Correction: Clodronate-nintedanib-loaded exosome-liposome hybridization enhances the liver fibrosis therapy by inhibiting Kupffer cell activity.

Correction for 'Clodronate-nintedanib-loaded exosome-liposome hybridization enhances the liver fibrosis therapy by inhibiting Kupffer cell activity' by Keqin Ji et al., Biomater. Sci., 2022, 10, 702-713, https://doi.org/10.1039/D1BM01663F.

Precipitating factors of bradycardia after remdesivir administration: ICU admission and cutoff value for declining heart rate.

BACKGROUND: Despite increasing concerns about the association between remdesivir and bradycardia in severe coronavirus disease 2019 (COVID-19) patients receiving remdesivir, information on its clinical course and precipitating factors is limited. Our aim was to investigate possible triggers of bradycardia after remdesivir administration. METHODS: We retrieved the medical records of hospitalized severe and critical COVID-19 patients who received remdesivir from May 1, 2021 to June 30, 2021. Bradycardia was defined as two episodes of a heart rate (HR) < 60 bpm in 24 h. Receiver operating characteristic (ROC) curve analysis was conducted to evaluate the discriminability of heart rate pattern on the occurrence of bradycardia. The precipitating factors of bradycardia were examined by a logistic regression model. RESULTS: Regardless of bradycardia status, the median heart rate dropped during remdesivir treatment (from 85 to 72 bpm, p < 0.001), with the heart rate dropping considerably within the first two days of remdesivir treatment. Among various heart rate descriptors, HR ratiomin (d2-d1) had the best discrimination (AUC = 0.7336), and a reduction in HR ratiomin (d2-d1) by 14.65% was associated with bradycardia. Intensive care unit (ICU) admission was associated with an increased risk of bradycardia (odds ratio: 3.41; 95% CI: 1.12-10.41). CONCLUSIONS: In severe COVID-19 patients receiving remdesivir, the risks of bradycardia were influenced by a substantial reduction in heart rate during the first two days of remdesivir treatment and ICU admission. These findings suggest that clinical practitioners should intensively monitor heart rates during remdesivir treatment.

Biological Hyperthermia-Inducing Nanoparticles for Specific Remodeling of the Extracellular Matrix Microenvironment Enhance Pro-Apoptotic Therapy in Fibrosis.

The extracellular matrix (ECM) is a major driver of fibrotic diseases and forms a dense fibrous barrier that impedes nanodrug delivery. Because hyperthermia causes destruction of ECM components, we developed a nanoparticle preparation to induce fibrosis-specific biological hyperthermia (designated as GPQ-EL-DNP) to improve pro-apoptotic therapy against fibrotic diseases based on remodeling of the ECM microenvironment. GPQ-EL-DNP is a matrix metalloproteinase (MMP)-9-responsive peptide, (GPQ)-modified hybrid nanoparticle containing fibroblast-derived exosomes and liposomes (GPQ-EL) and is loaded with a mitochondrial uncoupling agent, 2,4-dinitrophenol (DNP). GPQ-EL-DNP can specifically accumulate and release DNP in the fibrotic focus, inducing collagen denaturation through biological hyperthermia. The preparation was able to remodel the ECM microenvironment, decrease stiffness, and suppress fibroblast activation, which further enhanced GPQ-EL-DNP delivery to fibroblasts and sensitized fibroblasts to simvastatin-induced apoptosis. Therefore, simvastatin-loaded GPQ-EL-DNP achieved an improved therapeutic effect on multiple types of murine fibrosis. Importantly, GPQ-EL-DNP did not induce systemic toxicity to the host. Therefore, the nanoparticle GPQ-EL-DNP for fibrosis-specific hyperthermia can be used as a potential strategy to enhance pro-apoptotic therapy in fibrotic diseases.

Palladium-catalyzed stereoselective ring-opening reaction of aryl cyclopropyl ketones.

Herein, we report that α,ß-unsaturated ketones could be obtained by palladium-catalyzed ring-opening of mono-substituted cyclopropyl ketones efficiently and systematically. (E)-1-Arylbut-2-en-1-ones were generated from aryl cyclopropyl ketones stereoselectively in yields of 23-89% by the Pd(OAc)2/PCy3 catalytic system. The reaction exhibited stereoselectivity (only E products were found) and was suitable for both phenyl and heteroaryl cyclopropyl ketones.

Clodronate-nintedanib-loaded exosome-liposome hybridization enhances the liver fibrosis therapy by inhibiting Kupffer cell activity.

Liver fibrosis therapy remains limited due to the inefficiency of drug delivery and inflammation induced by Kupffer cells. In this study, an exosome-liposome hybrid drug delivery system (LIEV) was developed to increase the efficacy of clodronate (CLD)-inhibition of Kupffer cells and to effectively deliver nintedanib (NIN) to liver fibroblasts to ensure enhanced anti-fibrosis therapy. CLD and NIN co-loaded LIEV (CLD/NIN@LIEV) exerted non-specific inhibition of phagocytosis by Kupffer cells, reduced inflammatory cytokines, and showed homologous homing properties mediated by fibroblast-derived exosomes, thereby achieving superior antifibrotic effects in a CCl4-induced fibrosis mouse model by inhibiting the proliferation of fibroblasts. Furthermore, the inhibited Kupffer cells regenerated within 10 days after dosage withdrawal. Unlike carrier-free NIN treatment, CLD/NIN@LIEV induced a marked decrease in liver enzymes, indicating improved safety and anti-fibrosis efficacy. These results indicate its great potential for treatment with the combined anti-fibrosis agent and Kupffer cell inhibition strategies to enhance the liver fibrosis therapy.

Clodronate-loaded liposomal and fibroblast-derived exosomal hybrid system for enhanced drug delivery to pulmonary fibrosis.

Pulmonary fibrosis is a rapidly progressive and fatal fibrotic lung disease with high mortality and morbidity. However, pulmonary fibrosis therapy in the clinic has been limited by poor selectivity and inefficiency of drug delivery to fibroblasts. Herein, a clodronate (CLD)-loaded liposome and fibroblast-derived exosome (EL-CLD) hybrid drug delivery system with non-specific phagocytosis inhibition and fibroblast homing properties, was designed for the treatment of pulmonary fibrosis. EL-CLD effectively depleted Kupffer cells via apoptosis by passive targeting after intravenous injection, and thus significantly reduced accumulation in the liver. Notably, the EL-CLD hybrid system preferentially accumulated in the fibrotic lung, and significantly increased penetration inside pulmonary fibrotic tissue by targeted delivery due to the specific affinity for fibroblasts of the homologous exosome. Nintedanib (NIN), an anti-fibrotic agent used to treat pulmonary fibrosis, was loaded in the EL-CLD system, and achieved a remarkable improvement in curative effects. The enhanced therapeutic efficacy of NIN was a result of enhanced pulmonary fibrotic tissue accumulation and delivery, combined with a diminished macrophage-induced inflammatory response. Hence, the EL-CLD hybrid system acts as an efficient carrier for pulmonary anti-fibrotic drug delivery and should be developed as an efficient fibroblast specific therapy.

Nanodrug Delivery Systems Modulate Tumor Vessels to Increase the Enhanced Permeability and Retention Effect.

The use of nanomedicine for antitumor therapy has been extensively investigated for a long time. Enhanced permeability and retention (EPR) effect-mediated drug delivery is currently regarded as an effective way to bring drugs to tumors, especially macromolecular drugs and drug-loaded pharmaceutical nanocarriers. However, a disordered vessel network, and occluded or embolized tumor blood vessels seriously limit the EPR effect. To augment the EPR effect and improve curative effects, in this review, we focused on the perspective of tumor blood vessels, and analyzed the relationship among abnormal angiogenesis, abnormal vascular structure, irregular blood flow, extensive permeability of tumor vessels, and the EPR effect. In this commentary, nanoparticles including liposomes, micelles, and polymers extravasate through the tumor vasculature, which are based on modulating tumor vessels, to increase the EPR effect, thereby increasing their therapeutic effect.

Celastrol nanoemulsion induces immunogenicity and downregulates PD-L1 to boost abscopal effect in melanoma therapy.

Programmed cell death-ligand 1 (PD-L1)-based immune checkpoint blockade therapy using the anti-PD-L1 antibody is effective for a subset of patients with advanced metastatic melanoma but about half of the patients do not respond to the therapy because of the tumor immunosuppressive microenvironment. Immunogenic cell death (ICD) induced by cytotoxins such as doxorubicin (DOX) allows damaged dying tumor cells to release immunostimulatory danger signals to activate dendritic cells (DCs) and T-cells; however, DOX also makes tumor cells upregulate PD-L1 expression and thus deactivate T-cells via the PD-1/PD-L1 pathway. Herein, we show that celastrol (CEL) induced not only strong ICD but also downregulation of PD-L1 expression of tumor cells. Thus, CEL was able to simultaneously activate DCs and T-cells and interrupt the PD-1/PD-L1 pathway between T-cells and tumor cells. In a bilateral tumor model, intratumorally (i.t.) injected celastrol nanoemulsion retaining a high tumor CEL concentration activated the immune system efficiently, which inhibited both the treated tumor and the distant untreated tumor in the mice (i.e., abscopal effect). Thus, this work demonstrates a new and much cost-effective immunotherapy strategy - chemotherapy-induced immunotherapy against melanoma without the need for expensive immune-checkpoint inhibitors.

Combined Effects of Frailty and Polypharmacy on Health Outcomes in Older Adults: Frailty Outweighs Polypharmacy.

OBJECTIVES: Existing studies cannot evaluate the time-varying properties of frailty and polypharmacy despite raising concerns about their combined effects in older individuals. This study investigated the longitudinal association between different combined statuses of frailty and polypharmacy on risks of adverse outcomes. DESIGN: Retrospective cohort study. SETTING AND PARTICIPANTS: Subjects aged between 65 and 100 years (n = 100,000) were identified from Taiwan's National Health Insurance Research Database. MEASURES: Frailty was categorized into fit, mild, moderate, and severe frailty based on the multimorbidity frailty index. Concomitant use of 5 to 9 and ≥10 chronic medications was considered polypharmacy and excessive polypharmacy. We used generalized estimating equation models to examine the association among 12 groups of combined effects of frailty and polypharmacy and risks of all-cause mortality, all-cause hospitalization, and unplanned hospitalization. Age-stratified analyses were conducted for those aged 65 to 74, 75 to 84, and 85+ years. RESULTS: Compared with fit without polypharmacy, severe frailty with excess polypharmacy was associated with increased risks of adverse outcomes, particularly unplanned hospitalization (adjusted relative risk (aRR): 20.01 [95% confidence interval (CI)] 19.30-20.75). However, the combined effects varied in distinct groups. Within each polypharmacy category, there were dose-response associations between frailty category and adverse outcomes. For instance, within the polypharmacy group, the aRRs of mortality were 1.58 (1.52-1.64), 2.70 (2.60-2.80), 4.62 (4.44-4.82), and 6.81 (6.50-7.13) for the fit and mild, moderate, and severe frailty groups, respectively. By contrast, within each frailty category, the dose-response association between polypharmacy and adverse outcomes was limited to fit and mildly frail people. Age-stratified analyses yielded similar results. CONCLUSIONS AND RELEVANCE: Both frailty and polypharmacy modified the risks of mortality and hospital admissions in older people, but the combined effects varied in distinct groups. This study thus highlights the potential to optimize care of older people by capturing the dynamic and combined changes related to frailty and polypharmacy.

Vitamin E succinate-grafted-chitosan/chitosan oligosaccharide mixed micelles loaded with C-DMSA for Hg2+ detection and detoxification in rat liver.

AIM: To determine whether the use of a mixed polymeric micelle delivery system based on vitamin E succinate (VES)-grafted-chitosan oligosaccharide (CSO)/VES-grafted-chitosan (CS) mixed micelles (VES-g-CSO/VES-g-CS MM) enhances the delivery of C-DMSA, a theranostic fluorescent probe, for Hg2+ detection and detoxification in vitro and in vivo. METHODS: Mixed micelles self-assembled from two polymers, VES-g-CSO and VES-g-CS, were used to load C-DMSA and afforded C-DMSA@VES-g-CSO/VES-g-CS MM for cell and in vivo applications. Fluorescence microscopy was used to assess C-DMSA cellular uptake and Hg2+ detection in L929 cells. C-DMSA@VES-g-CSO/VES-g-CS MM was then administered intravenously. Hg2+ detection was assessed by fluorescence microscopy in terms of bio-distribution while detoxification efficacy in Hg2+-poisoned rat models was evaluated in terms of mercury contents in blood and in liver. RESULTS: The C-DMSA loaded mixed micelles, C-DMSA@VES-g-CSO/VES-g-CS MM, significantly enhanced cellular uptake and detoxification efficacy of C-DMSA in Hg2+ pretreated human L929 cells. Evidence from the reduction of liver coefficient, mercury contents in liver and blood, alanine transaminase and aspartate transaminase activities in Hg2+ poisoned SD rats treated with the mixed micelles strongly supported that the micelles were effective for Hg2+ detoxification in vivo. Furthermore, ex vivo fluorescence imaging experiments also supported enhanced Hg2+ detection in rat liver. CONCLUSION: The mixed polymeric micelle delivery system could significantly enhance cell uptake and efficacy of a theranostic probe for Hg2+ detection and detoxification treatment in vitro and in vivo. Moreover, this nanoparticle drug delivery system could achieve targeted detection and detoxification in liver.

Combined Cancer Chemo-Photodynamic and Photothermal Therapy Based on ICG/PDA/TPZ-Loaded Nanoparticles.

Although photodynamic therapy (PDT) has been an attractive strategy for several cancer treatments in the clinical setting, PDT efficacy is attenuated by consumption of oxygen. To address this photodynamic issue, we adopted a phototherapy-chemotherapy combination strategy based on targeted delivery of the near-infrared photosensitizer indocyanine green (ICG), photothermal conversion agent polydopamine (PDA), and tirapazamine (TPZ), a hypoxia-activated prodrug. Under laser irradiation, ICG consumption of oxygen and aggravated hypoxia in tumor sites can activate TPZ to damage DNA. In parallel, ICG produces reactive oxygen species which work in synergy with PDA to enhance phototherapeutic efficiency. Herein, hybrid CaCO3/TPGS nanoparticles delivering ICG, PDA, and TPZ (ICG-PDA-TPZ NPs) were designed for effective and safe cancer therapy. ICG-PDA-TPZ NPs showed significantly improved cellular uptake and accumulation in tumors. Furthermore, we demonstrated that ICG-PDA-TPZ NPs showed intensive photodynamic and photothermal effects in vitro and in vivo, which synergized with TPZ in subcutaneous U87 malignant glioma growth and orthotopic B16F10 tumor inhibition, with negligible side effects. Thus, ICG-PDA-TPZ NPs could be an effective strategy for improvement of PDT.

Vasodilator Hydralazine Promotes Nanoparticle Penetration in Advanced Desmoplastic Tumors.

Desmoplastic tumors are normally resistant to nanoparticle-based chemotherapy due to dense stroma and limited particle permeability inside the tumor. Herein, we reported that hydralazine (HDZ)-an antihypertension vasodilator-would dramatically promote nanoparticle penetration in advanced desmoplastic tumors. First, a HDZ-liposome system was developed for tumor-selective delivery of HDZ. After three injections of HDZ-liposomes at a dose of 15 mg/kg, the tumor stroma was remarkably reduced, along with ameliorated tumor hypoxia in murine models of desmoplastic melanoma (BPD6). Furthermore, HDZ-liposome treatment altered the immunosuppressive tumor microenvironment, which provided opportunities for applying this therapeutic system to aid immunotherapy in desmoplastic tumors. Using DiD-loaded liposome as a model nanoparticle, we showed that HDZ-liposome treatment significantly increased nanoparticle accumulation and penetration inside desmoplastic tumors. As a result, one single injection of doxorubicin-liposomes at a dose of 5 mg/kg resulted in strong tumor inhibition effect after HDZ-liposome pretreatment in the advanced desmoplastic melanoma with sizes over 400 mm3. Because HDZ is a widely used antihypertension drug, the findings here should be readily translatable for clinical benefits.

Cyclodextrin/chitosan nanoparticles for oral ovalbumin delivery: Preparation, characterization and intestinal mucosal immunity in mice.

A novel oral protein delivery system with enhanced intestinal penetration and improved antigen stability based on chitosan (CS) nanoparticles and antigen-cyclodextrin (CD) inclusion complex was prepared by a precipitation/coacervation method. Ovalbumin (OVA) as a model antigen was firstly encapsulated by cyclodextrin, either ß-cyclodextrin (ß-CD) or carboxymethyl-hydroxypropyl-ß-cyclodextrin (CM-HP-ß-CD) and formed OVA-CD inclusion complexes, which were then loaded to chitosan nanoparticles to form OVA loaded ß-CD/CS or CM-HP-ß-CD/CS nanoparticles with uniform particle size (836.3 and 779.2 nm, respectively) and improved OVA loading efficiency (27.6% and 20.4%, respectively). In vitro drug release studies mimicking oral delivery condition of OVA loaded CD/CS nanoparticles showed low initial releases at pH 1.2 for 2 h less than 3.0% and a delayed release which was below to 30% at pH 6.8 for further 72 h. More importantly, after oral administration of OVA loaded ß-CD/CS nanoparticles to Balb/c mice, OVA-specific sIgA levels in jejunum of OVA loaded ß-CD/CS nanoparticles were 3.6-fold and 1.9-fold higher than that of OVA solution and OVA loaded chitosan nanoparticles, respectively. In vivo evaluation results showed that OVA loaded CD/CS nanoparticles could enhance its efficacy for inducing intestinal mucosal immune response. In conclusion, our data suggested that CD/CS nanoparticles could serve as a promising antigen-delivery system for oral vaccination.

Targeting integrin-rich tumors with temoporfin-loaded vitamin-E-succinate-grafted chitosan oligosaccharide/d-α-tocopheryl polyethylene glycol 1000 succinate nanoparticles to enhance photodynamic therapy efficiency.

A major challenge in cancer photodynamic therapy (PDT) is the poor tumor selectivity of the photosensitizer. Therefore, temoporfin (mTHPC)-loaded nanoparticles, based on vitamin-E-succinate-grafted chitosan oligosaccharide and cyclic (arginine-glycine-aspartic acid-d-phenylalanine-lysine) (c[RGDfK])-modified d-α-tocopheryl polyethylene glycol 1000 succinate, were prepared (RGD-NPs) and were expected to enhance the accumulation of mTHPC in integrin-rich U87MG tumors. The RGD-NPs generated were 144.9nm in diameter and uniformly spherical. After irradiation, RGD-NPs effectively generated singlet oxygen, and displayed enhanced cellular uptake and cytotoxicity in U87MG cells. The RGD-NPs also penetrated deep into U87MG tumor spheroids, with a tumor-targeting ability and antitumor efficacy superior to those of unmodified nanoparticles in subcutaneous-tumor-bearing nude mice. A histopathological analysis confirmed the increased anticancer efficacy of RGD-NPs, with less systemic toxicity than unmodified nanoparticles. Therefore, the RGD-NPs developed in this study potentially target integrin-rich tumors and enhance the efficiency of PDT.

Vitamin E Succinate-Grafted-Chitosan Oligosaccharide/RGD-Conjugated TPGS Mixed Micelles Loaded with Paclitaxel for U87MG Tumor Therapy.

The poor therapeutic efficacy of hydrophobic chemotherapeutic drugs is an intrinsic limitation to successful chemotherapy. In the present study, a multitask delivery system based on arginine-glycine-aspartic acid peptide (RGD) decorated vitamin E succinate (VES)-grafted-chitosan oligosaccharide (CSO)/RGD-conjugated d-alpha-tocopheryl polyethylene glycol 1000 succinate (TPGS-RGD) mixed micelles (VeC/T-RGD MM) was first prepared for targeted delivery of a hydrophobic anticancer drug, paclitaxel (PTX), to improve the efficacy of U87MG tumor therapy. VES grafted CSO (VES-g-CSO) and TPGS-RGD were synthesized as nanocarriers, and PTX loaded VeC/T-RGD MM (PTX@VeC/T-RGD MM) was prepared via the organic solvent emulsification-evaporation method. The PTX@VeC/T-RGD MM was 150.2 nm in diameter with uniform size distribution, 5.92% drug loading coefficient, and no obvious particle size changes within 7 days. The PTX@VeC/T-RGD MM showed sustained-release properties in vitro and high cytotoxicity, and could be efficiently taken up by human glioma U87MG cells. The tumor inhibitory rate of PTX@VeC/T-RGD MM treatment in U87MG tumor spheroids and U87MG tumor bearing mice was 49.3% and 88.4%, respectively, which indicated a superior therapeutic effect. PTX@VeC/T-RGD MM did not damage normal tissues in safety evaluations. These findings suggested that PTX@VeC/T-RGD MM could be developed for the delivery of hydrophobic drugs to U87MG tumors.

c(RGDyK)-decorated Pluronic micelles for enhanced doxorubicin and paclitaxel delivery to brain glioma.

Brain glioma therapy is an important challenge in oncology. Here, doxorubicin (DOX) and paclitaxel (PTX)-loaded cyclic arginine-glycine-aspartic acid peptide (c(RGDyK))-decorated Pluronic micelles (cyclic arginine-glycine-aspartic acid peptide-decorated Pluronic micelles loaded with doxorubicin and paclitaxel [RGD-PF-DP]) were designed as a potential targeted delivery system to enhance blood-brain barrier penetration and improve drug accumulation via integrin-mediated transcytosis/endocytosis and based on integrin overexpression in blood-brain barrier and glioma cells. The physicochemical characterization of RGD-PF-DP revealed a satisfactory size of 28.5±0.12 nm with uniform distribution and core-shell structure. The transport rates across the in vitro blood-brain barrier model, cellular uptake, cytotoxicity, and apoptosis of U87 malignant glioblastoma cells of RGD-PF-DP were significantly greater than those of non-c(RGDyK)-decorated Pluronic micelles. In vivo fluorescence imaging demonstrated the specificity and efficacy of intracranial tumor accumulation of RGD-PF-DP. RGD-PF-DP displayed an extended median survival time of 39 days, with no serious body weight loss during the regimen. No acute toxicity to major organs was observed in mice receiving treatment doses via intravenous administration. In conclusion, RGD-PF-DP could be a promising vehicle for enhanced doxorubicin and paclitaxel delivery in patients with brain glioma.

ß-Cyclodextrin-Based Inclusion Complexation Bridged Biodegradable Self-Assembly Macromolecular Micelle for the Delivery of Paclitaxel.

In this study, a novel adamantanamine-paclitaxel (AD-PTX) incorporated oligochitosan- carboxymethyl-ß-cyclodextrin (CSO-g-CM-ß-CD) self-assembly macromolecular (CSO-g-CM-ß-CD@AD-PTX) micelle was successfully prepared in water through sonication. The formed molecules were characterized by Fourier transform infrared spectroscopy, proton nuclear magnetic resonance (NMR) spectroscopy, two-dimensional NMR, elemental analysis, and liquid chromatography-mass spectrometry, while the correspondent micelles were characterized by dynamic light scattering and transmission electron microscopy. We showed that the macromolecular micelle contained a spherical core-shell structure with a diameter of 197.1 ± 3.3 nm and zeta potential of -19.1 ± 4.3 mV. The CSO-g-CM-ß-CD@AD-PTX micelle exhibited a high drug-loading efficacy up to 31.3%, as well as a critical micelle concentration of 3.4 × 10-7 M, which indicated good stability. Additionally, the in vitro release profile of the CSO-g-CM-ß-CD@AD-PTX micelle demonstrated a long-term release pattern, 63.1% of AD-PTX was released from the micelle during a 30-day period. Moreover, the CSO-g-CM-ß-CD@AD-PTX micelle displayed cytotoxicity at a sub-µM scale similar to PTX in U87 MG cells, and CSO-g-CM-ß-CD exhibited a good safety profile by not manifesting significant toxicity at concentrations up to 100 µM. These results indicated that ß-CD-based inclusion complexation resulting in biodegradable self-assembled macromolecular micelles can be utilized as nanocarrier, and may provide a promising platform for drug delivery in the future medical applications.

In Vivo Biodistribution and Anti-Tumor Efficacy Evaluation of Doxorubicin and Paclitaxel-Loaded Pluronic Micelles Decorated with c(RGDyK) Peptide.

The treatment of squamous carcinoma, especially multidrug resistance (MDR) tumors, represents one of the most formidable challenges in oncology. In this study, integrin-mediated Pluronic-based micellar system (c(RGDyK)-FP-DP) was proposed as a drug delivery system to enhance the in vivo anti-tumor efficacy in MDR human squamous carcinoma (KBv)-bearing. Following the recognition by integrin proteins express on the cell surface, cellular uptake and in vitro anti-tumor efficacy of c(RGDyK)-FP-DP were better than conventional PF-DP in KBv cells. The tumor homing specificity and further in vivo anticancer efficacy of c(RGDyK)-FP-DP were performed using subcutaneous KBv tumor-bearing mice model, respectively. Compared with PF-DP, c(RGDyK)-FP-DP demonstrated more drug accumulation in tumor and relatively less drug accumulation in heart, and an extended median survival time in the KBv tumor-bearing mice model. Furthermore, preliminary in vivo subacute toxicity evaluation was also conducted by the measurement of histopathology, blood cell counts and clinical biochemistry parameters. Results showed that no obvious toxicity was observed to the hematological system or heart after a series of intravenous administration of c(RGDyK)-FP-DP. In conclusion, our results suggested that c(RGDyK) peptide conjugated Pluronic micelles could be a promising vehicle for enhancing the treatment of MDR human squamous carcinoma.

Dual-functional c(RGDyK)-decorated Pluronic micelles designed for antiangiogenesis and the treatment of drug-resistant tumor.

Dual-functional drug delivery system was developed by decorating c(RGDyK) (cyclic RGD [arginine-glycine-aspartic acid] peptide) with Pluronic polymeric micelles (c[RGDyK]-FP-DP) to overcome the drawbacks of low transport of chemotherapeutics across the blood-tumor barrier and poor multidrug-resistant (MDR) tumor therapy. c(RGDyK) that can bind to the integrin protein richly expressed at the site of tumor vascular endothelial cells and tumor cells with high affinity and specificity was conjugated to the N-hydroxysuccinimide-activated PEO terminus of the Pluronic F127 block copolymer. In this study, decreased tumor angiogenic and increased apoptotic activity in MDR cancer cells were observed after the treatment with c(RGDyK)-FP-DP. c(RGDyK)-FP-DP was fully characterized in terms of morphology, particle size, zeta potential, and drug release. Importantly, in vitro antiangiogenesis results demonstrated that c(RGDyK)-FP-DP had a significant inhibition effect on the tubular formation of human umbilical vein endothelial cells and promoted cellular apoptotic activity in MDR KBv cells. In addition, the growth inhibition efficacy of KBv tumor spheroids after crossing the blood-tumor barrier was obviously increased by c(RGDyK)-FP-DP compared to other control groups. Results suggested that c(RGDyK)-decorated Pluronic polymeric micelles can take pharmacological action on both human umbilical vein endothelial cells and KBv MDR cancer cells, resulting in a dual-functional anticancer effect similar to that observed in our in vitro cellular studies.