Angiography-based hemodynamic features predict recurrent ischemic events after angioplasty and stenting of intracranial vertebrobasilar atherosclerotic stenosis.

OBJECTIVES: To assess the predictive value of hemodynamic features for stroke relapse in patients with intracranial vertebrobasilar atherosclerotic stenosis treated with percutaneous transluminal angioplasty and stenting (PTAS) using quantitative digital subtraction angiography (q-DSA). METHODS: In this retrospective longitudinal study, patients with intracranial vertebrobasilar atherosclerotic stenosis and who underwent PTAS treatment between January 2012 and May 2020 were enrolled. The q-DSA assessment was performed before and after PTAS. ROIs 1-4 were placed along the vertebral artery, proximal and distal basilar artery, and posterior cerebral artery; ROIs 5-8 were in 5 mm and 10 mm proximal and distal to the lesion, respectively. Relative time to peak (rTTP) was defined as the difference in TTP between ROIs. Cox regression analyses were performed to determine risk factors for recurrent stroke. RESULTS: A total of 137 patients (mean age, 62 years ± 10 [standard deviation], 83.2% males) were included, and 26 (19.0%) patients had stroke relapse during follow-up (median time of 42.6 months [interquartile range, 19.7-60.7]). Preprocedural rTTP4-1 (adjusted hazard ratio (HR) = 2.270; 95% CI 1.371-3.758; p = 0.001) and preprocedural rTTP8-5 (adjusted HR = 0.240; 95% CI 0.088-0.658; p = 0.006) were independently associated with the recurrent stroke. These hemodynamic parameters provided an incremental prognostic value for stroke relapse (AUC, 0.817 [0.704-0.931]; the net reclassification index, 0.431 [0.057-0.625]; and the integrated discrimination index, 0.140 [0.035-0.292]). CONCLUSIONS: In patients with intracranial vertebrobasilar atherosclerosis treated with PTAS, preprocedural prolonged TTP of the target vessel and shortened trans-stenotic TTP difference were associated with stroke relapse. Q-DSA-defined hemodynamic parameters provided incremental predictive value over conventional parameters for stroke recurrence. CLINICAL RELEVANCE STATEMENT: Quantitative DSA analysis enables intuitive observation and semi-quantitative evaluation of peri-therapeutic cerebral blood flow. More importantly, quantitative DSA-defined hemodynamic parameters have the potential for risk stratification of patients with intracranial atherosclerotic stenosis. KEY POINTS: Semi-quantitative angiography-based parameters can reflect pre- and postprocedural subtle changes in blood flow in patients with intracranial atherosclerotic stenosis. Although angioplasty procedures can significantly improve blood flow status, patients with more restricted baseline blood flow still show a higher risk of stroke recurrence. Angiography-based hemodynamic features possess prognostic value and can serve as clinical markers to assess stroke risk of patients with intracranial atherosclerotic stenosis.

The MRI enhancement ratio and plaque steepness may be more accurate for predicting recurrent ischemic cerebrovascular events in patients with intracranial atherosclerosis.

OBJECTIVES: To assess the complementary value of high-resolution multi-contrast MRI (hrMRI) in identifying symptomatic patients with intracranial atherosclerosis (ICAS) who are likely to experience recurrent ischemic cerebrovascular events. METHODS: In this retrospective cohort study, eighty patients with acute ischemic events attributed to ICAS who underwent hrMRI examination between January 2015 and January 2019 were included. Median follow-up for all patients was 30 months (range: 1 to 52 months) and recurrent ischemic cerebrovascular events were recorded. Cox regression analysis and time-dependent ROC were performed to quantify the association between the plaque characteristics and recurrent events. RESULTS: During the follow-up, 14 patients experienced recurrent ischemic cerebrovascular events. Young males and those with diabetes and poor medication persistence were more likely to experience recurrent events. ICAS in patients with recurrence had significantly higher enhancement ratio and steepness which is defined as the ratio between the plaque height and length than those without (p < 0.001 and p = 0.015, respectively). After adjustment of clinical factors, enhancement ratio (HR, 13.13 [95% CI, 3.58-48.20], p < 0.001) and plaque steepness (HR, 110.27 [95% CI, 4.75-2560.91], p = 0.003) were independent imaging biomarkers associated with recurrent events. Time-dependent ROC indicated that integrated high enhancement ratio and steepness into clinical risk factors improved discrimination power with the ROC increased from 0.79 to 0.94 (p = 0.008). CONCLUSIONS: The enhancement ratio and plaque steepness improved the accuracy over traditional clinical risk factors in predicting recurrent ischemic cerebrovascular events for patients with ICAS. KEY POINTS: • High-resolution magnetic resonance imaging helps clinicians to evaluate high-risk Intracranial plaque. • The higher enhancement ratio and plaque steepness (= height/length) were the primary biomarkers associated with future ischemic cerebrovascular events. • High-resolution magnetic resonance imaging combined with clinical characteristics showed a higher accuracy for the prediction of recurrent events in patients with intracranial atherosclerosis.

Prognostic value of angiographic based quantitative flow ratio and anatomic features in intracranial atherosclerotic stenosis.

BACKGROUND: Patients with intracranial atherosclerotic stenosis (ICAS) are prone to stroke recurrence despite aggressive medical treatment. Further assessment of the anatomy and physiology of ICAS is urgently needed to facilitate individualized therapy. We explored the predictive value of angiography based hemodynamic and anatomical features for ICAS patients. METHODS: In this retrospective study, patients with moderate-to-severe stenosis of the middle cerebral artery (MCA) were enrolled. The hemodynamic assessment was performed using the single view Murray's law based quantitative flow ratio (µQFR) approach. The locations of lesions were categorized as perforator rich segments of the MCA (pMCA) and others. Multivariate Cox models were developed to identify significant predictors. The primary outcomes were defined as stroke and transient ischemic attack. RESULTS: Among the 333 patients (median (IQR) age, 56 (49-63) years, 70.3% men) over a median follow-up period of 64.5 months, 50 (15.0%) had the primary outcomes, and 80.0% occurred within 5 years. Patients with lower µQFR values (dichotomized at 0.73) had a higher risk of the 5 year primary outcomes (log rank P=0.023), and good collateral circulation may have attenuated the risk. In the multivariate analyses, µQFR (adjusted HR=0.345; 95% CI 0.155 to 0.766; P=0.009), lesion located in pMCA (adjusted HR=0.377; 95% CI 0.190 to 0.749; P=0.005), and diameter ratio of the internal carotid artery (adjusted HR=4.187; 95% CI 1.071 to 16.370; P=0.040) were significantly associated with the 5 year primary outcomes. CONCLUSIONS: Angiography based µQFR and anatomical features, namely plaque localization and internal carotid artery expansion, could serve as promising prognostic indexes for MCA atherosclerosis.

Angiography­based quantitative flow ratio for functional assessment of intracranial atherosclerotic disease.

BACKGROUND: Intracranial atherosclerotic stenosis (ICAS), an important cause of stroke, is associated with a considerable stroke recurrence rate despite optimal medical treatment. Further assessment of the functional significance of ICAS is urgently needed to enable individualised treatment and, thus, improve patient outcomes. AIMS: We aimed to evaluate the haemodynamic significance of ICAS using the quantitative flow ratio (QFR) technique and to develop a risk stratification model for ICAS patients. METHODS: Patients with moderate to severe stenosis of the middle cerebral artery, as shown on angiography, were retrospectively enrolled. For haemodynamic assessment, the Murray law-based QFR (µQFR) was performed on eligible patients. Multivariate logistic regression models composed of µQFR and other risk factors were developed and compared for the identification of symptomatic lesions. Based on the superior model, a nomogram was established and validated by calibration. RESULTS: Among 412 eligible patients, symptomatic lesions were found in 313 (76.0%) patients. The µQFR outperformed the degree of stenosis in discriminating culprit lesions (area under the curve [AUC]: 0.726 vs 0.631; DeLong test p-value=0.001), and the model incorporating µQFR and conventional risk factors also performed better than that containing conventional risk factors only (AUC: 0.850 vs 0.827; DeLong test p-value=0.034; continuous net reclassification index=0.620, integrated discrimination improvement=0.057; both p<0.001). The final nomogram showed good calibration (p for Hosmer-Lemeshow test=0.102) and discrimination (C-statistic 0.850, 95% confidence interval: 0.812-0.883). CONCLUSIONS: The µQFR was significantly associated with symptomatic ICAS and outperformed the angiographic stenosis severity. The final nomogram effectively discriminated symptomatic lesions and may provide a useful tool for risk stratification in ICAS patients.

Series of High Magnetic Resonance-Guided Photoinduced Nanodelivery Systems for Precisely Improving the Efficiency of Cancer Therapy.

Nanochemotherapy is recognized as one of the most promising cancer treatment options, and the design of the carrier has a crucial impact on the final efficacy. To precisely improve the efficacy and reduce the toxicity, we combined the clinical contrast agent (Gd-DTPA) with a stimulus-sensitive o-nitrobenzyl ester and then prepared a series of nNBGD lipids by varying the carbon chain length of the hydrophobic group. The self-assembled nNBGD liposomes can be tracked by MRI to localize the aggregation of drug carriers in vivo, so as to prompt the application of light stimulation at the optimal time to facilitate the precise release of carriers at the lesion site. And the application potential of this strategy was verified with 88% tumor suppression effect in the 12NBGD-DOX+UV group. In addition, this paper emphasizes that small differences in structure can affect the overall performance of the carriers. By exploration of the differences in stability, drug loading, stimulus responsiveness, MRI imaging effect, and toxicity of the series of nNBGD carriers, the relationship between the length of the hydrophobic group of nNBGD lipids and the overall performance of the carriers is given, which provides experimental support and design reference for other carriers.

Precise delivery of multi-stimulus-responsive nanocarriers based on interchangeable visual guidance.

Cancer treatment is imminent, and controlled drug carriers are an important development direction for future clinical chemotherapy. Visual guidance is a feasible means to achieve precise treatment, reduce toxicity and increase drug efficacy. However, the existing visual control methods are limited by imaging time-consuming, sensitivity and side effects. In addition, the ability of the carrier to respond to environmental stimuli in vivo is another difficulty that limits its application. Here, we propose a highly stimulus-responsive GC liposome with precise tracing and sensitive feedback capabilities. It combines magnetic resonance imaging and fluorescence imaging, and addresses the need for precise visualization by alternating imaging modalities. More importantly, GC liposomes are a carrier that can accumulate stimuli. In this paper, by tracking the fragmentation process of empty GC and drug-loaded D-GC liposomes, we confirm the synergistic effect between multiple stimuli, which can result in a more efficient drug release performance. Finally, in mice models we examined the GC liposome imaging approach and the D-GC + UV group guided by this visualization exhibited the highest tumor inhibition efficiency (6.85-fold). This study highlights the advantages of alternate visualization-guided and co-stimulation treatment strategies, and provides design ideas and potential materials for efficient and less toxic cancer treatments.

Sensitive and precise visually guided drug delivery nanoplatform with dual activation of pH and light.

Controlled-release drug carriers in cancer therapy are the most ideal way to reduce toxicity and improve drug efficacy. Since light stimulation is precise and operable, most multi-stimulation response carriers utilize phototherapy to enhance release efficiency. However, phototoxicity severely limits the application of phototherapy. Herein, we designed and synthesized a Cou-ONB lipid with sensitive fluorescence feedback and multi-stimulus response. COBL liposomes prepared from Cou-ONB lipids will passively aggregate at the tumor and guide phototherapy by fluorescence. More importantly, it can reflect the drug release effect in vivo through its own sensitive fluorescence changes, further enabling precise phototherapy and reducing phototoxicity. In this paper, the multi-stimulus superimposed response and precise fluorescence-guided performance of COBL liposomes were investigated at the molecular, liposome, cellular, and animal levels. Finally, tumor treatment experiments showed that the d-COBL-UV group had the best tumor suppression effect (5.3-fold). This paper highlights a real-time fluorescence-guided multi-stimulus superposition strategy and provides a design idea to precisely implement exogenous stimuli by displaying the degree of drug release, aiming to achieve less toxic and more efficient cancer therapy through timely and precise multi-stimulation. STATEMENT OF SIGNIFICANCE: Multi-stimulus responsive drug carriers have been extensively developed in the last decade. Visual guidance is an important tool to achieve precision medicine and precise control of drug release. However, the available visualization materials are more aimed at directing stimulation at the optimal moment. There is little discussion on when to stop exogenous stimulation and how to minimize the damage of stimulation to the patient. Here, we provide a Cou-ONB lipid that not only responds to multiple stimuli, but also provides sensitive feedback on its own dissociation with a fluorescent signal so that physicians can adjust exogenous stimuli in a timely manner. This paper provides insights to facilitate precision drug delivery systems, providing viable design ideas for precise, efficient, and less toxic cancer therapies.

Functional Assessment of Cerebral Artery Stenosis by Angiography-Based Quantitative Flow Ratio: A Pilot Study.

BACKGROUND: Increasing attention has been paid to the hemodynamic evaluation of cerebral arterial stenosis. We aimed to demonstrate the performance of angiography-based quantitative flow ratio (QFR) to assess hemodynamic alterations caused by luminal stenoses, using invasive fractional pressure ratios (FPRs) as a reference standard. METHODS: Between March 2013 and December 2019, 29 patients undergoing the pressure gradient measurement of cerebral atherosclerosis were retrospectively enrolled. Wire-based FPR was defined by the arterial pressure distal to the stenotic lesion (Pd) to proximal (Pa) pressure ratios (Pd/Pa). FPR < 0.70 or FPR < 0.75 was assumed as hemodynamically significant stenosis. The new method of computing QFR from a single angiographic view, i.e., the Murray law-based QFR, was applied to the interrogated vessel. An artificial intelligence algorithm was developed to realize the automatic delineation of vascular contour. RESULTS: Fractional pressure ratio and QFR were assessed in 38 vessels from 29 patients. Excellent correlation and agreement were observed between QFR and FPR [r = 0.879, P < 0.001; mean difference (bias): -0.006, 95% limits of agreement: -0.198 to 0.209, respectively). Intra-observer and inter-observer reliability in QFR were excellent (intra-class correlation coefficients, 0.996 and 0.973, respectively). For predicting FPR < 0.70, the area under the receiver-operating characteristic curves (AUC) of QFR was 0.946 (95% CI, 0.820 to 0.993%). The sensitivity and specificity of QFR < 0.70 for identifying FPR < 0.70 was 88.9% (95% CI, 65.3 to 98.6%) and 85.0% (95% CI, 62.1 to 96.8%). For predicting FPR < 0.75, QFR showed similar performance with an AUC equal to 0.926. CONCLUSION: Computational QFR from a single angiographic view achieved comparable results to the wire-based FPR. The excellent diagnostic performance and repeatability empower QFR with high feasibility in the functional assessment of cerebral arterial stenosis.

Motor Network Reorganization After Repetitive Transcranial Magnetic Stimulation in Early Stroke Patients: A Resting State fMRI Study.

OBJECTIVE: To compare the effects of high-frequency (10 Hz) versus low-frequency (1 Hz) repetitive Transcranial Magnetic Stimulation (rTMS) on motor recovery and functional reorganization of the cortical motor network during the early phase of stroke. METHODS: Forty-six hospitalized, first-ever ischemic stroke patients in early stage (within two weeks) with upper limb motor deficits were recruited. They were randomly allocated to three groups with 10 Hz ipsilesional rTMS, 1 Hz contralesional rTMS, and sham rTMS of five daily session. All patients underwent motor function (Upper Extremity Fugl-Meyer), neurophysiological and resting-state  functional Magnetic Resonance Imaging (fMRI) (rs-fMRI) assessments before and after rTMS intervention. Motor recovery (△Fugl-Meyer Assessment) was defined as motor function changes before and after rTMS intervention. Motor function assessment was reevaluated at time point of three month follow-up. RESULTS: The two real rTMS groups manifested greater motor improvements than the sham group. The effect sustained for at least 3 months after the end of the treatment sessions. Compared with the sham group, 10 Hz ipsilesional rTMS group presented increased resting-state functional connectivity (FC) between ipsilesional primary motor cortex (M1) and contralesional M1 (P = .007), whereas 1 Hz contralesional rTMS group presented increased FC between contralesional M1 and ipsilesional supplementary motor area (P = .010), which were positively correlated with motor recovery (P < .05). CONCLUSION: Beneficial effect of rTMS on motor recovery might be underlaid by increased FC between stimulating site and the remote motor areas, highlighting the motor network reorganization mechanism of rTMS in early post-stroke phase.

An MRI-guided targeting dual-responsive drug delivery system for liver cancer therapy.

The targeting dual-responsive drug delivery system was employed for cancer treatment as a positive strategy. Herein, Lactobionic acid (LA)-modified and non-modified UV/reduction dual-responsive molecules (10,10-NB-S-S-P-LA and 10,10-NB-S-S-P-OMe) were synthesized. Functional magnetic resonance imaging (MRI) contrast agent (12,12-NB-DTPA-Gd) was mixed with 10,10-NB-S-S-P-LA or 10,10-NB-S-S-P-OMe in the optimal ratio (3:1) to develop targeted empty liposomes (GNSPL) or non-targeted empty liposomes (GNSPM) with superior UV/reduction dual-responsiveness, biocompatibility and magnetic resonance imaging (MRI) performance. The drug-loaded liposomes (GNSPLD and GNSPMD) can keep stable in two weeks, and the drug cumulative release rate reached to the maximum under dual stimulation of ultraviolet (UV) and reducing agent (TCEP). The treatment with GNSPLD + UV significantly inhibited the growth and migration of cancer cells in vitro. The GNSPLD liposomes were more effectively accumulated in tumor site than GNSPMD liposomes, due to the targeting property of GNSPLD liposomes. The treatment with GNSPLD + UV showed a better therapeutic efficacy than Doxorubicin (DOX) in vivo, and almost no side effects during the treatment period. Thus, the MRI-guided targeting dual-responsive drug delivery system provided a reliable therapeutic strategy for treating liver cancer.

A traceable, GSH/pH dual-responsive nanoparticles with spatiotemporally controlled multiple drugs release ability to enhance antitumor efficacy.

Constructing highly efficient and multifunctional nanoparticles to overcome the multiple challenges of targeted drug delivery is a new strategy urgently needed in tumor therapy. Here, we synthesized pH-responsive prodrug (PEG2K-NH-N-DOX), GSH-responsive prodrug (PEG2K-S-S-CPT), folate-receptor targeting polymers (FA-PEG2K-L8, FA-PEG2K-TOS) and T1-enhanced magnetic resonance imaging contrast agents (Gd-DTPA-N16-16), used to encapsulate combrestatinA4 (CA4) to prepare multifunctional nanoparticles (FTDCAG NPs). Unlike other nanoparticles, FTDCAG NPs contains three drugs with the ability to control the release in time and space, which can maximize the effectiveness of precise cancer chemotherapy. We first confirmed that specific binding between FTDCAG NPs and overexpressed folate-receptor cells by flow cytometry and confocal laser scanning microscopy. We then investigated the spatiotemporally controlled release ability of FTDCAG NPs loaded with doxorubicin (DOX), CA4 and camptothecin (CPT). Relative to pH = 7.4, the release efficiency of CA4 in the pH = 6.5 increased by 63.4 %. The first released CA4 is able to destroy the angiogenesis and help tumor cells to be exposed to the remaining FTDCG NPs. After being internalized into the tumor cells, FTDCG NPs is disassembled and the CPT and DOX were released due to the increase of intracellular GSH concentration and the decrease of pH value. Besides, the relaxation time of FTDCAG NPs is 3.86 times that of clinical Gd-DTPA, and the in vitro and vivo T1-weighted imaging is brighter, which can be used to trace the nanoparticles by MRI. Therefore, FTDCAG NPs provide an efficient strategy for the design of multifunctional drug delivery systems for enhancing antitumor efficacy.

Endogenous reactive oxygen species burst induced and spatiotemporally controlled multiple drug release by traceable nanoparticles for enhancing antitumor efficacy.

Reactive oxygen species (ROS) are not only used as a therapeutic reagent in chemodynamic therapy (CDT), to stimulate the release of antineoplastic drugs, they can also be used to achieve a combined effect of CDT and chemotherapy to enhance anticancer effects. Herein, we synthesized a pH-responsive prodrug (PEG2k-NH-N-DOX), ROS-responsive prodrug (PEG2k-S-S-CPT-ROS), organic CDT agents (TPP-PEG2k-LND, TPP-PEG2k-TOS), and T1-enhanced magnetic resonance imaging contrast agents (Gd-DTPA-N16-16), and used them to encapsulate combrestatinA4 (CA4) to prepare traceable pH/ROS dual-responsive multifunctional nanoparticles (TLDCAG NPs) with endogenous ROS burst and spatiotemporally controlled multiple drug release ability. Firstly, TLDCAG NPs were accumulated in the tumor cell microenvironment via an enhanced permeability and retention (EPR) effect. Secondly, CA4 was released and specifically destroyed angiogenesis to facilitate the interaction between the tumor and the remaining TLDCG NPs. After accumulating in tumor cells, the TLDCG NPs could be destroyed under acidic conditions to quickly release doxorubicin (DOX), TPP-PEG2k-LND, and TPP-PEG2k-TOS. Thirdly, TPP-PEG2k-LND and TPP-PEG2k-TOS quickly targeted mitochondria, induced endogenous ROS bursts, reduced the mitochondrial membrane potential, and induced tumor cell apoptosis. Endogenous ROS can not only be used as a therapeutic reagent for CDT, but also can cut off the thioketal bond in PEG2k-S-S-CPT-ROS and release camptothecin (CPT). Finally, TLDCAG NPs were traced by magnetic resonance imaging (MRI). Furthermore, in vitro and vivo results indicate that the TLDCAG NPs have vigorous antitumor activity and negligible systemic toxicity. Therefore, the TLDCAG NPs provide an efficient strategy for enhancing antitumor efficacy.

Magnetic Resonance Imaging-Guided Multi-Stimulus-Responsive Drug Delivery Strategy for Personalized and Precise Cancer Treatment.

The emergence of nano-targeted controlled release liposomal drug carriers has provided a breakthrough in cancer therapy. However, their clinical efficacy is unsatisfactory, which is related to individualized differences in targeted drugs and poor in vivo release efficiency. In this paper, we prepared a class of personalized targeted and precisely controlled-release therapeutic drug carriers (GF liposomes) by co-assembling targeting and traceable o-nitrobenzyl ester lipids to propose a magnetic resonance imaging (MRI)-guided personalized in vivo targeted drug screening strategy and a multi-stimulus superimposed controlled-release strategy. Furthermore, by following the drug release process of drug-loaded liposomes (GF-D), it was found that these liposomes could rely on energy superposition to achieve more sensitive and efficient controlled drug release. In addition, the indispensable adjustment of liposome formulation for personalized MRI-based targeted therapy was verified by differential cellular uptake and in vivo magnetic resonance imaging. In the end, the 10.22-fold tumor suppression effect in the stimulus superposition group (GF-D-UV) indicates that the multi-stimulus cumulative response strategy and MRI-guided in vivo screening strategy can more effectively treat cancer. This contribution provides a concise and clever design idea for the future development of personalized precise and efficient clinical cancer therapies.

A Multifunctional Lipid Incorporating Active Targeting and Dual-Control Release Capabilities for Precision Drug Delivery.

Active targeting and precise control of drug release based on nanoparticle therapies are urgently required to precisely treat cancer. We have custom-synthesized a functional lipid (termed Fa-ONB) by introducing a folic acid-targeting group into an o-nitro-benzyl ester lipid. As designed, the liposomes formed by Fa-ONB combine active targeting and dual trigger release capabilities, which help to improve drug efficacy and reduce the toxicity of traditional liposomes. We first verified that both pH-induced hydrolysis and light treatment were able to cleave the Fa-ONB lipid. We then prepared a series of liposomes (termed FOBD liposomes) by compounding the Fa-ONB lipid with DOPC at different ratios. After encapsulation of doxorubicin (DOX), we found that the particle size of DOX-loaded FOBD liposomes (DOX/FOBD) first increased (290 to 700 nm) and then decreased again (to 400 nm) under continuous UV irradiation (120 min). The photocatalytic release efficiency under different pH conditions was investigated by dialysis experiments, and it was found that the release efficiency in an acidic environment was significantly increased relative to neutral pH. This pH-triggered release response helps distinguish pathological tissues such as lysosomal compartments and tumors. The light-induced formation of a DOX precipitate increases in efficiency with increasing UV exposure time as well as with increasing environmental acidity or alkalinity. In addition, confocal imaging and flow cytometry showed that the ability of FOBD lipids to actively target HeLa cells increased with increasing Fa-ONB lipid content. Real-time in vivo fluorescence small animal experiments proved targeting to tumors and pH- and photo-induced release properties. Furthermore, therapeutic experiments using a mouse model found a significant tumor inhibitory effect for DOX/FOBD55 liposomes with UV irradiation, clearly demonstrating the benefit of light treatment: the tumor size of the control (PBS) group was 7.59 times that of the light treatment group. Therefore, this research demonstrates the benefits of combining triggerable release functions and effective active tumor targeting in one small lipid molecule for precise cancer treatment.

Efficient antibacterial dextran-montmorillonite composite sponge for rapid hemostasis with wound healing.

Montmorillonite (MMT) powder, as the most effective hemostats in natural silicates, is restricted for commercial application due to its embolic effect. Until now, it's still a challenge to control the leakage of MMT and avoid its side-effects. Herein, poly aldehyde dextran (PDA)/MMT composite sponge (PM) with commendable tissue adhesion, antibacterial, and wound healing performances is developed for massive hemorrhage control. Based on the high degree of perfect synergism of PDA and MMT, the PM sponge can rapidly seal the wound, and promote cells aggregation and adhesion, whole coagulation system activation, resulting in shortened clotting time from 480 s to <10 s in vitro. Therefore, PM sponge with low exothermic effects achieves hemostasis in limited time, decreasing nearly 95% blood loss in the femoral artery and vein incision in rat models. Furthermore, with the intensive tissue adhesion (~47 kPa), PM sponge not only exhibits antibacterial activity to Escherichia coli, but also succeeds in accelerating wound healing. Importantly, the low cytotoxic sponge verifies to be a little hemolytic and skin irritant hemostat. Thus, the biocompatible PM sponge may provide a new strategy for reintroduction of MMT in hemostatic fields, and a safe-effective avenue for clays to control bleeding.

Synthesis and evaluation of mono- and multi-hydroxyl low toxicity pH-sensitive cationic lipids for drug delivery.

Cationic lipids can easily assemble into spherical liposomes in aqueous phase which showed unique superiority in drug and gene delivery. However, the toxicity of cationic lipids is still an obstacle to application. To develop low toxicity cationic lipids, we designed two cationic lipids contained different number of hydroxyl groups. Biocompatible mono-hydroxyl and multi-hydroxyl galactose head group was respectively modified to a biodegradable quaternary amine lipid, and two novel hydroxyl cationic lipids were synthesized and characterized by MS, 1H NMR and 13C NMR. Two lipids showed good surface activity and both of them can assemble to about 80 nm stable small unilamellar vesicles (SUVs) with cholesterol in aqueous phase. Both of lipids showed relatively lower toxicity than the well-known cationic lipid 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP). In vitro 24 h IC50 of two assemblies were more than 50 µg/mL, which were about 10 µg/mL higher than the IC50 of DOTAP. Multi-hydroxyl galactose lipids group showed much lower toxicity than mono-hydroxyl lipids group. Moreover, Both of the assemblies with lower hemolysis were nearly non-hemolytic risk under the concentration of 30 µg/mL. Transmission electron microscopy (TEM) and dynamic light scattering (DLS) showed that the average sizes of both doxorubicin (DOX) loaded liposomes were about 110 nm. The DOX entrapment efficiencies of galactose liposome and mono-hydroxyl liposome were 58% and 91%, respectively. Both of the DOX loaded liposomes were stable after one month placed at room temperature. Two DOX loaded liposomes showed better anti-cancer effect than free DOX above 5 µg/mL, and they can be internalized into cells and produce more release of DOX inside MCF-7 cells and HepG2 cells at pH 5.0. These results suggested that synthesized lipids are suitable as potential low toxicity cationic drug delivery systems.

A highly efficient, in situ wet-adhesive dextran derivative sponge for rapid hemostasis.

Uncontrolled hemorrhage is closely related to the high risk of death. However, local hemostats still have various defects and side effects. Herein, an aldehyde dextran (PDA) sponge with proper absorption and adhesion properties is developed for hemorrhage control. PDA sponge with pore size of ∼30-50 µm fabricated by lyophilization not only absorbs blood quickly (47.7 g/g), but also possesses strong tissue adhesion (∼100 kPa). PDA sponge with low cytotoxicity and hemolysis achieves effective hemostasis and remarkable blood loss reduction in the ear vein, femoral artery and liver injuries of rabbit models. Furthermore, the exploration of hemostatic mechanisms related to tissue, blood, plasma, cells and coagulation system indicates that PDA sponge can significantly accelerate coagulation by rapid wound block, fast cells aggregation and initiation, and high coagulation factors concentration, instead of by the coagulation cascade activation. Importantly, this hemostat exhibits excellent biodegradability and nearly no skin irritation. Overall, the biodegradable and tissue adhesive PDA sponge will be a promising quick-hemostatic dressing for uncontrollable hemorrhage.

Mussel-inspired degradable antibacterial polydopamine/silica nanoparticle for rapid hemostasis.

High-performance hemostasis becomes increasingly essential in civilian and military trauma. However, available topical hemostats still exist various drawbacks and side-effects. Herein, a silica nanoparticle coated with polydopamine (PDA/SiNP) with good degradability, antibacterial performance was developed for hemorrhage control. PDA/SiNP formed a porous network via lyophilization and rendered material with phenol hydroxyls, aminos, proper hydrophobicity, promising for further cells aggregation and inducing clotting. The degradation behaviors in vitro indicated that the weight loss of PDA/SiNP could attain approximately 40% just after 24 h. All results demonstrated that clotting time of blood was shortened by nearly 150 s for PDA/SiNP compared with that of commercial Celox in vitro hemostasis. PDA/SiNP could significantly accelerate coagulation by activating the extrinsic pathway of the coagulation cascade, adhering platelets and aggregating erythrocytes. Therefore, not only the PDA/SiNP achieved adequate hemostasis with low exothermic effects, but also blood loss was remarkably reduced in the femoral artery and vein injury, liver injury models. Importantly, PDA/SiNP exhibited long-lasting inhibition of Escherichia coli even after 208 h. Also, the hemolysis of PDA/SiNP with low cytotoxicity was much lower, while erythrocytes maintained regular morphology. Thus, amorphous nanoscale PDA/SiNP provided a new avenue for design of silica hemostats and nonmetallic ion antimicrobial.