Anti-tumor effect of pH-sensitive drug-loaded nanoparticles optimized via an integrated computational/experimental approach.

The acidic pH of tumor tissue has been used to trigger drug release from nanoparticles. However, dynamic interactions between tumor pH and vascularity present challenges to optimize therapy to particular microenvironment conditions. Despite recent development of pH-sensitive nanomaterials that can accurately quantify drug release from nanoparticles, tailoring release to maximize tumor response remains elusive. This study hypothesizes that a computational modeling-based platform that simulates the heterogeneously vascularized tumor microenvironment can enable evaluation of the complex intra-tumoral dynamics involving nanoparticle transport and pH-dependent drug release, and predict optimal nanoparticle parameters to maximize the response. To this end, SPNCD nanoparticles comprising superparamagnetic cores of iron oxide (Fe3O4) and a poly(lactide-co-glycolide acid) shell loaded with doxorubicin (DOX) were fabricated. Drug release was measured in vitro as a function of pH. A 2D model of vascularized tumor growth was calibrated to experimental data and used to evaluate SPNCD effect as a function of drug release rate and tissue vascular heterogeneity. Simulations show that pH-dependent drug release from SPNCD delays tumor regrowth more than DOX alone across all levels of vascular heterogeneity, and that SPNCD significantly inhibit tumor radius over time compared to systemic DOX. The minimum tumor radius forecast by the model was comparable to previous in vivo SPNCD inhibition data. Sensitivity analyses of the SPNCD pH-dependent drug release rate indicate that slower rates are more inhibitory than faster rates. We conclude that an integrated computational and experimental approach enables tailoring drug release by pH-responsive nanomaterials to maximize the tumor response.

Multimodal Cross-Device and Marker-Free Co-Registration of Preclinical Imaging Modalities.

Integrated preclinical multimodal imaging systems, such as X-ray computed tomography (CT) combined with positron emission tomography (PET) or magnetic resonance imaging (MRI) combined with PET, are widely available and typically provide robustly co-registered volumes. However, separate devices are often needed to combine a standalone MRI with an existing PET-CT or to incorporate additional data from optical tomography or high-resolution X-ray microtomography. This necessitates image co-registration, which involves complex aspects such as multimodal mouse bed design, fiducial marker inclusion, image reconstruction, and software-based image fusion. Fiducial markers often pose problems for in vivo data due to dynamic range issues, limitations on the imaging field of view, difficulties in marker placement, or marker signal loss over time (e.g., from drying or decay). These challenges must be understood and addressed by each research group requiring image co-registration, resulting in repeated efforts, as the relevant details are rarely described in existing publications. This protocol outlines a general workflow that overcomes these issues. Although a differential transformation is initially created using fiducial markers or visual structures, such markers are not required in production scans. The requirements for the volume data and the metadata generated by the reconstruction software are detailed. The discussion covers achieving and verifying requirements separately for each modality. A phantom-based approach is described to generate a differential transformation between the coordinate systems of two imaging modalities. This method showcases how to co-register production scans without fiducial markers. Each step is illustrated using available software, with recommendations for commercially available phantoms. The feasibility of this approach with different combinations of imaging modalities installed at various sites is showcased.

Bivalirudin vs heparin in cardiac-cerebral ischemic and bleeding events among Chinese STEMI patients during percutaneous coronary intervention: a retrospective cohort study.

Although bivalirudin has been recently made available for purchase in China, large-scale analyses on the safety profile of bivalirudin among Chinese patients is lacking. Thus, this study aimed to compare the safety profile of bivalirudin and heparin as anticoagulants in Chinese ST-segment elevation myocardial infarction (STEMI) patients undergoing percutaneous coronary intervention (PCI). A total of 1063 STEMI patients undergoing PCI and receiving bivalirudin (n=424, bivalirudin group) or heparin (n=639, heparin group) as anticoagulants were retrospectively enrolled. The net adverse clinical events (NACEs) within 30 days after PCI were recorded, including major adverse cardiac and cerebral events (MACCEs) and bleeding events (bleeding academic research consortium (BARC) grades 2-5 (BARC 2-5)). The incidences of NACEs (10.1 vs 15.6%) (P=0.010), BARC 2-5 bleeding events (5.2 vs 10.3%) (P=0.003), and BARC grades 3-5 (BARC 3-5) bleeding events (2.1 vs 5.5%) (P=0.007) were lower in the bivalirudin group compared to the heparin group, whereas general MACCEs incidence (8.9 vs 6.4%) (P=0.131) and each category of MACCEs (all P>0.05) did not differ between two groups. Furthermore, the multivariate logistic analyses showed that bivalirudin (vs heparin) was independently correlated with lower risk of NACEs (OR=0.508, P=0.002), BARC 2-5 bleeding events (OR=0.403, P=0.001), and BARC 3-5 bleeding events (OR=0.452, P=0.042); other independent risk factors for NACEs, MACCEs, or BARC bleeding events included history of diabetes mellitus, emergency operation, multiple lesional vessels, stent length >33.0 mm, and higher CRUSADE score (all P<0.05). Thus, bivalirudin presented a better safety profile than heparin among Chinese STEMI patients undergoing PCI.

Comparison of net adverse clinical events between bivalirudin and heparin as anticoagulants for percutaneous coronary intervention in Chinese patients.

Bivalirudin, as a direct thrombin inhibitor, is considered to be safer compared with other anticoagulants, such as heparin; however, relevant data in China are unclear. The present study aimed to compare the safety of bivalirudin and heparin as anticoagulants in Chinese patients who underwent percutaneous coronary intervention (PCI). In the present study, 2,377 patients with ST-segment elevation myocardial infarction (STEMI), unstable angina, non-STEMI or stable coronary artery disease who underwent primary PCI while receiving bivalirudin or heparin (low molecular weight heparin or unfractionated heparin) were reviewed, and then analyzed as the bivalirudin group (n=944) and heparin group (n=1,433). The net adverse clinical events (NACEs) within 30 days were obtained, which were defined as major adverse cardiac and cerebral events (MACCEs) + Bleeding Academic Research Consortium (BARC) grade 2-5 bleeding events. Compared with the heparin group, the incidence of NACEs was reduced in the bivalirudin group (9.3 vs. 13.4%; P=0.003). However, no discrepancy was found in the incidence of MACCEs between the groups (5.9 vs. 7.6%; P=0.116). Moreover, the incidences of BARC 2-5 (4.8 vs. 8.7%; P<0.001) and BARC 3-5 bleeding events (1.9 vs. 4.4%; P=0.001) were decreased in the bivalirudin group compared with the heparin group. Following adjustment using multivariate logistic regression analysis, bivalirudin treatment (vs. heparin treatment) was independently associated with lower risks of NACEs [odds ratio (OR), 0.587; P<0.001], MACCEs (OR, 0.689; P=0.041) and BARC 2-5 (OR, 0.459; P<0.001) and 3-5 bleeding events (OR, 0.386; P=0.002). Overall, the present study demonstrated that bivalirudin decreased the risks of NACEs and bleeding events compared with heparin in Chinese patients who undergo PCI. However, further validation is required.

Nanoparticle-Based Therapies in Hypertension.

Nearly 1.4 billion people worldwide suffer from arterial hypertension, a significant risk factor for cardiovascular disease which is now the leading cause of death. Despite numerous drugs designed to treat hypertension, only ≈14% of hypertensive individuals have their blood pressure under control. A critical factor negatively impacting the efficacy of available treatments is their poor bioavailability. This leads to increased dosing requirements which can result in more side effects, resulting in patient noncompliance. A recent solution to improve dosing and bioavailability issues has been to incorporate drugs into nanoparticle carriers, with over 50 nanodrugs currently on the market across all diseases, and another 51 currently in clinical trials. Given their ability to improve solubility and bioavailability, nanoparticles may offer significant advantages in the formulation of antihypertensives to overcome pharmacokinetic shortcomings. To date, however, no antihypertensive nanoformulations have been clinically approved. This review assesses in vivo study data from preclinical antihypertensive nanoformulation development and testing. Combined, the results of these studies suggest nanoformulation of antihypertensive drugs may be a promising solution to overcome the poor efficacy of currently available antihypertensives, and with further advances has the potential to open paths for new substances that have heretofore been clinically unrealistic due to poor bioavailability.

The dynamic evolution and IS26-mediated interspecies transfer of a blaNDM-1-bearing fusion plasmid leading to a hypervirulent carbapenem-resistant Klebsiella pneumoniae strain harbouring blaKPC-2 in a single patient.

OBJECTIVES: To characterize the evolution and interspecies transfer of plasmids between Klebsiella pneumoniae and Escherichia coli within a single patient. METHODS: Minimum inhibitory concentrations were measured using broth microdilution assays. Conjugation assays, string tests, and Galleria mellonella infection model experiments were also conducted. Whole-genome sequencing was performed on the Illumina and Nanopore platforms. Antimicrobial resistance determinants, insertion sequences, and virulence factors were identified using ABRicate/ResFinder database, ISFinder, and virulence factor database. Wzi and capsular polysaccharide (KL) were typed using Kleborate and Kaptive. Multi-locus sequence typing (MLST), replicon typing, and single nucleotide polymorphism analyses were conducted using the BacWGSTdb server. RESULTS: The carbapenem-resistant K. pneumoniae 2111KP was characterized as ST11, wzi64, and KL64, with a positive string test result and a relatively high virulence phenotype. Analysis of the 2111KP genome revealed that blaNDM-1 was located in a 268,400-bp IncFIB/IncHI1B/IncX3 conjugative plasmid (p2111KP-1), regulated by IS26, IS5, and ISKox3. p2111KP-1 was also a rmpA2-associated virulence plasmid with an iutA-iucABCD gene cluster and a IS26-mediated multidrug-resistant fusion plasmid, which contained 8-bp (AGCTGCAC or GGCCTTTG) target site duplications. Segments flanked by IS26 of p2111KP-1 were 99.99% identical to a 49,016-bp E. coli plasmid. CONCLUSIONS: This study provided direct evidence of plasmid fusion via IS26 between two different bacterial species within one patient and revealed the process by which genetic elements conferring carbapenem resistance and virulence were simultaneously transferred between these species. It highlights the need for strategic antibiotic use and rigorous monitoring to prevent the plasmid-mediated fusion and transmission of drug-resistance/virulence factors.

Bivalirudin vs heparin in cardiac-cerebral ischemic and bleeding events among Chinese STEMI patients during percutaneous coronary intervention: a retrospective cohort study

Although bivalirudin has been recently made available for purchase in China, large-scale analyses on the safety profile of bivalirudin among Chinese patients is lacking. Thus, this study aimed to compare the safety profile of bivalirudin and heparin as anticoagulants in Chinese ST-segment elevation myocardial infarction (STEMI) patients undergoing percutaneous coronary intervention (PCI). A total of 1063 STEMI patients undergoing PCI and receiving bivalirudin (n=424, bivalirudin group) or heparin (n=639, heparin group) as anticoagulants were retrospectively enrolled. The net adverse clinical events (NACEs) within 30 days after PCI were recorded, including major adverse cardiac and cerebral events (MACCEs) and bleeding events (bleeding academic research consortium (BARC) grades 2-5 (BARC 2-5)). The incidences of NACEs (10.1 vs 15.6%) (P=0.010), BARC 2-5 bleeding events (5.2 vs 10.3%) (P=0.003), and BARC grades 3-5 (BARC 3-5) bleeding events (2.1 vs 5.5%) (P=0.007) were lower in the bivalirudin group compared to the heparin group, whereas general MACCEs incidence (8.9 vs 6.4%) (P=0.131) and each category of MACCEs (all P>0.05) did not differ between two groups. Furthermore, the multivariate logistic analyses showed that bivalirudin (vs heparin) was independently correlated with lower risk of NACEs (OR=0.508, P=0.002), BARC 2-5 bleeding events (OR=0.403, P=0.001), and BARC 3-5 bleeding events (OR=0.452, P=0.042); other independent risk factors for NACEs, MACCEs, or BARC bleeding events included history of diabetes mellitus, emergency operation, multiple lesional vessels, stent length >33.0 mm, and higher CRUSADE score (all P<0.05). Thus, bivalirudin presented a better safety profile than heparin among Chinese STEMI patients undergoing PCI.

Rapid bacterial identification and antimicrobial susceptibility testing assay in positive blood cultures / 预防医学

Objective@#To establish a rapid bacterial identification and antimicrobial susceptibility testing assay in positive blood cultures, so as to provide insights into timely diagnosis and treatment of bloodstream infections.@*Methods@#A total of 1 154 blood culture samples were collected from inpatients in Zhejiang Hospital from February to May, 2022. The bacterial isolates were enriched and purified using improved separation gel method, and bacterial identification and antimicrobial susceptibility tests were performed using VITEK2 mass spectrometry system and VITEK2 Compact automated microbiology system. The accuracy of the new assay for bacterial identification and antimicrobial susceptibility tests was evaluated with the conventional VITEK 2 compact system as the standard. @*Results@#Of 1 154 blood culture specimens, the conventional VITEK 2 compact system detected 174 positives and 980 negatives. The new assay and the conventional VITEK 2 compact system identified consistent bacterial isolates in 165 out of 174 positive blood culture samples, and the accuracy of bacterial identification was 94.83% for the new assay, with a 99.21% accuracy for identifying Gram-negative bacteria and 82.22% for Gram-positive bacteria. Antimicrobial susceptibility tests were performed in 158 bacterial isolates, and the new assay presented a 90.17% accuracy, with a 90.27% accuracy for Gram-negative bacteria and 89.74% for Gram-positive bacteria. The conventional VITEK 2 compact system required 30 hours and longer to complete bacterial identification and antimicrobial susceptibility tests, and the new assay required 9 to 18 hours.@*Conclusions@#The new rapid bacterial identification and antimicrobial susceptibility testing assay shortens the time of bacterial culture, achieves rapid bacterial identification and antimicrobial susceptibility testing in blood culture specimens and has a high accuracy that meets clinical needs, which facilitates rapid diagnosis and treatment of bloodstream infections.

Corrigendum: "Jianbing" styling multifunctional electrospinning composite membranes for wound healing.

[This corrects the article DOI: 10.3389/fbioe.2022.943695.].

"Jianbing" styling multifunctional electrospinning composite membranes for wound healing.

Wound infection and excessive exudate can affect the process of wound healing. However, the disadvantage of the anti-microbial wound dressings is that the biological fluids are ineffectively removed. Inspired by making "Chinese Jianbing", a composite wound nano-dressing was developed consisting of a hydrophilic outer layer (chitosan&polyvinyl alcohol: CTS-PVA) and a hydrophobic inner layer (propolis&polycaprolactone: PRO-PCL) by combining casting and electrospinning methods for effective antibacterial and unidirectional removing excess biofluids. In vitro, the composite wound nano-dressing of PRO-PCL and CTS-PVA (PPCP) could strongly inhibit Pseudomonas aeruginosa. Furthermore, PPCP wound dressing had excellent antioxidant properties and blood coagulation index for effective hemostatic. Importantly, it had a preferable water absorption for removing excess biofluid. In vivo, it had anti-inflammatory properties and promoted collagen Ⅰ preparation, which realized 80% wound healing on day 7. In short, the PPCP wound dressing provides a new direction and option for antibacterial and removes excess biofluid.

Cold Atmospheric Plasma Activates Selective Photothermal Therapy of Cancer.

Due to the body's systemic distribution of photothermal agents (PTAs), and to the imprecise exposure of lasers, photothermal therapy (PTT) is challenging to use in treating tumor sites selectively. Striving for PTT with high selectivity and precise treatment is nevertheless important, in order to raise the survival rate of cancer patients and lower the likelihood of adverse effects on other body sections. Here, we studied cold atmospheric plasma (CAP) as a supplementary procedure to enhance selectivity of PTT for cancer, using the classical photothermic agent's gold nanostars (AuNSs). In in vitro experiments, CAP decreases the effective power of PTT: the combination of PTT with CAP at lower power has similar cytotoxicity to that using higher power irradiation alone. In in vivo experiments, combination therapy can achieve rapid tumor suppression in the early stages of treatment and reduce side effects to surrounding normal tissues, compared to applying PTT alone. This research provides a strategy for the use of selective PTT for cancer, and promotes the clinical transformation of CAP.

Cancer tracking system improves timeliness of liver cancer care at a Veterans Hospital: A comparison of cohorts before and after implementation of an automated care coordination tool.

INTRODUCTION: Hepatocellular carcinoma (HCC) requires complex care coordination. Patient safety may be compromised with untimely follow-up of abnormal liver imaging. This study evaluated whether an electronic case-finding and tracking system improved timeliness of HCC care. METHODS: An electronic medical record-linked abnormal imaging identification and tracking system was implemented at a Veterans Affairs Hospital. This system reviews all liver radiology reports, generates a queue of abnormal cases for review, and maintains a queue of cancer care events with due dates and automated reminders. This is a pre-/post-intervention cohort study to evaluate whether implementation of this tracking system reduced time between HCC diagnosis and treatment and time between first liver image suspicious for HCC, specialty care, diagnosis, and treatment at a Veterans Hospital. Patients diagnosed with HCC in the 37 months before tracking system implementation were compared to patients diagnosed with HCC in the 71 months after its implementation. Linear regression was used to calculate mean change in relevant intervals of care adjusted for age, race, ethnicity, BCLC stage, and indication for first suspicious image. RESULTS: There were 60 patients pre-intervention and 127 post-intervention. In the post-intervention group, adjusted mean time from diagnosis to treatment was 36 days shorter (p = 0.007), time from imaging to diagnosis 51 days shorter (p = 0.21), and time from imaging to treatment 87 days shorter (p = 0.05). Patients whose imaging was performed for HCC screening had the greatest improvement in time from diagnosis to treatment (63 days, p = 0.02) and from first suspicious image to treatment (179 days, p = 0.03). The post-intervention group also had a greater proportion of HCC diagnosed at earlier BCLC stages (p<0.03). CONCLUSIONS: The tracking system improved timeliness of HCC diagnosis and treatment and may be useful for improving HCC care delivery, including in health systems already implementing HCC screening.

Ultra-selective carbon nanotubes for photoacoustic imaging of inflamed atherosclerotic plaques.

Disruption of vulnerable atherosclerotic plaques often leads to myocardial infarction and stroke, the leading causes of morbidity and mortality in the United States. A diagnostic method that detects high-risk atherosclerotic plaques at early stages could prevent these sequelae. The abundance of immune cells in the arterial wall, especially inflammatory Ly-6Chi monocytes and foamy macrophages, is indicative of plaque inflammation, and may be associated with plaque vulnerability. Hence, we sought to develop a new method that specifically targets these immune cells to offer clinically-relevant diagnostic information about cardiovascular disease. We combine ultra-selective nanoparticle targeting of Ly-6Chi monocytes and foamy macrophages with clinically-viable photoacoustic imaging (PAI) in order to precisely and specifically image inflamed plaques ex vivo in a mouse model that mimics human vulnerable plaques histopathologically. Within the plaques, high-dimensional single-cell flow cytometry (13-parameter) showed that our nanoparticles were almost-exclusively taken up by the Ly-6Chi monocytes and foamy macrophages that heavily infiltrate plaques. PAI identified inflamed atherosclerotic plaques that display ~6-fold greater signal compared to controls (P<0.001) six hours after intravenous injection of ultra-selective carbon nanotubes, with in vivo corroboration via optical imaging. Our highly selective strategy may provide a targeted, non-invasive imaging strategy to accurately identify and diagnose inflamed atherosclerotic lesions.

Self-assembled peptide and protein nanostructures for anti-cancer therapy: Targeted delivery, stimuli-responsive devices and immunotherapy.

Self-assembled peptides and proteins possess tremendous potential as targeted drug delivery systems and key applications of these well-defined nanostructures reside in anti-cancer therapy. Peptides and proteins can self-assemble into nanostructures of diverse sizes and shapes in response to changing environmental conditions such as pH, temperature, ionic strength, as well as host and guest molecular interactions; their countless benefits include good biocompatibility and high loading capacity for hydrophobic and hydrophilic drugs. These self-assembled nanomaterials can be adorned with functional moieties to specifically target tumor cells. Stimuli-responsive features can also be incorporated with respect to the tumor microenvironment. This review sheds light on the growing interest in self-assembled peptides and proteins and their burgeoning applications in cancer treatment and immunotherapy.

Gum polysaccharide/nanometal hybrid biocomposites in cancer diagnosis and therapy.

Biopolymers are of prime importance among which gum polysaccharides hold an eminent standing owing to their high availability and non-toxic nature. Gum biopolymers offer a greener alternative to synthetic polymers and toxic chemicals in the synthesis of metal nanostructures. Metal nanostructures accessible via eco-friendly means endow astounding characteristics to gum-based biocomposites in the field of diagnosis and therapy towards cancer diseases. In this review, assorted approaches for the assembly of nanomaterials mediated by gum biopolymers are presented and their utility in cancer diagnosis and therapy, e.g., bioimaging, radiotherapy, and phototherapy, are deliberated to provide a groundwork for future stimulative research.

Assessing the Impact of Referral on Multidisciplinary Tumor Board Outcomes in Patients With Hepatocellular Carcinoma.

BACKGROUND AND AIMS: Hepatocellular carcinoma (HCC) is a complex and unique cancer. At many tertiary care institutions, optimal treatment is planned at a multidisciplinary liver tumor board (MDLTB). This study examined the impact of referral on MDLTB outcomes for patients with HCC. METHODS: Chart review was performed of incident HCC cases presented over 3 years at an American College of Surgeons accredited MDLTB. Internal cases were defined as patients whose care originated within the tertiary care institution of the MDLTB; external cases were defined as patients who received initial care from outside institutions and referred to the tertiary care MDLTB for consultation. Internal and external cases were compared for differences in HCC diagnosis, treatment, and survival. RESULTS: There were 120 internal cases and 163 external cases. Compared with internal cases, external cases took significantly more time to be diagnosed with HCC (4.5 versus 37.5 days, P < .001) and to be discussed at MDLTB (19 versus 53 days, P < .001). Internal cases were more often diagnosed by imaging studies (77.5%), and external cases were more often diagnosed by biopsy (43%) or by consensus of experts at MDLTB (26%). CONCLUSION: Patients with HCC, whose care originated within the tertiary care institution of the MDLTB, were less likely to require biopsy and had shorter time from initial suspicion to diagnosis of HCC. The data suggest that referral of external HCC cases to a tertiary center MDLTB at initial suspicion may limit unnecessary diagnostic procedures, possibly resulting in decreased health care costs and reduced uncertainty for patients.

A glutathione responsive nitric oxide release system based on charge-reversal chitosan nanoparticles for enhancing synergistic effect against multidrug resistance tumor.

The combination therapy of nitric oxide (NO) and anticancer drug was developed for reversing multidrug resistance (MDR). In order to avoid NO release during the blood circulation, and realize pinpointed release in the tumor cells, we designed a tumor-specific NO-release system based on 10-hydroxycamptothecin (HCPT)-loaded charge-reversal chitosan nanoparticles and covalently linked phenylsulfonyl furoxan (glutathione (GSH)-responsive NO donor) on the surface. The results showed that only 6.0% of NO was eventually released under physiology condition (pH 7.4 and 2 µM GSH) within 8 h. In contrast, 93.0% of NO was released within 4 h in the presence of 10 mM GSH. Western blot result displayed the P-glycoprotein expression was significantly decreased by 50.1%. Hence, this system performed remarkable cytotoxicity in vitro and the highest tumor inhibition rate (79.7%) comparing with free HCPT group (20.7%) in vivo. Such GSH-responsive NO-release system is a promising candidate with prominent therapeutic effect against MDR tumor.

Fluorescence-enhanced covalent organic framework nanosystem for tumor imaging and photothermal therapy.

Fluorescent dyes, as a key factor in fluorescence imaging, usually exhibit a low signal-to-noise ratio (SNR) due to the limited loading capacities of delivery systems (usually less than 10.0 wt%) and their uncontrolled release. Herein, we developed a type of pH-responsive nanoplatform (MnO2/ZnCOF@Au&BSA) based on a zinc porphyrin covalent organic framework (COF), in which the zinc porphyrin (ZnPor) loading rate is 22.5 wt%. At pH = 7.4, the interlinked ZnPor in the assembly state did not show a fluorescence signal ("off" state). Together with the pH-triggered disintegration of ZnCOF in tumor cells (pH = 5.5), the scattered ZnPor displayed an obvious fluorescence signal recovery ("on" state). Simultaneously, the shed BSA-coated gold nanoparticles ingeniously caused the fluorescence signal to be further amplified through the metal-enhanced fluorescence effect, which was about 3.0-fold higher in vivo than in the free ZnPor group. Combined with the excellent photothermal therapy effect by the nanoplatform itself with the tumor inhibition rate of 79.5%, this nanosystem effectively solves the problem of low loading capacities and imaging SNR by traditional delivery systems, and successfully develops the potential of COFs for fluorescence imaging, achieving the purpose of integration of diagnosis and treatment.

Near-infrared-light induced nanoparticles with enhanced tumor tissue penetration and intelligent drug release.

Tumor tissue presents much denser and stiffer extracellular matrix (ECM), which can hinder the penetration of most nanoparticles (NPs) and contribute to the tumor cell proliferation. Here, NIR-activated losartan was encapsulated in hollow mesoporous prussian blue nanoparticles (HMPBs) to degrade ECM. The results showed that losartan enhanced the penetration of DOX, 1.47% of the injected dose (ID) of DOX reached the tumor tissues, which was 3.00-fold higher than the control group (0.49%). In addition, as the existence of thermo-sensitive lauric acid, (Losartan + DOX)@HMPBs could achieve near "zero drug leakage" during blood circulation, so as to reduce the damage of DOX to normal tissues. Furthermore, the animal experiments proved tumor inhibition ability of (Losartan + DOX)@HMPBs in synergistic of photothermal/chemotherapy, with the tumor growth inhibition rate of 81.3%. Taken together, these findings can be a candidate for developing vectors with enhanced tumor penetration and therapeutic effect in future clinical application. STATEMENT OF SIGNIFICANCE: Due to the existence of denser extracellular matrices (ECM), only 0.7% of the administered nanoparticles dose is delivered to tumor, which will limit the tumors' therapeutic effect. Degradation of ECM can improve the penetration of nanoparticles in tumors. However, no researchers has encapsulated losartan in nanoparticles to degrade ECM. Herein, we developed a NIR induced losartan and DOX co-delivery system based on hollow mesoporous prussian blue nanoparticles (HMPBs) to degrade ECM and improve the penetration of nanoparticles in tumors. The prepared nanoparticles can also acheive near "zero drug leakage" during blood circulation and "fixed-point drug release" in tumor, so as to reduce the damage of DOX to normal tissues. We believe the prepared nanoparticles provide a new platform for cancer treatment.