoc-Trp-OH generate dimers. In contrast, only Fmoc-Tyr-OH participates in the riboflavin-mediated dimerization under irradiation at 365nm. The participation of both amino acids in forming the dimers leads to more stable crosslinked nanoparticles, allowing also to perform further chemical modifications for cancer applications. The anticancer drug doxorubicin (Dox) is adsorbed onto the crosslinked nanoparticles, subsequently coated by a tannic acid-iron complex, endowing the nanoparticles with glutathione-responsiveness and photothermal properties, allowing to control the release of Dox. A remarkable anticancer efficiency is obtained in vitro and in vivo in tumor-bearing mice thanks to the combined chemo- and photothermal treatment.

Metal-Organic Framework as a New Type of Magnetothermally-Triggered On-Demand Release Carrier.

The development of external stimuli-controlled payload systems has been sought after with increasing interest toward magnetothermally-triggered drug release (MTDR) carriers due to their non-invasive features. However, current MTDR carriers present several limitations, such as poor heating efficiency caused by the aggregation of iron oxide nanoparticles (IONPs) or the presence of antiferromagnetic phases which affect their efficiency. Herein, a novel MTDR carrier is developed using a controlled encapsulation method that fully fixes and confines IONPs of various sizes within the metal-organic frameworks (MOFs). This novel carrier preserves the MOF's morphology, porosity, and IONP segregation, while enhances heating efficiency through the oxidation of antiferromagnetic phases in IONPs during encapsulation. It also features a magnetothermally-responsive nanobrush that is stimulated by an alternating magnetic field to enable on-demand drug release. The novel carrier shows improved heating, which has potential applications as contrast agents and for combined chemo and magnetic hyperthermia therapy. It holds a great promise for magneto-thermally modulated drug dosing at tumor sites, making it an exciting avenue for cancer treatment.

Magnetic Mesoporous Janus Microrollers for Combined Chemo‐ and Photothermal Ablation Therapy

AbstractMobile microrobots have been proposed as a promising approach to overcome the limitations of traditional drug/gene delivery systems. Magnetically actuated surface rolling microrobots, or magnetic surface microrollers, have shown potential for navigation in physiologically relevant environments due to their robust locomotion characteristics. Although much is known about their locomotion abilities in various environments, the full extent of their potential in medical applications has yet to be fully explored. Here, the potential of surface microrollers for combined chemo‐ and photothermal ablation therapy under medical imaging modalities is demonstrated. The surface microrollers are half‐coated with magnetic material, allowing for photothermal heating and magnetic locomotion, and loaded with a biopharmaceutics classification system (BCS) class IV anti‐cancer drug, Docetaxel (DTX), for combined therapy. Synergistic action of on‐demand photothermal ablation and the controlled release of DTX result in the efficient elimination of cancer cells. Furthermore, microrollers can be detected ex vivo with magnetic resonance imaging (MRI) and photoacoustic imaging (PA), highlighting the potential of surface microrollers for future targeted medical applications.

Targosomes: Anti-HER2 PLGA nanocarriers for bioimaging, chemotherapy and local photothermal treatment of tumors and remote metastases

Developing combined cancer therapy strategies is of utmost importance as it can enhance treatment efficacy, overcome drug resistance, and ultimately improve patient outcomes by targeting multiple pathways and mechanisms involved in cancer growth and progression. Specifically, the potential of developing a combination chemo&photothermal therapy using targeted polymer nanoparticles as nanocarriers offers a promising approach for synergistic cancer treatment by combining the benefits of both therapies, such as targeted drug delivery and localized hyperthermia. Here, we report the first targeted anti-HER2 PLGA nanocarriers, called targosomes, that simultaneously possess photothermal, chemotherapeutic and diagnostic properties using only molecular payloads. Biocompatible poly(lactic-co-glycolic acid), PLGA, nanoparticles were loaded with photosensitizer phthalocyanine, diagnostic dye Nile Blue, and chemotherapeutic drug irinotecan, which was chosen as a result of screening a panel of theragnostic nanoparticles. The targeted delivery to cell surface oncomarker HER2 was ensured by nanoparticle modification with the anti-HER2 monoclonal antibody, trastuzumab, using the one-pot synthesis method without chemical conjugation. The irradiation tests revealed prominent photothermal properties of nanoparticles, namely heating by 35 °C in 10 min. Nanoparticles exhibited a 7-fold increase in binding and nearly an 18-fold increase in cytotoxicity for HER2-overexpressing cells compared to cells lacking HER2 expression. This enhancement of cytotoxicity was further amplified by >20-fold under NIR light irradiation. In vivo studies proved the efficacy of nanoparticles for bioimaging of primary tumor and metastasis sites and demonstrated 93% tumor growth inhibition, making these nanoparticles excellent candidates for translation into theragnostic applications.

Oxidative Stress in Xenograft Mouse Model Exposed to Dendrimers Decorated Polydopamine Nanoparticles and Targeted Chemo- and Photothermal Therapy

Polydopamine (PDA)-based nanostructures are used for biomedical purposes. A hybrid drug nanocarrier based on a PDA decorated with polyamidoamine (PAMAM) dendrimers G 3.0 (DG3) followed by a connection with glycol (PEG) moieties, folic acid (FA), and drug doxorubicin (DOX) was used for combined chemo- and photothermal therapy (CT-PTT) of liver cancer. Oxidative stress plays a crucial role in the development of cancer, and PDA seems to have the ability to both donate and accept electrons. We investigated oxidative stress in organs by evaluating oxidative stress markers in vivo. In the liver, the level of reduced glutathione (GSH) was lower and the level of Trolox equivalent antioxidant capacity (TEAC) was higher in the group receiving doxorubicin encapsulated in PDA nanoparticles with phototherapy (PDA@DG3@PEG@FA@DOX + PTT) compared to the control group. The concentration of thiobarbituric acid reactive substances (TBARS) in livers, was higher in the group receiving PDA coated with PAMAM dendrimers and functionalized with PEG and FA (PDA@DG3@PEG@FA) than in other groups. Markers in the brain also showed lower levels of GSH in the PDA@DG3@PEG@FA group than in the control group. Markers of oxidative stress indicated changes in the organs of animals receiving PDA nanoparticles with PAMAM dendrimers functionalized with FA in CT-PTT of liver cancer under in vivo conditions. Our work will provide insights into oxidative stress, which can be an indicator of the toxic potential of PDA nanoparticles and provide new strategies to improve existing therapies.

Biomimetic theranostic nanoparticles for effective anticancer therapy and MRI imaging

Cancer remains a leading cause of mortality worldwide, necessitating the development of innovative therapeutic approaches. Nanoparticle-based drug delivery systems have garnered significant interest due to their multifunctionality, offering the potential to enhance cancer treatment efficacy and improve patient tolerability. Membrane-coated drug delivery systems hold great potential for enhancing the therapeutic outcome of nanoparticle-based anticancer therapies. In this study, we report the synthesis of multifunctional iron-functionalized mesoporous polydopamine nanoparticles (MPDAFe NPs). These nanoformulations demonstrate substantial potential for combining efficient drug delivery and magnetic resonance imaging (MRI) and showcase the advantages of biomimetic coating with tumor cell-derived membranes. This coating confers prolonged circulation and improved the targeting capabilities of the nanoparticles. Furthermore, comprehensive biosafety evaluations reveal negligible toxicity to normal cells, while the combined chemo- and phototherapy exhibited significant cytotoxicity towards cancer cells. Additionally, the photothermal effect evaluation highlights the enhanced cytotoxicity achieved through laser irradiation, showcasing the synergistic effects of the nanomaterials and photothermal therapy. Importantly, our chemotherapeutic effect evaluation demonstrates the superior efficacy of doxorubicin-loaded MPDAFe@Mem NPs (cancer cell membrane-coated MPDAFe NPs) in inhibiting cancer cell viability and proliferation, surpassing the potency of free doxorubicin. This study comprehensively investigates theranostic, membrane-coated drug delivery systems, underlining their potential to increase the efficacy of cancer treatment strategies. The multifunctional nature of the iron-functionalized polydopamine nanoparticles allows for efficient drug delivery and imaging capabilities, while the biomimetic coating enhances their biocompatibility and targeting ability. These findings contribute valuable insights towards the development of advanced nanomedicine for improved cancer therapeutics.

1490P Removal of TNF-Rs frees TNF-α’s anticancer activity alone or in combination chemo- or immunotherapy in advanced NSCLC

1490P Removal of TNF-Rs frees TNF-α’s anticancer activity alone or in combination chemo- or immunotherapy in advanced NSCLC

Powerful Synergy of Traditional Chinese Medicine and Aggregation-Induced Emission-Active Photosensitizer in Photodynamic Therapy.

Breast cancer (BC) remains a significant global health challenge for women despite advancements in early detection and treatment. Isoliquiritigenin (ISL), a compound derived from traditional Chinese medicine, has shown potential as an anti-BC therapy, but its low bioavailability and poor water solubility restrict its effectiveness. In this study, we created theranostic nanoparticles consisting of ISL and a near-infrared (NIR) photosensitizer, TBPI, which displays aggregation-induced emission (AIE), with the goal of providing combined chemo- and photodynamic therapies (PDT) for BC. Initially, we designed an asymmetric organic molecule, TBPI, featuring a rotorlike triphenylamine as the donor and 1-methylpyridinium iodide as the acceptor, which led to the production of reactive oxygen species in mitochondria. We then combined TBPI with ISL and encapsulated them in DSPE-PEG-RGD nanoparticles to produce IT-PEG-RGD nanoparticles, which showed high affinity for BC, better intersystem crossing (ISC) efficiency, and Förster resonance energy transfer (FRET) between TBPI and ISL. In both 4T1 BC cell line and a 4T1 tumor-bearing BC mouse model, the IT-PEG-RGD nanoparticles demonstrated excellent drug delivery, synergistic antitumor effects, enhanced tumor-killing efficacy, and reduced drug dosage and side effects. Furthermore, we exploited the optical properties of TBPI with ISL to reveal the release process and distribution of nanoparticles in cells. This study provides a valuable basis for further exploration of IT-PEG-RGD nanoparticles and their anticancer mechanisms, highlighting the potential of theranostic nanoparticles in BC treatment.

Prognostic Factors for Survival in Adult Patients with Cerebral Low-Grade Glioma

Background Low-grade gliomas are considered a therapeutic dilemma because of the heterogeneity of their clinical behavior. Patients affected by these tumors are often young and management decisions should put into consideration the potential indolent nature of these tumors and the potential long-term side effects of available therapies. Aim of the Work to analyze the collective data from studies to define prognostic factors for overall survival in adult patients with cerebral low-grade gliomas. Materials and Methods We prepared this systematic review with a careful following of the Cochrane Handbook for Systematic Reviews of Interventions guidelines. We conducted a literature search till December 2020 using PubMed, Scopus, Web of Science, and Cochrane Library. We performed a search for all published articles that evaluated the impact of several factors (patient’s age, KPS, neurological symptoms, histological subtype, pre-op tumor size, tumor crossing the midline, tumor enhancement, extent of resection, radiotherapy, and chemotherapy) on the overall survival (OS) and progression-free survival (PFS) of adult patients with cerebral low-grade glioma (LGG), Studies were independently assessed for risk of bias using (Cochrane Risk of Bias 2.0) for randomized controlled trials, and (Newcastle–Ottawa Scale) for retrospective cohort studies. Results Patient-related factors (age was found significant according to 14 of total 19 studies, KPS according to 7 of total 11 studies, and presence of seizures according to 5 of total 7 studies). Tumor-related factors (tumor subtype was significant according to 10 of total 13 studies, IDH-mutation according to 4 of total 5 studies, 1p/19q codeletion according to 5 of total 5 studies, and tumor enhancement according to 4 of total 7 studies), and treatmentrelated factors (extent of resection was significant according to 18 of total 20 studies, while timing and dose of radiation, combined chemotherapy and radiotherapy failed to show major statistical significance, with better PFS in delayed radiotherapy “till progression”, and slightly better OS in combined chemo, radiotherapy). Conclusion Highly significant factors are extent of tumor resection, patient’s age, pre-op tumor volume and molecular subtype.

Albumin pre-opsonized membrane-active iPep nanomedicine potentiates chemo to immunotherapy of cancer

Chemotherapy-conjugated immunotherapy in clinical oncology conceptually resembles the combined effects of cytoreduction and immunostimulation in membrane targeted cell killings mediated by pore-forming proteins or host defense peptides. Of the similar concept, targeting cancer cell membrane using membrane active peptides is a hopeful therapeutic modality but had long been hindered from in vivo application. Here we report an enabling strategy of pre-opsonizing a membrane penetrating Ir-complexed octa-arginine peptide (iPep) with serum albumin via intrinsic amphipathicity-driven bimodal interactions into nanoparticles (NP). We found that NP triggered stress-mediated 4T1 cell oncosis which induced potent immunological activation, surpassing several well-known immunogenic medicines. Vested with albumin-enhanced in vivo tumor targeting specificity and pharmacokinetic properties, NP showed combined chemo to immunotherapies of s. c. tumors in mice, with decreased percentages of MDSC, Treg, M2-like macrophage and improved infiltration of CTLs in tumor site, caused complete regression of 4T1 and CT26 tumors, outperforming clinical medicines. In a challenging orthotopic breast cancer model, boost i. v. injections of NP acted as in situ tumor vaccine that drastically enhanced 4T1-specific cellular and humoral immunities to reverse disease progression. Thus, with combined effects of direct cytoreduction, immune activation and tumor vaccine, iPep-NP presents the promise and potential of a new modality of cancer medicine.

Boosting the abscopal effect with chemoradiotherapy/immunotherapy combination in metastatic cervical cancer: a case report.

The prognosis for patients with distant-organ metastatic cervical cancer (CC) is poor owing to the lack of effective treatment modalities. We present a case of CC with lung metastasis that achieved partial remission of the cervical mass after two cycles of chemotherapy, while the pulmonary nodules remained stable. Moreover, the level of the tumor marker squamous cell carcinoma antigen was slightly higher than before. The patient was recommended to receive pelvic concurrent chemoradiotherapy combined with camrelizumab. Remarkably, after undergoing 16 cycles of immunotherapy, the patient's primary cervical mass and pulmonary nodules were in complete remission, and the tumor marker had returned to normal levels. This inspiring case demonstrates that a combination of chemo-/radio-/immunotherapy can be effective in treating lung metastatic CC and can also enhance the abscopal effect.

A chemo-biocatalyst based on glutamate oxidase-integrated biomimetic trimanganese tetraoxide as cascade composite nano-catalyst for synthesis of α‑Ketoglutaric acid

The combination of chemo- and biocatalysts to perform one-pot synthetic route has presented great challenges for decades. Herein, glutamate oxidase (GLOX) and trimanganese tetraoxide (Mn3O4) nanocrystals were combined for the first time by one-step biomineralization to construct a mimic multi-enzyme system (GLOX@Mn3O4) for chemoenzymatic synthesis of α‑ketoglutaric acid (α‑KG). Mn3O4 not only served as a support for the enzyme immobilization, but also contributed its catalytic activity to co-operate with natural enzymes for the cascade reactions. The as-synthesized chemo-enzyme catalysts with directly contacted catalytic sites of the enzyme and inorganic catalyst maximizes the substrate channeling effffects for in situ rapid decomposition of the oxidative intermediate, H2O2, during the enzymatic oxidation of sodium glutamate, thus relieving the inhibition of H2O2 accumulation for GLOX. Benefiting from the excellent stability and reusability of GLOX@Mn3O4, a nearly 100% conversion (99.7%) of l-glutamate to α-KG was achieved, over 4.7 times higher than that of the free GLOX system (21.2%). This work provides a feasibility for constructing a high-performance chemo-enzyme catalyst for cascade catalysis, especially for those reactions with toxic intermediates.

Mitochondria Targeted Nanoparticles Potentiate Tumor Chemo-Phototherapy by Toxic Oxidative Stress Mediated Oxeiptosis.

Insufficient accumulation of drug at the tumor site and the low drug response are the main reason for the unsatisfactory effect of cancer therapy. Delivery drugs exquisitely to subcellular level can be employed to reduce side effects, and expand the therapeutic window. Herein, a triphenylphosphine (TPP) modified lipid nanoparticles is designed which are loaded with the photosensitizer indocyanine green (ICG) and chemotherapeutic paclitaxel (PTX) for mitochondria-targeted chemo-phototherapy. Owing to the movement of majority mitochondria along microtubules in cytoplasm, mitochondrial targeting may enable PTX to act more effectively. Meanwhile, the existence of chemo-drug potentiates the phototherapy to achieve synergistic anti-tumor activity. As expected, mitochondria targeting nanomedicine (M-ICG-PTX NPs) showed improved mitochondria targeted cellular distribution and enhanced cell cytotoxicity in vitro. Also, M-ICG-PTX NPs exhibited higher tumor growth inhibition ability by promoting cell apoptosis and oxeiptosis pathway, and high effective inhibition of primary tumor growth and tumor metastasis. Taken together, M-ICG-PTX NPs may be promising nanoplatforms to achieve potent therapeutic effect for the combination of chemo- and photo-therapy (PTT).

Calcium carbonate nanoparticles tumor delivery for combined chemo-photodynamic therapy: Comparison of local and systemic administration.

The use of nanoparticles (NPs) as delivery vehicles for multiple drugs is an intensively developing area. However, the success of NPs' accumulation in the tumor area for efficient tumor treatment has been recently questioned. Distribution of NPs in a laboratory animal is mainly related to the administration route of NPs and their physicochemical parameters, which significantly affect the delivery efficiency. In this work, we aim to compare the therapeutic efficiency and side effects of the delivery of multiple therapeutic agents with NPs by both intravenous and intratumoral injections. For this, we systematically developed universal nanosized carriers based on calcium carbonate (CaCO3) NPs (< 100nm) that were co-loaded with a photosensitizer (Chlorin e6, Ce6) and chemotherapeutic agent (doxorubicin, Dox) for combined chemo- and photodynamic therapy (PDT) of B16-F10 melanoma tumors. By performing intratumoral or intravenous injections of NPs, we observed different biodistribution profiles and tumor accumulation efficiencies. In particular, after intratumoral administration of NPs, they mostly remained in the tumors (> 97%); while for intravenous injection, the tumor accumulation of NPs was determined to be 8.67-12.4 ID/g%. Although the delivery efficiency of NPs (presented in ID/g%) in the tumor differs, we have developed an effective strategy for tumor inhibition based on combined chemo- and PDT by both intratumoral and intravenous injections of NPs. Notably, after the combined chemo- and PDT treatment with Ce6/Dox@CaCO3 NPs, all B16-F10 melanoma tumors in mice shrank substantially, by approximately 94% for intratumoral injection and 71% for intravenous injection, which are higher values compared to mono-therapy. In addition, the CaCO3 NPs showed negligible in vivo toxicity towards major organs such as the heart, lungs, liver, kidneys, and spleen. Thus, this work demonstrates a successful approach for the enhancement of NPs' efficiency in combined anti-tumor therapy.

Development and physicochemical characterization of a biodegradable microspheres formulation loaded with samarium-153 and doxorubicin for chemo-radioembolization of liver tumours.

Transarterial chemoembolization (TACE) and transarterial radioembolization (TARE) are promising treatments for unresectable liver tumours. Some recent studies suggested that combining TACE and TARE in one treatment course might improve treatment efficacy through synergistic cytotoxicity effects. Nonetheless, current formulations do not facilitate a combination of chemo- and radio-embolic agents in one delivery system. Therefore, this study aimed to synthesise a hybrid biodegradable microsphere loaded with both radioactive agent, samarium-153 (153 Sm) and chemotherapeutic drug, doxorubicin (Dox) for potential radio-chemoembolization of advanced liver tumours. 152 Sm and Dox-loaded polyhydroxybutyrate-co-3-hydroxyvalerate (PHBV) microspheres were prepared using water-in-oil-in-water solvent evaporation method. The microspheres were then sent for neutron activation in a neutron flux of 2 × 1012 n/cm2 /s. The physicochemical properties, radioactivity, radionuclide purity, 153 Sm retention efficiency, and Dox release profile of the Dox-153 Sm-PHBV microspheres were analysed. In addition, in vitro cytotoxicity of the formulation was tested using MTT assay on HepG2 cell line at 24 and 72 h. The mean diameter of the Dox-153 Sm-PHBV microspheres was 30.08 ±2.79 μm. The specific radioactivity was 8.68 ±0.17 GBq/g, or 177.69 Bq per microsphere. The 153 Sm retention efficiency was more than 99%, tested in phosphate-buffered saline (PBS) and human blood plasma over 26 days. The cumulative release of Dox from the microspheres after 41 days was 65.21 ±1.96% and 29.96 ±0.03% in PBS solution of pH7.4 and pH5.5, respectively. The Dox-153 Sm-PHBV microspheres achieved a greater in vitro cytotoxicity effect on HepG2 cells (85.73 ±3.63%) than 153 Sm-PHBV (70.03 ±5.61%) and Dox-PHBV (74.06 ±0.78%) microspheres at 300 μg/mL at 72 h. In conclusion, a novel biodegradable microspheres formulation loaded with chemotherapeutic drug (Dox) and radioactive agent (153 Sm) was successfully developed in this study. The formulation fulfilled all the desired physicochemical properties of a chemo-radioembolic agent and achieved better in vitro cytotoxicity on HepG2 cells. Further investigations are needed to evaluate the biosafety, radiation dosimetry, and synergetic anticancer properties of the formulation.