Developing multifunctional nanoplatforms to comprehensively modulate the tumor microenvironment and enhance diagnostic and therapeutic outcomes still remains a great challenge. Here, we report the facile construction of a multivariate nanoplatform based on cancer cell membrane (CM)-encapsulated redox-responsive poly(N-vinylcaprolactam) (PVCL) nanogels (NGs) co-loaded with Cu(II) and chemotherapeutic drug toyocamycin (Toy) for magnetic resonance (MR) imaging-guided combination tumor chemodynamic therapy/chemoimmunotherapy. We show that redox-responsive PVCL NGs formed through precipitation polymerization can be aminated, conjugated with 3,4-dihydroxyhydrocinnamic acid for Cu(II) complexation, physically loaded with Toy, and finally camouflaged with CMs. The created ADCT@CM NGs with an average size of 113.0 nm are stable under physiological conditions and can efficiently release Cu(II) and Toy under tumor microenvironment with a high level of glutathione. Meanwhile, the developed NGs are able to enhance cancer cell oxidative stress and endoplasmic reticulum stress by synergizing the effects of chemodynamic therapy mediated by Cu-based Fenton-like reaction and Toy-mediated chemotherapy, thereby triggering significant immunogenic cell death (ICD). In a melanoma mouse model, the NGs show potent immune activation effects to reinforce tumor therapeutic efficacy through ICD induction and immune modulation including high levels of immune cytokine secretion, increased tumor infiltration of CD8+ cytotoxic T cells, and reduced tumor infiltration of regulatory T cells. With the CM coating and Cu(II) loading, the developed NG platform demonstrates homologous tumor targeting and T1-weighted MR imaging, hence providing a general biomimetic NG platform for ICD-facilitated tumor theranostic nanoplatform. Statement of Significance Developing multifunctional nanoplatforms to comprehensively modulate the tumor microenvironment (TME) and enhance theranostic outcomes remains a challenge. Here, a cancer cell membrane (CM)-camouflaged nanoplatform based on aminated poly(N-vinylcaprolactam) nanogels (NGs) co-loaded with Cu(II) and toyocamycin (Toy) was prepared for magnetic resonance (MR) imaging-guided combination tumor chemodynamic therapy/chemoimmunotherapy. The tumor targeting specificity and efficient TME-triggered release of Cu(II) and Toy could enhance tumor cell oxidative stress and endoplasmic reticulum stress by synergizing the effects of chemodynamic therapy mediated by Cu-based Fenton-like reaction and Toy-mediated chemotherapy, respectively, thereby leading to significant immunogenic cell death (ICD) and immune response. With the CM coating and Cu(II) loading, the developed NG platform also demonstrates good T1-weighted tumor MR imaging performance. Hence, this study provides a general biomimetic NG platform for ICD-facilitated tumor theranostics.

Macrophage membrane-camouflaged nanoclusters of ultrasmall iron oxide nanoparticles can be developed to cross the blood–brain barrier for magnetic resonance imaging and chemo/chemodynamic therapy.

We report a zwitterionic USIO-based platform for tumor T 1 WI not only in a subcutaneous tumor, but also in an orthotopic GBM with MRgFUS-mediated BBB opening. The formed USIO NPs-1,3-PS may improve the precision imaging and therapeutic efficacy of GBM.

Development of a nanoscale drug delivery system that can simultaneously exert efficient tumor therapeutic efficacy while creating the desired antitumor immune responses is still challenging. Herein, we report the use of a manganese dioxide (MnO2)-entrapping dendrimer nanocarrier to codeliver glucose oxidase (GOx) and cyclic GMP-AMP (cGAMP), an agonist of the stimulator of interferon genes (STING) for improved tumor chemodynamic/starvation/immune therapy. Methoxy poly(ethylene glycol) (mPEG)- and phenylboronic acid (PBA)-modified generation 5 (G5) poly(amidoamine) dendrimers were first synthesized and then entrapped with MnO2 nanoparticles (NPs) to generate the hybrid MnO2@G5-mPEG-PBA (MGPP) NPs. The created MGPP NPs with an MnO2 core size of 2.8 nm display efficient glutathione depletion ability, and a favorable Mn2+ release profile under a tumor microenvironment mimetic condition to enable Fenton-like reaction and T1-weighted magnetic resonance (MR) imaging. We show that the MGPP-mediated GOx delivery facilitates enhanced chemodynamic/starvation therapy of cancer cells in vitro, and further codelivery of cGAMP can effectively trigger immunogenic cell death (ICD) to strongly promote the maturation of dendritic cells. In a bilateral mouse colorectal tumor model, the dendrimer delivery nanosystem elicits a potent antitumor performance with a strong abscopal effect, greatly improving the overall mouse survival rate. Importantly, the dendrimer-mediated codelivery not only allows the coordination of Mn2+ with GOx and cGAMP for respective chemodynamic/starvation-triggered ICD and augmented STING activation to boost systemic antitumor immune responses, but also enables T1-weighted tumor MR imaging, potentially serving as a promising nanoplatform for enhanced antitumor therapy with desired immune responses.

Novel strategies to facilitate tumor-specific drug delivery and restore immune attacks remain to be developed to overcome the current limitations of chemotherapy. Herein, a cancer cell membrane (CM)-camouflaged and ultrasmall iron oxide nanoparticles (USIO NPs)-loaded polyethylenimine nanogel (NG) system is reported to co-deliver docetaxel (DTX) and CD47 siRNA (siCD47). The prepared co-delivery system exhibits good colloidal stability, biocompatibility, and r1 relaxivity (1.35 mM-1 s-1 ) and enables redox-responsive release of the loaded DTX in the tumor microenvironment. The NG system realizes homologous targeting delivery of DTX and siCD47 to murine breast cancer cells (4T1 cells) for efficient chemotherapy and gene silencing; thus, inducing immunogenic cell death (ICD) and restoring macrophage phagocytic effect through downregulation of "don't eat me" signals on cancer cells. Likewise, the co-delivery system can also act on macrophages to promote their M1 polarization, which can be combined with DTX-mediated ICD and antibody-mediated immune checkpoint blockade to generate effector T cells for robust chemoimmunotherapy. Further, the USIO NPs-incorporated NG system also allows for magnetic resonance imaging of tumors. The developed biomimetic NG system acting on both cancer cells and macrophages holds a promising potential for macrophage phagocytosis-restored chemoimmunotherapy.

BackgroundRadiomics‐based preoperative evaluation of lymph node metastasis (LNM) and histological grade (HG) might facilitate the decision‐making for pancreatic cancer and further efforts are needed to develop effective models.PurposeTo develop multiparametric MRI (MP‐MRI)‐based radiomics models to evaluate LNM and HG.Study TypeRetrospective.PopulationThe pancreatic cancer patients from the main center (n = 126) were assigned to the training and validation sets at a 4:1 ratio. The patients from the other center (n = 40) served as external test sets.Field Strength/SequenceA 3.0 T and 1.5 T/T2‐weighted imaging, diffusion‐weighted imaging, and dynamic contrast enhancement T1‐weighted imaging.AssessmentA total of 10,686 peritumoral and intratumoral radiomics features were extracted which contained first‐order, shape‐based, and texture features. The following three‐step method was applied to reduce the feature dimensionality: SelectKBest (a function from scikit‐learn package), least absolute shrinkage and selection operator (LASSO), and recursive feature elimination based on random forest (RFE‐RF). Six classifiers (random forest, logistic regression, support vector machine, K‐nearest neighbor, decision tree, and XGBOOST) were trained and selected based on their performance to construct the clinical, radiomics, and combination models.Statistical TestsDelong's test was used to compare the models' performance. P value less than 0.05 was considered significant.ResultsTwelve significant features for LNM and 11 features for HG were obtained. Random forest and logistic regression performed better than the other classifiers in evaluating LNM and HG, respectively, according to the surgical pathological results. The best performance was obtained with the models that combined peritumoral and intratumoral features with area under curve (AUC) values of 0.944 and 0.892 in the validation and external test sets for HG and 0.924 and 0.875 for LNM.Data ConclusionRadiomics holds the potential to evaluate LNM and HG of pancreatic cancer. The combination of peritumoral and intratumoral features will make models more accurate.Evidence Level4.Technical EfficacyStage 2.

Objectives: Bladder cancer is among the most prevalent urothelial malignancies. Radiomics-based preoperative prediction of Ki67 and histological grade will facilitate clinical decision-making. Methods: This retrospective study recruited 283 bladder cancer patients between 2012 and 2021. Multiparameter MRI sequences included: T1WI, T2WI, diffusion-weighted imaging (DWI), and dynamic contrast-enhanced (DCE) imaging. The radiomics features of intratumoral and peritumoral regions were extracted simultaneously. Max-Relevance and Min-Redundancy (mRMR) and least absolute shrinkage and selection operator (LASSO) algorithms were employed to select the features. Six machine learning-based classifiers were adopted to construct the radiomics models, and the best was chosen for the model construction. Results: The mRMR and LASSO algorithms were more suitable for Ki67 and histological grade, respectively. Additionally, Ki67 had a higher proportion of intratumoral features, while peritumoral features accounted for a greater proportion of the histological grade. Random forests performed the best in predicting both pathological outcomes. Consequently, the multiparameter MRI (MP-MRI) models achieved area under the curve (AUC) values of 0.977 and 0.852 for Ki67 in training and test sets, respectively, and 0.972 and 0.710 for the histological grade. Conclusion: Radiomics holds the potential to predict multiple pathological outcomes of bladder cancer preoperatively and are expected to provide clinical decision-making guidance. Furthermore, our work inspired the process of radiomics research. Advances in knowledge: This study demonstrated that different feature selection techniques, segmentation regions, classifiers, and MRI sequences will affect the performance of the model. We systematically demonstrated that radiomics can predict histological grade and Ki67.

Despite radiotherapy (RT) is considered as an indispensable treatment that improves clinical symptoms and survival rates of glioblastoma multiforme (GBM), the overall survival time of GBM based on multimodal treat-ment synergic with RT is still unsatisfying. Herein, we designed an immunostimulated nanoplatform consisting of MnO2 and cytosine-phosphorothioate-guanine oligodeoxynucleotides (CpG ODNs) within the poly(N-vinyl-caprolactam) nanogels (PVCL-MnO2-CpG NGs) for magnetic resonance imaging (MRI)-guided immuno-activated RT against GBM. In this system, I) CpG ODNs can be protected by PVCL NGs from degradation, which can in-crease the cellular uptake by immune cells and promote the activation of Toll-like receptor 9 (TLR9) pathway, thus enhance the immune responses to assist the therapeutic efficacy of tumour RT. II) PVCL-MnO2-CpG NGs are able to be dissociated to release Mn2+ in the tumour microenvironment, resulting in excellent T1-weighted tumour MRI along with the activation of cyclic GMP-AMP synthase/stimulator of interferon genes (cGAS/ STING) pathway and elevated secretion of type-I interferons (IFN-I) in the downstream. III) MnO2 can also act as nanoenzyme to relieve tumour radioresistance through increasing the reactive oxygen species (ROS) level. Compared with RT alone, combinational immunoradiotherapy remarkably promotes the proportion of cytotoxic T cells (CD3+CD8+) and exhibits systemic therapeutic efficacy. Thus, MnO2 and CpG ODNs-loaded PVCL NGs may serve as a potential theranostic platform for MRI-guided immunostimulated RT of GBM.

Development of a powerful photothermal agent to exert combinational photothermo-immunotherapy of tumors through autophagy inhibition remains challenging. Herein, we report an indocyanine green (ICG)-modified dendrimer nanomedicine formulation encapsulated with an autophagy inhibitor chloroquine (CQ) for synergistic autophagy inhibition-enhanced photothermo-immunotherapy. Poly(amidoamine) dendrimers of generation 5 (G5) were covalently conjugated with ICG, full acetylated to neutralize their remaining amine termini, and physically loaded with CQ. The created G5. NHAc-ICG/CQ (GIC) complexes display desired colloidal stability, cytocompatibility and photothermal conversion efficiency (39.7%), and can induce apoptosis and immunogenic cell death of cancer cells under laser irradiation in coordination with autophagy inhibition, thereby promoting maturation of dendritic cells and subsequent tumoral infiltration of activated CD4+/CD8+ T cells. The incorporated autophagy inhibitor CQ also enhances the antitumor efficacy through NF-κB pathway activation to remodel the tumor microenvironment through repolarization of the tumor-associated macrophages to anti-tumor M1 type. With the combination of programmed cell death ligand 1 antibody-elicited immune check-point blockade, the developed GIC nanodrug enables effective restriction of the growth of both primary and distal tumors with amplified antitumor immune response. The developed GIC nanodrug with the minimalist composition displays a promising translation potential for autophagy inhibition-enhanced photothermo-immunotherapy of different tumor types.

OBJECTIVES:This study aims to develop and evaluate multiparametric MRI (MP-MRI)-based radiomic models as a noninvasive diagnostic method to predict several biological characteristics of prostate cancer.METHODS:A total of 252 patients were retrospectively included who underwent radical prostatectomy and MP-MRI examinations. The prediction characteristics of this study were as follows: Ki67, S100, extracapsular extension (ECE), perineural invasion (PNI), and surgical margin (SM). Patients were divided into training cohorts and validation cohorts in the ratio of 4:1 for each group. After lesion segmentation manually, radiomic features were extracted from MP-MRI images and some clinical factors were also included. Max relevance min redundancy (mRMR) and recursive feature elimination (RFE) based on random forest (RF) were adopted to select features. Six classifiers were included (SVM, KNN, RF, decision tree, logistic regression, XGBOOST) to find the best diagnostic performance among them. The diagnostic efficiency of the construction models was evaluated by ROC curves and quantified by AUC.RESULTS:RF performed best among the six classifiers for the four groups according to AUC values (Ki67 = 0.87, S100 = 0.80, ECE = 0.85, PNI = 0.82). The performance of SVM was relatively the best for SM (AUC = 0.77). The number and importance of DCE features ranked first in the models of each group. The combined models of MP-MRI and clinical characteristics showed no significant difference compared with MP-MRI models according to Delong's tests.CONCLUSIONS:Radiomics models based on MP-MRI have the potential to predict biological characteristics and are expected to be a noninvasive method to evaluate the risk stratification of prostate cancer.

While cytotoxic reactive oxygen species (ROS) play an important role in fighting cancer, developing an activable ROS‐generating system to achieve highly specific cancer therapy with minimum side effects to normal tissues remains challenging. This work reports the development of a tumor microenvironment‐activable ROS‐generating system via multistage self‐assembly engineered protein‐based nanomedicine containing cascade enzymes and photosensitizers. The multistage self‐assembly‐induced aggregation not only prevents the premature exposure of cascade enzymes to produce toxic by‐products in noncancerous sites, but also quenches the photosensitizers to diminish skin phototoxicity, contributing to effective self‐protection of normal tissues. Once triggered by the intratumoral reduction microenvironment, the aggregation effect is unlocked to expose cascade enzymes and recover the photosensitivity, which can decompose intratumor glucose for hydroxyl radical generation and respond to external laser irradiation for singlet oxygen production respectively, realizing tumor‐specific chemodynamic–photodynamic combinational therapy. This work demonstrates a protein‐based multistage self‐assembly approach for ROS‐mediated cancer‐specific therapy with effective self‐protection, offering a powerful strategy for nanomedicine design and more precise cancer therapy.

目的:探讨PVCL-MnO2对多形性胶质母细胞瘤的放疗增敏作用,并进行体内MRI成像研究.方法:制备PVCL-MnO2纳米探针,利用透射电子显微镜(Transmission Electron Microscope,TEM)对其形态进行表征,并使用Image J分析其尺寸分布.采用细胞增殖-毒性实验(3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide,MTT),测定 PVCL-MnO2协同放疗处理肿瘤细胞48h后的细胞活性.将多形性胶质母瘤细胞瘤细胞进行PVCL-MnO2共孵育后,协同放疗处理,分别使用免疫荧光,蛋白质印迹法等实验技术检测H2AX组蛋白异型的磷酸化形式(phosphorylated form of the histone protein H2AX,γ-H2AX),活性氧自由基(reactive oxygen species,ROS)的产生及Bax,Bcl-2凋亡相关蛋白的表达.PVCL-MnO2尾静脉注射至原位多形性胶质母细胞瘤小鼠中,在不同的时间点进行MRI扫描,观察成像效果.结果:PVCL-MnO2颗粒粒径分布均匀,结构规整,表现出良好的单分散性.PVCL-MnO2联合放疗可有效增强DNA双链的断裂,ROS及促凋亡蛋白Bax的产生,同时下调了抗凋亡蛋白Bcl-2.MRI成像显示,PVCL-MnO2具有较好的T1-加权MRI成像效果,在尾静脉注射PVCL-MnO2后4 h,肿瘤部位的信号增强最明显,随后信号开始下降.结论:PVCL-MnO2可实现多形性胶质母细胞瘤的放疗增敏及MRI成像.

The development of promising strategies to improve the treatment efficacy of pancreatic carcinoma still remains to be a challenging task. We report here the development of a new dendrimer-based nanomedicine formulation to tackle pancreatic carcinoma through apoptosis-enhanced ferroptosis therapy. In this article, G5 dendrimers were partially modified with a Fe(III) chelator hydroxyquinoline-2-carboxylic acid (8-HQC) on their periphery, entrapped with gold nanoparticles (Au NPs) within their internal cavities, and chelated with Fe(III). The thus created dendrimer-entrapped Au NPs (Fe-Au DENP-HQC) with an Au core size of 1.9 nm and 20.0 Fe(III) ions complexed per dendrimer are stable, have a pH-dependent Fe(III) release profile, and can generate reactive oxygen species under the tumor microenvironment (TME) and effectively compact plasmid DNA encoding p53 protein to form polyplexes with a hydrodynamic size of 143.9 nm and a surface potential of 33.6 mV. We show that cancer cells treated with the created Fe-Au DENP-HQC/p53 polyplexes can be more significantly inhibited through vector-mediated chemodynamic therapy (CDT) effect via Fe(III)-induced Fenton reaction and the p53 gene delivery-boosted cell apoptosis and oxidative stress in the TME than single-mode CDT and gene therapy. Further investigations using a xenografted tumor model validated the effectiveness of apoptosis-enhanced ferropotosis therapy through the downregulation of GPX-4 and SLC7A11 proteins, upregulation of p53 and PTEN proteins, as well as histological examinations. Meanwhile, the dendrimer nanoplatform enabled tumor fluorescence imaging through gene delivery-mediated enhanced green fluorescent protein expression. The Fe(III)-complexed dendrimer vector system may be developed as a promising theranostic nanoplatform for ferroptosis or ferroptosis-based combination therapy of other cancer types.

Unobtrusive metastasis and invasion of malignant tumors are major causes for the death of cancer patients, and unfortunately the lack of specificity and abrupt release of anticancer drugs applied to the primary tumors are causing serious side effects in cancer management. Hence, the development of controlled local drug delivery systems that can effectively treat primary tumors and inhibit tumor metastasis is of critical importance for improved cancer therapeutics. Herein, we developed hyaluronic acid (HA)-modified porous fibrous microspheres as a drug delivery system with the functions of long-acting local chemotherapy, tumor metastasis inhibition and magnetic resonance (MR) imaging. Poly (lactic-co-glycolic acid) (PLGA) short fibers obtained by combined electrospinning and homogenization techniques were successfully modified with gadolinium (Gd 3+ ) chelates and HA, which were subsequently mixed with doxorubicin (DOX) to obtain the multifunctional drug-loaded fibrous microspheres of DOX-PLGA-PEI-DTPA-Gd/HA (DOX − PGH) by electrospray and further crosslinking. The developed DOX − PGH microspheres with an average diameter of 118.8 μm possess good structural stability and a high r 1 relaxivity, and can achieve long-term DOX release. The cellular and animal experiments demonstrated that the DOX − PGH microspheres could facilitate targeted delivery of DOX to accelerate 4T1 cell death while reducing cancer cell metastasis due to the cooperative actions of long-term DOX-mediated chemotherapy and the fibrous microsphere-induced tumor anchoring to likely avoid primary tumor cell shedding, and render MR imaging of tumors during the treatment. The developed DOX − PGH microspheres may represent one of the updated local tumor chemotherapy formulations for improved tumor therapy with justified antitumor and anti-metastasis efficacy. Graphical abstract