Effective Tumor Therapy Research Articles

Breaking the Redox Homeostasis: an Albumin‐Based Multifunctional Nanoagent for GSH Depletion‐Assisted Chemo‐/Chemodynamic Combination Therapy

AbstractRedox homeostasis is vital for cell survival. Nowadays, developing novel nanoagents that can efficiently break the redox homeostasis, which includes improving the reactive oxygen species level while reducing the glutathione (GSH) level, has emerged as a promising but challenging strategy for tumor therapy. In this work, a novel albumin‐based multifunctional nanoagent is developed for GSH‐depletion assisted chemo‐/chemodynamic combination therapy. Briefly, CuO and MnOX are in situ co‐grown inside the albumin molecules through a facile biomineralization process, followed by the conjugation of Pt (IV) prodrug to obtain the final nanoagent. Thereinto, copper species can produce •OH with optimal efficiency under weakly acidic conditions (pH = 6.5), while MnOX can react with GSH, leading to the GSH depletion, which reduces the formation of GSH‐Pt adducts and •OH consumption, thus favoring a better chemotherapy and chemodynamic therapy effect, respectively. Significantly, both GSH depletion and •OH generation contributes to the inhibited expression of GPX‐4, which further increases the oxidative stress. Moreover, during the reaction between MnOX and GSH or H2O2, Mn2+ ions are released for MR imaging while O2 is produced for hypoxia relief. It is believed that the proposed strategy can provide a new perspective on effective tumor therapy.

Does significantly elevated lung shunt fraction (LSF >20%) promote extrahepatic progression in patients with hepatocellular carcinoma treated with radioembolization?

Radioembolization with yttrium-90 (Y-90) is an effective locoregional therapy for primary and metastatic liver tumors, but its use is restricted or contraindicated for patients with elevated lung shunt fraction (LSF) because of an increased risk of developing pulmonary adverse events, including but not limited to radiation pneumonitis. Elevated LSF is also thought to be correlated with liver tumor progression and metastases. In this retrospective cohort study, we examine rates of metastasis development, rates of adverse events and overall survival (OS) in 23 patients with hepatocellular carcinoma (HCC) and elevated LSF >20% on Tc-99 m macroaggregated albumin scan treated with Y-90 radioembolization at our institution from 2005 to 2016. To minimize confounding variables, patients with baseline extrahepatic metastases or portal vein tumor thrombosis were excluded. Kaplan-Meier estimates were performed for OS and time to development of metastases. No patient developed clinical and imaging signs of radiation pneumonitis. Median intention to treat OS from day of radioembolization was 21.3 months; median censored OS was 14.7 months. Five out of 23 patients (22%) developed at least one metastasis during follow-up, for an incidence of 20 per 1000 patient-years (compared to the historical rate of 6 per 1000 patient-years for HCC patients in general). HCC patients with LSF >20% treated with Y-90 radioembolization have acceptable toxicities and appear to have a rate of extrahepatic tumor development (22%) higher than expected for patients with HCC.

Multifunctional Programmable DNA Nanotrain for Activatable Hypoxia Imaging and Mitochondrion-Targeted Enhanced Photodynamic Therapy.

Programmable DNA-based nanostructures (e.g., nanotrains, nanoflowers, and DNA dendrimers) provide new approaches for safe and effective biological imaging and tumor therapy. However, few studies have reported that DNA-based nanostructures respond to the hypoxic microenvironment for activatable imaging and organelle-targeted tumor therapy. Herein, we innovatively report an azoreductase-responsive, mitochondrion-targeted multifunctional programmable DNA nanotrain for activatable hypoxia imaging and enhanced efficacy of photodynamic therapy (PDT). Cyanine structural dye (Cy3) and black hole quencher 2 (BHQ2), which were employed as a fluorescent mitochondrion-targeted molecule and azoreductase-responsive element, respectively, covalently attached to the DNA hairpin monomers. The extended guanine (G)-rich sequence at the end of the DNA hairpin monomer served as a nanocarrier for the photosensitizer 5,10,15,20-tetrakis(4-N-methylpyridiniumyl) porphyrin (TMPyP4). Upon initiation between the DNA hairpin monomer and initiation probe, the fluorescence of Cy3 and the singlet oxygen (1O2) generation of TMPyP4 in the programmable nanotrain were effectively quenched by BHQ2 through the fluorescence resonance energy transfer (FRET) process. Once the programmable nanotrain entered cancer cells, the azo bond in BHQ2 will be reduced to amino groups by the high expression of azoreductase under hypoxia conditions; then, the fluorescence of Cy3 and the 1O2 generation of TMPyP4 will significantly be restored. Furthermore, due to the mitochondrion-targeting characteristic endowed by Cy3, the TMPyP4-loaded nanotrain would accumulate in the mitochondria of cancer cells and then demonstrate enhanced PDT efficacy under light irradiation. We expect that this programmable DNA nanotrain-based multifunctional nanoplatform could be effectively used for activatable imaging and high performance of PDT in hypoxia-related biomedical field.

Long‐Lasting Reactive Oxygen Species Generation by Porous Redox Mediator‐Potentiated Nanoreactor for Effective Tumor Therapy

AbstractThe therapeutic efficiency of reactive oxygen species (ROS)‐based nanotherapeutics is restrained by the rigorous production conditions of relatively sufficient and kinetically matching supply of intracellular substrates. The cumulative disruption of redox homeostasis and consequent pathology (e.g., Parkinson's disease) with low levels of substrates in living organisms may provide a promising model for ROS‐based therapy. Herein, a catechol chemistry‐mediated ternary nanostructure is prepared for long‐lasting generation of oxidative •OH in weakly acidic, low H2O2 homeostasis conditions of tumor. This platform employs mesoporous polydopamine (MPDA) as the porous redox mediator, while PDA‐induced sequential precipitation and biomineralization lead to hydroxy iron oxide (FeOOH) as the “iron reservoir,” and calcium phosphate (CaP) as the pH‐sensitive sheddable shell. In weakly acidic conditions, the CaP layer can be degraded to expose the catalytic surface of Fe‐dopamine interplay, where FeOOH dissolution, Fe(III) chelation, Fe(III) reduction, Fe(II) release take place sequentially and continuously for Fe(II) recycling and Fenton catalysis. Both in vitro and in vivo studies verify the significant inhibition of cancer cells and tumor regression, which can also be strengthened by the local photothermal heating. This work establishes the first paradigm of pathologically inspired nanohybrids of ROS generators with long‐lasting efficacy for cancer therapy.

Water Solubilization and Thermal Stimuli-Triggered Release of Porphyrin Derivatives Using Thermoresponsive Polysaccharide Hydroxypropyl Cellulose for Mitochondria-Targeted Photodynamic Therapy.

With minimal invasiveness and spatiotemporal therapeutic effects, photodynamic therapy is one of the most elegant strategies for achieving effective tumor therapy. Herein, a facile preparation and thermal process-triggered release of water-soluble photosensitizer 5,10,15,20-tetrakis(4-hydroxyphenyl)porphyrin (THPP) has been developed using a thermoresponsive polysaccharide, hydroxypropyl cellulose. Current systems using hydroxypropyl cellulose enable manipulation of the loading capacity of THPP into a polymer matrix and the size of the complex by varying the temperature of the solution in preparation. Furthermore, current systems have enabled the release of THPP using a heating process, mimicking the surrounding of mitochondria, and have resulted in THPP potency as a mitochondria-targeted photodynamic therapy.

Macrophage-mediated tumor homing of hyaluronic acid nanogels loaded with polypyrrole and anticancer drug for targeted combinational photothermo-chemotherapy.

Rationale: Development of nanosystems that can be integrated with macrophages (MAs), an emerging carrier system, for effective tumor therapy remains to be challenging. We report here the development of MAs specifically loaded with hyaluronic acid (HA) nanogels (NGs) encapsulated with a photothermal agent of polypyrrole (PPy) and anticancer drug doxorubicin (DOX) (HA/DOX@PPy NGs) for tumor homing and combination photothermo-chemotherapy.Methods: Cystamine dihydrochloride-crosslinked HA NGs were first prepared through a double emulsification method, then loaded with PPy via an in-situ oxidization polymerization and physically encapsulated with DOX. The created HA/DOX@PPy NGs were well characterized and subjected to be endocytosed by MAs (MAs-NGs). The MAs-mediated tumor-homing property, phenotype changes and photothermal performance of MAs-NGs were investigated in vitro, and a subcutaneous tumor model was also established to confirm their targeting capability and enhanced antitumor therapy effect in vivo.Results: The generated hybrid NGs possess a size around 77 nm and good colloidal stability, and can be specifically endocytosed by MAs without appreciably affecting their normal biofunctionalities. In particular, NG-loaded MAs display excellent in-vitro cancer cell and in-vivo tumor homing property. Systemic administration of the MAs-NGs leads to the significant inhibition of a subcutaneous tumor model through combination photothermo-chemotherapy under laser irradiation.Conclusions: The developed hybrid HA-based NG nanosystem incorporated with PPy and DOX fully integrates the coordination and heating property of PPy to regulate the optimized DOX release in the tumor region with the assistance of MA-mediated tumor homing, providing a promising cell therapy strategy for enhanced antitumor therapy.

In Vivo Regenerable Cerium Oxide Nanozyme-Loaded pH/H2O2-Responsive Nanovesicle for Tumor-Targeted Photothermal and Photodynamic Therapies.

Photodynamic therapy (PDT) and photothermal therapies (PTTs) are both promising strategies for effective tumor therapy. However, the absence of O2 at tumor sites hinders the sustained response of photosensitizers. Here, we develop a recycled cerium oxide (CeO2) catalase nanozyme-loaded hyaluronic acid nanovesicle to address the hypoxic tumor microenvironments and targeted delivery of the photosensitizers [indocyanine green (ICG)] to tumors. A polysaccharide complex effectively modifies the surface of a polyethylenimine phenylboronic acid nanostructure to achieve the CeO2 nanozyme-loading nanovesicles that exhibit both tumor-targeted enhancement and an improved hypoxic microenvironment. Also, the hydrogen peroxide responsiveness and acid-sensitive cleavage of phenylboronic acid specifically disintegrate the ICG/nanozyme coloaded nanovesicles in the tumor microenvironment. The in vitro synergistic tests and tumor suppression rate tests indicated that the cerium oxide nanozyme significantly improves the outcomes of PDT via cerium-element valence state recycling and hypoxia improvement, thus enhancing the tumor suppression efficiency. This pH/H2O2-responsive nanozyme/ICG codelivery system provides a good carrier model for improving the tumor microenvironment and increasing the efficiency of tumor-targeted PTT and PDT therapies.

Selection-driven tumor evolution with public goods leads to patterns of clonal expansion consistent with neutral growth.

SummaryCancers are the result of eco-evolutionary processes fueled by heritable phenotypic diversification and driven by environmentally dependent selection. Space represents a key growth-limiting ecological resource, the ability to explore this resource is likely under strong selection. Using agent-based modeling, we explored the interplay between phenotypic strategies centered on gaining access to new space through cell-extrinsic degradation of extracellular matrix barriers and the exploitation of this resource through maximizing cell proliferation. While cell proliferation is a cell-intrinsic property, newly accessed space represents a public good, which can benefit both producers and non-producers. We found that this interplay results in ecological succession, enabling emergence of large, heterogeneous, and highly proliferative populations. Even though in our simulations both remodeling and proliferation strategies were under strong positive selection, their interplay led to sub-clonal architecture that could be interpreted as evidence for neutral evolution, warranting cautious interpretation of inferences from sequencing of cancer genomes.

Abdominal FLASH irradiation reduces radiation-induced gastrointestinal toxicity for the treatment of ovarian cancer in mice

Radiation therapy is the most effective cytotoxic therapy for localized tumors. However, normal tissue toxicity limits the radiation dose and the curative potential of radiation therapy when treating larger target volumes. In particular, the highly radiosensitive intestine limits the use of radiation for patients with intra-abdominal tumors. In metastatic ovarian cancer, total abdominal irradiation (TAI) was used as an effective postsurgical adjuvant therapy in the management of abdominal metastases. However, TAI fell out of favor due to high toxicity of the intestine. Here we utilized an innovative preclinical irradiation platform to compare the safety and efficacy of TAI ultra-high dose rate FLASH irradiation to conventional dose rate (CONV) irradiation in mice. We demonstrate that single high dose TAI-FLASH produced less mortality from gastrointestinal syndrome, spared gut function and epithelial integrity, and spared cell death in crypt base columnar cells compared to TAI-CONV irradiation. Importantly, TAI-FLASH and TAI-CONV irradiation had similar efficacy in reducing tumor burden while improving intestinal function in a preclinical model of ovarian cancer metastasis. These findings suggest that FLASH irradiation may be an effective strategy to enhance the therapeutic index of abdominal radiotherapy, with potential application to metastatic ovarian cancer.

Biodegradable Multifunctional Nanotheranostic Based on Ag2S-Doped Hollow BSA-SiO2 for Enhancing ROS-Feedback Synergistic Antitumor Therapy.

Stimuli-responsive silica nanoparticles are an attractive therapeutic agent for effective tumor ablation, but the responsiveness of silica nanoagents is limited by intrastimulation level and silica framework structure. Herein, a biodegradable hollow SiO2-based nanosystem (Ag2S-GOx@BHS NYs) is developed by a novel one-step dual-template (bovine serum albumin (BSA) and cetyltrimethylammonium bromide (CTAB)) synthetic strategy for image-guided therapy. The Ag2S-GOx@BHS NYs can be specifically activated in the tumor microenvironment via a self-feedback mechanism to achieve reactive oxygen species (ROS)-induced multistep therapy. In response to the inherent acidity and H2O2 at the tumor sites, Ag2S-GOx@BHS would accelerate the structural degradation while releasing glucose oxidase (GOx), which could efficiently deplete intratumoral glucose to copious amounts of gluconic acid and H2O2. More importantly, the sufficient H2O2 not only acts as a reactant to generate Ag+ from Ag2S for metal-ion therapy and improves the oxidative stress but also combines with gluconic acid results in the self-accelerating degradation process. Moreover, the released Ag2S nanoparticles can help the Ag2S-GOx@BHS NYs realize the second near-infrared window fluorescence (NIR-II FL) and photoacoustic (PA) imaging-guided precise photothermal therapy (PTT). Taken together, the development of a self-feedback nanosystem may open up a new dimension for a highly effective multistep tumor therapy.

Modelling of combination therapy using implantable anticancer drug delivery with thermal ablation in solid tumor

Local implantable drug delivery system (IDDS) can be used as an effective adjunctive therapy for solid tumor following thermal ablation for destroying the residual cancer cells and preventing the tumor recurrence. In this paper, we develop comprehensive mathematical pharmacokinetic/pharmacodynamic (PK/PD) models for combination therapy using implantable drug delivery system following thermal ablation inside solid tumors with the help of molecular communication paradigm. In this model, doxorubicin (DOX)-loaded implant (act as a transmitter) is assumed to be inserted inside solid tumor (acts as a channel) after thermal ablation. Using this model, we can predict the extracellular and intracellular concentration of both free and bound drugs. Also, Impact of the anticancer drug on both cancer and normal cells is evaluated using a pharmacodynamic (PD) model that depends on both the spatiotemporal intracellular concentration as well as characteristics of anticancer drug and cells. Accuracy and validity of the proposed drug transport model is verified with published experimental data in the literature. The results show that this combination therapy results in high therapeutic efficacy with negligible toxicity effect on the normal tissue. The proposed model can help in optimize development of this combination treatment for solid tumors, particularly, the design parameters of the implant.

Preparation and in vitro evaluation of doxorubicin loaded alendronate modified hollow gold nanoparticles for bone-targeted chemo-photothermal therapy

The treatment of malignant bone tumors (including primary bone tumors and metastatic bone tumors) has always been a clinical challenge. The purpose of this study is to design a bone-targeted nano-carrier with photothermal effect to achieve chemo-photothermal therapy (CPT), which allows the minimal use of photothermal agents and chemical drugs to target bone tumors. Alendronate modified hollow gold nanoparticles (HGNPs- ALN) were synthesized using mercapto polyethylene glycol carboxyl (SH-PEG2000-COOH) as the connecting arm, fourier transform infrared spectroscopy (FTIR) and transmission electron microscopy (TEM) data show that HGNPs-ALN with a particle size of about 80 nm has been successfully synthesized. The hydroxyapatite affinity experiment in vitro indicated that HGNPs-ALN exhibited a high affinity to bone. In addition, the temperature of HGNPs-ALN under near-infrared laser irradiation can rise to 53 °C, which can achieve effective photothermal therapy for bone tumors. Bone-targeted hollow gold nanoparticles (DOX@HGNPs-ALN) loaded with doxorubicin hydrochloride (DOX) were synthesized by one-pot method. By comparing the stability and drug loading of HGNPs-ALN, it was concluded that the optimal mass ratio of HGNPs-ALN (calculated by the amount of gold) to DOX was about 1:2. HGNPs-ALN and DOX@HGNPs-ALN both have good photothermal stability and photothermal transformation properties, and confirmed the safety of HGNPs on human osteosarcoma cells. MTT experiments showed that DOX@HGNPs-ALN had the strongest killing effect on MG-63 osteosarcoma cells under laser irradiation (the killing rate is about 65%). According to these results, it can be considered that DOX@HGNPs-ALN has the potential of CPT synergistic targeting therapy for bone tumors.

Mineralized manganese dioxide channel as the stent coating for in situ precise tumor navigation

Drug-eluting stent (DES) is a promising strategy for esophageal cancer. However, full-covered drug-loaded stents cause damage to non-tumor tissue in the esophagus, and the development controlled-release system to prevent non-tumor tissue injure is currently a major challenge. Here, in situ mineralized manganese dioxide coating on Ce6 embedded electrospun fibers covered stent was developed for effective tumor therapy via intraluminal photodynamic therapy (PDT), which could reduce phototoxicity to normal esophageal tissue. Oxidation of manganese ions, which was previously swelled between fibers, was used to accomplish mineralization. After implantation, the manganese dioxide coating in situ reacts with tumor endogenous H+ and H2O2, which, on the one hand, could effectively alleviate the hypoxic microenvironment which leads to resistance to PDT, and on the other hand, could expose the Ce6-fibers below the coating for intraluminal PDT. In addition, due to the slow degradation of the coating, this stent could own sustained photodynamic performance for up to one month. Notably, the PDT efficiency of the stent was investigated on orthotopic rabbit esophageal cancer models. Overall, this work suggests that in situ mineralized manganese dioxide coated electrospun fibers covered stent may provide a new strategy for advanced esophageal cancer patients as a functional drug delivery platform.

Stereotactic body radiation therapy (SBRT) in recurrent, persistent or oligometastatic gynecological cancers

ObjectiveSBRT is a well-tolerated technique and provides local-regional control in a variety of metastatic and recurrent tumor types. The role of SBRT in extracranial recurrent, persistent, or oligometastatic gynecological tumors is not well-studied. We therefore retrospectively analyzed a sizeable number of patients in this setting. MethodsWe performed a retrospective review of 86 patients with 209 tumors treated at our institution with SBRT for recurrent, persistent, or oligometastatic extracranial gynecological tumors. The median follow-up was 20 months (range 1–91). The median SBRT dose was 24 Gy (range 10–50) delivered in a median of 4 fractions (range 1–6). The Kaplan-Meier curves and log rank tests were used to assess local control (LC) and overall survival (OS). Cox proportional hazards model was used to evaluate for covariates associated with LC and OS. ResultsThe 1- and 3-year LC were 80% and 68% respectively. The 1- and 3-year OS were 70% and 39%. 32% of the lesions demonstrated complete response, 23% partial response and 20% stable disease. SBRT achieved better local control in smaller tumors. Toxicity was typically mild with grade 1 gastrointestinal toxicity and fatigue being the most common. Only 4.3% of treatments resulted in grade 2 or greater toxicity. There was only one case of grade 3 and no grade 4 or 5 toxicities. ConclusionsSBRT offers a high rate of local control with low incidence of toxicity, mainly grade 1 GI toxicity and fatigue, and provides effective salvage therapy for oligometastatic extracranial pelvic and extra-pelvic gynecological tumors.

Functional LAPONITE Nanodisks Enable Targeted Anticancer Chemotherapy in Vivo.

Development of nanoplatforms for targeted anticancer drug delivery for effective tumor therapy still remains challenging in the development of nanomedicine. Here, we present a facile method to formulate a LAPONITE (LAP) nanodisk-based nanosystem for anticancer drug doxorubicin (DOX) delivery to folic acid (FA) receptor-overexpressing tumors. In the current work, aminated LAP nanodisks were first prepared through silanization, then functionalized with polyethylene glycol-linked FA (PEG-FA) via 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC) chemistry, and finally employed to physically encapsulate DOX. The formed functional LAP nanodisks (for short, LM-PEG-FA) possess a high DOX loading efficiency (88.6 ± 1.2%) and present a pH-dependent release feature with a quicker DOX release under acidic pH conditions (pH 5.0) than under physiological pH conditions (pH 7.4). In vitro flow cytometry, confocal microscopic observation, and cell viability assay show that the LM-PEG-FA/DOX complexes can be specifically taken up by FAR-overexpressing human ovarian cancer cells (SK-OV-3 cells) and present a specific cancer cell therapeutic effect. Further tumor treatment results reveal that the LM-PEG-FA/DOX complexes can exert a specific therapeutic efficacy to a xenografted SK-OV-3 tumor model in vivo when compared with nontargeted LM-mPEG/DOX complexes. Therefore, the developed LM-PEG-FA nanodisks could be employed as a potential platform for targeted cancer chemotherapy.

Versatile hollow COF nanospheres via manipulating transferrin corona for precise glioma-targeted drug delivery

Covalent organic framework (COF) nanoparticles for interference-free targeted drug delivery to glioma remains in its infancy. Herein, hollow COF nanospheres with high crystallinity and uniformed sizes were facilely prepared via heterogeneous nucleation-growth. The prepared COF had large surface area/pore volume and exhibited appropriate degradation behavior under acid environment, where therefore doxorubicin was effectively encapsulated and exhibited a pH-sensitive release. Most charmingly, T10 peptide that has high affinity with transferrin (Tf), was conjugated to endow the hollow COF interesting properties to specifically absorb Tf in vivo as Tf corona. For the first time, multifunctional hollow COF nanospheres (the better one named DCPT-2) were successfully synthesized to achieve interference-free cascade-targeting glioma drug delivery across the blood-brain barrier. Treatment with DCPT-2 brought an improved therapeutic outcome with significantly prolonged median survival time and low side effects. This work promised not only a potential protein corona-mediated COF-based drug delivery platform with good biocompatibility for effective and precise brain tumor therapy, but also an endogenous protein corona-mediated targeting strategy for general cancer therapy.

Potential Therapeutic Effects of the Neural Stem Cell-Targeting Antibody Nilo1 in Patient-Derived Glioblastoma Stem Cells.

Glioblastoma (GBM) is the most devastating and least treatable brain tumor with median survival <15 months and extremely high recurrence rates. Promising results of immune checkpoint blockade obtained from pre-clinical studies in mice did not translate to clinic, and new strategies are urgently needed, particularly those targeting GBM stem cells (GSCs) that are held responsible for drug resistance and tumor recurrence. Patient-derived GSC cultures are critical for finding effective brain tumor therapies. Here, we investigated the ability of the recently described monoclonal antibody Nilo1 to specifically recognize GSCs isolated from GBM surgical samples. We employed five patient-derived GSC cultures with different stemness marker expression and differentiation potential, able to recapitulate original tumors when xenotransplanted in vivo. To answer whether Nilo1 has any functional effects in patient-derived GSCs lines, we treated the cells with Nilo1 in vitro and analyzed cell proliferation, cell cycle, apoptosis, sphere formation, as well as the expression of stem vs. differentiation markers. All tested GSCs stained positively for Nilo1, and the ability of Nilo1 to recognize GSCs strongly relied on their stem-like phenotype. Our results showed that a subset of patient-derived GSCs were sensitive to Nilo1 treatment. In three GSC lines Nilo1 triggered differentiation accompanied by the induction of p21. Most strikingly, in one GSC line Nilo1 completely abrogated self-renewal and led to Bax-associated apoptosis. Our data suggest that Nilo1 targets a molecule functionally relevant for stemness maintenance and pinpoint Nilo1 as a novel antibody-based therapeutical strategy to be used either alone or in combination with cytotoxic drugs for GSC targeting. Further pre-clinical studies are needed to validate the effectiveness of GSC-specific Nilo1 targeting in vivo.

Abstract 5632: PBMC-humanized mouse model for the assessment of cytokine release syndrome caused by checkpoint and bispecific immunotherapy

Abstract Immunotherapeutic antibodies and cell therapies have proven to be highly effective cancer therapy for solid tumors, leukemia and lymphomas. The immunotherapy acts in part by stimulating and redirecting the immune system to attack cancer cells, and cytokines can be released during the process. As a consequence cytokine release syndrome (CRS) is a common adverse effect caused by immunotherapy which could be very severe in patients. The animal models and in vitro human PBMC assays presently in use unfortunately can't reliably predict the CRS in patients. To address the gap between pre-clinical testing and clinical trials we have developed a rapid, sensitive and reproducible humanized mouse model for quantitating CRS. Immunodeficient NSG™ mice were irradiated and injected with human PBMCs intravenously. In general PBMC-engrafted mice had 10-20% human immune cells (hCD45+) in blood with ~70% of the hCD45+ cells being CD3+ T cells and ~20% being CD56+ NK cells. PBMC-engrafted mice were used for treatment within 6 days. We demonstrated that a number of human cytokines including IFN-γ, IL-2, IL-4, IL-6, IL-10 and TNF-α were elevated in blood in the humanized mice treated with monoclonal antibodies and bispecifics including anti-CD3, anti-CD28, anti-PD-1 and BiTE molecules. The cytokine release was dependent on the dose and time of treatment, and PBMCs from every human donor tested were capable of responding to produce cytokines. Notably the amount of cytokines produced varied from donor to donor in &amp;gt;40 different PBMCs tested so far and cytokine levels of &amp;gt;10-fold difference were frequently observed, indicating that the animal model could reveal individual differences in human donors. As a result human donors could be divided into three types as high, medium or low responders. PBMC-engrafted mice implanted with tumors could also be used. Tumor-bearing PBMC-humanized model would be required to evaluate molecules such as BiTE since CRS activity was most evident when both targets for BiTE molecules were present during the assay. PBMC-engrafted NSG™ mice were used for CRS assessment prior to the development of acute graft-vs-host disease (GVHD) in all of the experiments. We were able to reproduce the data using a NSG™ strain [NSG-(Kb Db)null (IAnull)] doubly deficient in murine MHC class I and II molecules, or double knockout (KO) mice. The double KO mice are known to engraft human PBMCs in a manner very similar to NSG™ and have a significantly delayed onset of GVHD [Brehm et al., FASEB J. 33, 3137 (2019)]. Results from the double KO mice further validated cytokine release was not GvHD related and the NSG™ mice is a robust model for CRS assessment of immunotherapy in vivo. We have described a PBMC-humanized model using NSG™ mice that offers rapid assessment of potential risks of therapeutic agents in causing CRS in vivo. The model could differentiate individual human differences based on the cytokine release. Citation Format: Danying Cai, Jing Jiao, Chunting Ye, Hongyuan Yang, Mingshan Cheng, Michael A. Brehm, Dale L. Greiner, Leonard D. Shultz, James G. Keck. PBMC-humanized mouse model for the assessment of cytokine release syndrome caused by checkpoint and bispecific immunotherapy [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5632.

Pivotal Role of Peptides in Gastric Carcinoma: Diagnosis and Therapy

Gastric cancer (GC) is still ranked fourth among malignant cancers and remained as the second leading cause of cancer related death. There is mounting evidence that emphasizes on the need for further investigation on the specific receptors overexpression roles in GC progression. Low efficiency and impotence of the common methods for targeting gastric tumorigenesis and related metastases are enough to convince researchers to continue their investigation on new approaches of effective GC targeting. Due to the suitable characteristics of peptides, such as high affinity and specificity, they have great potential for cancer cell targeting. Overexpression of specific targets in GC can facilitate the application of peptide-based pharmaceuticals for effective tumor targeting and therapy and early diagnosis with help of fluorescents or radionuclides. In this review article, we paid particular attention to the characterization of peptide-based pharmaceuticals and radiopharmaceuticals that have been investigated in recent years for GC diagnosis and therapy.

A novel clustered SPIO nanoplatform with enhanced magnetic resonance T2 relaxation rate for micro-tumor detection and photothermal synergistic therapy

Construction of micro tumor sensitive theranostic nanoagents that can increase the accuracy of imaging diagnosis and boost the therapeutic efficacy has been demonstrated for a promising approach for diagnosis and treatment of cancer. Herein, we reported a novel super-paramagnetic iron oxide (SPIO) based nanoplatform that possess significantly enhanced magnetic resonance property and photothermal effect for tumor theranostic purpose. This polyethylene glycol with four phenylboronic acid (PEG-B4)/CNTs@porphyrin (ph)/SPIO (BCPS) nanoplatform was simply prepared via integrated SPIO, ph, and a novel dendrimer with PEG liner and four PBA groups (PEG-B4) on the surface of carbon nanotubes (CNTs). Subsequently, a significant T2 relaxation rate enhanced can be achieved by the reduced accessibility of water to SPIO clustering. Moreover, the synergetic enhanced photothermal from BCPS nanoplatform contributed to better photothermal effect for cancer therapy. Furthermore, the targeting ability to sialic acid overexpressed tumor was further introduced from phenylboronic acid from PEG-B4. We showed that BCPS nanoplatform could not only selectively identify solid tumors and detect micro-sized metastatic tumor (1 mm) in the liver, but also effectively ablate tumors in a xenograft model, thereby achieving a complete cure rate of 100% at low laser dose. Our results highlight the potential of BCPS nanoplatform for accurate micro-tumor diagnosis and effective tumor therapy. [Figure not available: see fulltext.].