Focused Ultrasound (FUS)-triggered nano-sized drug delivery, as a smart stimuli-responsive system for treating solid tumors, is computationally investigated to enhance localized delivery of drug and treatment efficacy. Integration of thermosensitive liposome (TSL), as a doxorubicin (DOX)-loaded nanocarrier, and FUS, provides a promising drug delivery system. A fully coupled partial differential system of equations, including the Helmholtz equation for FUS propagation, bio-heat transfer, interstitial fluid flow, drug transport in tissue and cellular spaces, and a pharmacodynamic model is first presented for this treatment approach. Equations are then solved by finite element methods to calculate intracellular drug concentration and treatment efficacy. The main objective of this study is to present a multi-physics and multi-scale model to simulate drug release, transport, and delivery to solid tumors, followed by an analysis of how FUS exposure time and drug release rate affect these processes. Our findings not only show the capability of model to replicate this therapeutic approach, but also confirm the benefits of this treatment with an improvement of drug aggregation in tumor and reduction of drug delivery in healthy tissue. For instance, the survival fraction of tumor cells after this treatment dropped to 62.4%, because of a large amount of delivered drugs to cancer cells. Next, a combination of three release rates (ultrafast, fast, and slow) and FUS exposure times (10, 30, and 60 min) was examined. Area under curve (AUC) results show that the combination of 30 min FUS exposure and rapid drug release leads to a practical and effective therapeutic response.

Chimeric antigen receptor-T (CAR-T) cell therapy based on functional immune cell transfer is showing a booming situation. However, complex manufacturing processes, high costs, and disappointing results in the treatment of solid tumors have limited its use. Encouragingly, it has facilitated the development of new strategies that fuse immunology, cell biology, and biomaterials to overcome these obstacles. In recent years, CAR-T engineering assisted by properly designed biomaterials has improved therapeutic efficacy and reduced side effects, providing a sustainable strategy for improving cancer immunotherapy. At the same time, the low cost and diversity of biomaterials also offer the possibility of industrial production and commercialization. Here, we summarize the role of biomaterials as gene delivery vehicles in the generation of CAR-T cells and highlight the advantages of in-situ construction in vivo. Then, we focused on how biomaterials can be combined with CAR-T cells to better enable synergistic immunotherapy in the treatment of solid tumors. Finally, we describe biomaterials\' potential challenges and prospects in CAR-T therapy. This review aims to provide a detailed overview of biomaterial-based CAR-T tumor immunotherapy to help investigators reference and customize biomaterials for CAR-T therapy to improve the efficacy of immunotherapy.

Chimeric antigen receptor T cell (CAR T) therapy was a milestone in the treatment of relapsed and refractory B cell malignancies. However, beneficial effects of CAR T cells have not been obtained in solid tumors yet. Herein, we implement a porous microneedle patch that accommodates CAR T cells and allows in situ penetration-mediated seeding of CAR T cells when implanted in the tumor bed or in the post-surgical resection cavity. CAR T cells loaded in the pores of the microneedle tips were readily escorted to the tumor in an evenly scattered manner without losing their activity. Such microneedle-mediated local delivery enhanced infiltration and immunostimulation of CAR T cells as compared to direct intratumoral injection. This tailorable patch offers a transformative platform for scattered seeding of living cells for treating a variety of tumors.

OBJECTIVE: The present meta-analysis study was performed to identify the potential cardiotoxicity risks when using Vascular Endothelial Growth Factor Receptor Tyrosine kinase inhibitors (VEGFR-TKIs) as anticancer drugs in patients with solid tumors.
METHODS: Pubmed, Embase, the Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov databases were searched for the randomized controlled trials. We have included 45 randomized controlled trials (RCTs) associated with nine VEGFR-TKIs Food and Drug Administration (FDA)-approved drugs used to treat patients with solid tumors. To evaluate the trials\' risk of bias, Cochrane Risk of Bias Tool was assessed. A direct comparison was assessed by RevMan5.3 software, calculating the odds ratio (OR) and 95% confidence interval (CI). Heterogeneity was tested by the I2 statistic and Chi-square test for P value. Bayesian network meta-analysis was performed using Stata 15.0 and GeMTC 0.14.3 software, calculated OR along with corresponding 95% credible interval (CrI). The model\'s convergence was evaluated by the potential scale reduced factor (PSRF). Consistency between direct and indirect comparisons was assessed by the \"node-splitting\" method.
RESULTS: In this network meta-analysis, a total of 20,027 patients from 45 randomized controlled trials and associated with nine FDA-approved VEGFR-TKIs (axitinib, cabozantinib, lenvatinib, nintedanib, pazopanib, regorafenib, sorafenib, sunitinib, vandetanib), were enrolled. Findings indicated that lenvatinib had the most significant probability of provoking all grades cardiovascular incident and hypertension, followed by vandetanib, cabozantinib, axitinib, pazopanib, sorafenib, sunitinib, regorafenib and nintedanib. The nine agent\'s severe cardiovascular and severe hypertension risk was probably similar. The ranking probability of cardiac toxicity shows that vandetanib ranked most likely to have the highest risk for cardiotoxicity among all the VEGFR-TKIs reviewed, followed by pazopanib, axitinib, sorafenib, sunitinib. In contrast, regorafenib and nintedanib did not exhibit an increased risk of cardiac damage.
CONCLUSIONS: The association between the nine VEGFR-TKIs with potential cardiotoxicity occurrence was reviewed. Both the regorafenib and nintedanib did not display detectable signs of cardiotoxic damage. In contrast, lenvatinib and vandetanib are ranked to have the most severe cardiotoxicity side impacts. These results may provide information for clinical practice guidelines, implementing strategies in selecting the adequate VEGFR-TKIs, and understanding the cardiovascular toxicity inflicted by the VEGFR-TKIs.
UNASSIGNED: CRD 42,020,167,307.

Chimeric antigen receptor T-cell (CAR-T) therapy has achieved good therapeutic efficacy in the treatment of hematological malignancies. In August 2017, Novartis Kymriah (CAR-T cells targeting CD19) was approved by the FDA, indicating the real entry of CAR-T cell therapy into clinical applications and making CAR-T cell therapy the most attractive technology in the field of tumor treatment. In October 2017, the FDA approved the world\'s second CAR-T cell therapy-Yescarta. The launch of these products has attracted wide attention to CAR-T cell therapy. CAR-T cell therapy has achieved significant effect in the treatment of tumors, however, CAR-T therapy also faces clinical problems, such as cytokine release syndrome (CRS), poor therapeutic efficacy in solid tumors, and high rates of tumor recurrence. At present, the side effects of CAR-T therapy have attracted a large amount of attention, which has resulted in investigations into strategy establishment. With a deepening understanding of CAR-T therapy and the continuous optimization of therapeutic regimens, its toxicity and side effects have been partially controlled. This study set out to analyze the problems in the clinical application of CAR-T therapy encountered in recent years and to introduce corresponding strategies, with the aim of providing a basis of reference for clinicians and scientists in the management of CAR-T therapy in clinical practice and in the CAR-T therapy research.

Herein, the biodegradable micelle-forming amphiphilic N-(2-hydroxypropyl) methacrylamide (HPMA)-based polymer conjugates with the anticancer drug doxorubicin (Dox) designed for enhanced tumor accumulation were investigated, and the influence of their stability in the bloodstream on biodistribution, namely, tumor uptake, and in vivo antitumor efficacy were evaluated in detail. Dox was attached to the polymer carrier by a hydrazone bond enabling pH-controlled drug release. While the polymer-drug conjugates were stable in a buffer at pH 7.4 (mimicking bloodstream environment), Dox was released in a buffer under mild acidic conditions modeling the tumor microenvironment or cells. The amphiphilic polymer carriers differed in the structure of hydrophobic cholesterol derivative moieties bound to the HPMA copolymers via a hydrolyzable hydrazone bond, exhibiting different rates of micellar structure disintegration at various pH values. Considerable dependence of the studied polymer-drug conjugate biodistribution on the stability of the micellar structure was observed in neutral, bloodstream-mimicking, environment, showing that a faster rate of the micelle disintegration in pH 7.4 increased the conjugate blood clearance, decreased tumor accumulation, and significantly reduced the tumor:blood and tumor:muscle ratios. Similarly, the final therapeutic outcome was strongly affected by the stability of the micellar structure because the most stable micellar conjugate showed an almost similar therapeutic outcome as the water-soluble, nondegradable, high-molecular-weight starlike HPMA copolymer-Dox conjugate, which was highly efficient in the treatment of solid tumors in mice. Based on the results, we conclude that the bloodstream stability of micellar polymer-anticancer drug conjugates, in addition to their low side toxicity, is a crucial parameter for their efficient solid tumor accumulation and high in vivo antitumor activity.