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Immune checkpoint blockade treatment is one of the most promising immunotherapies, which exhibits promising therapeutic effects on inhibition of metastasis. However, immunotherapy has little effect on pancreatic cancer, due to its extensive fibrotic matrix and immunosuppressive tumor microenvironment. Mild hyperthermia induced by photothermal therapy (PTT) has been proven to activate the immune responses in the tumor microenvironment. Herein, we designed a combine strategy of mild hyperthermia and immune checkpoint blockade (BMS-202) treatment with size-adjustable thermo- and fibrotic matrix- sensitive liposomes (HSA-BMS@CAP-ILTSL), in which BMS-202 loaded small-sized albumin nanoparticle (HSA-BMS) was encapsulated. Mild hyperthermia reduced the tumor hypoxia, relieved the interstitial pressure and increased the recruitment of endogenous immune cells in tumors. In the meantime, small-sized HSA-BMS was released from large-sized HSA-BMS@CAP-ILTSL in response to fibroblast activation protein-α (FAP-α) and near-infrared (NIR) laser, and enhanced the immunological responses by recovering the activity of T lymphocytes, accompanied by secreting relevant cytokines (TNF-α and IFN-γ). The combined therapy (HSA-BMS@CAP-ILTSL) could not only significantly suppress the tumor growth in vivo , but also decrease the amounts of metastatic nodules in distant organs. These results suggested that size-adjustable nanoparticles had a great potential in the treatment of metastatic pancreatic cancer. The desmoplastic stroma and hypoperfusion of pancreatic cancer imposed physical barriers to effective therapies, including chemotherapy, radiotherapy, targeted therapy, and immunotherapy. We constructed size-adjustable thermo- and fibrotic matrix- sensitive liposomes (HSA-BMS@CAP-ILTSL) with size around 120 nm, where small sized albumin nanoparticle (10 nm) of immune checkpoint inhibitor (HSA-BMS) were encapsulated inside. Mild hyperthermia not only contributed to release HSA-BMS for penetration (blocking the immunosuppressive signals deep in the tumor), but enhanced tumor blood perfusion for infiltration of endogenous immune cells. In the two-pronged treatment, the pancreatic cancer immunotherapy significantly enhanced and the risk of cancer metastasis was reduced. Overall, the strategy provides a promising approach to increase drug accumulation and improve the anti-tumor immune activity in pancreatic cancer. [Display omitted] [ABSTRACT FROM AUTHOR]

Liposomal Amphotericin B, known as AmBisome®, is a life-saving antifungal product that sold $407 million in 2019. AmBisome® has a rather complex physical structure in that Amphotericin B (AmpB) forms a stable ionic complex with the lipid bilayer to maintain AmBisome®'s low toxicity and high stability in systemic circulation. Failed attempts to reproduce AmBisome®'s precise structure has resulted in faster drug release and higher toxicity both in vitro and in vivo. In this study, we established several analytical methodologies to quantify liposomal AmpB components, characterize thermal properties of the liposome, and determine particle size distribution, AmpB aggregation state, and drug release kinetics. We applied these methodologies together with in vitro hemolytic potential and antifungal activity tests to characterize multiple lots of AmBisome® and two generic products approved in India, Phosome® and Amphonex®. We also used Fungizone®, a micellar AmpB formulation, and "leaky" AmpB liposomes as negative controls. Our results showed that Phosome® and Amphonex® were both similar to AmBisome®, while Fungizone® and 'leaky" liposomes exhibited differences in both thermal properties and AmpB aggregation state, leading to faster drug release and higher toxicity. Due to the increased interest of the pharmaceutical industry in making generic AmBisome® and the lack of standard analytical methods to characterize liposomal AmpB products, the methodologies described here are valuable for the development of generic liposomal AmpB products. [ABSTRACT FROM AUTHOR]

Human chromosome 7 open reading frame 24 has been identified as a tumor-related protein, and later it was shown to be γ-glutamylcyclotransferase ( GGCT). This protein is upregulated in various types of cancer and is proved to be associated with cellular proliferation. RNA interference is an effective method to achieve highly specific gene regulation. In this study, the anti- GGCT si RNA was incorporated into a comprehensively evaluated polyethylene glycol-hyaluronic acid-modified liposomal si RNA delivery system ( PEG- HA- NP) for drug-resistant MCF-7 breast cancer therapy by systemic administration. The PEG- HA- NP had a diameter of 216 nm and a zeta potential of −17.4 mV. Transfection of anti- GGCT si RNA-loaded PEG- HA- NP could achieve effective GGCT downregulation and induce the subsequent cell cytotoxicity against MCF-7/ ADR cells. Systemic administration of PEG- HA- NP at 0.35 mg/kg si RNA could retard the tumor growth and induce necrosis of tumor tissue while showing no obvious toxicity to normal tissues. Therefore, systemic administration of anti- GGCT-loaded PEG- HA- NP was proved to be a promising strategy for drug-resistant MCF-7 breast cancer therapy. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 104:476-484, 2015 [ABSTRACT FROM AUTHOR]

Synthetic high-density lipoprotein (sHDL) and rapamycin (Rap) have both been shown to be potential treatments for age-related macular degeneration (AMD). The low aqueous solubility of Rap, however, limits its therapeutic utility. Here we used an Apolipoprotein A-I mimetic peptide and phospholipid-based sHDL for the intravitreal delivery of Rap. By incorporation of Rap in sHDL nanoparticles (sHDL-Rap), we achieve 125-fold increase in drug aqueous concentration. When applied in vitro to retinal pigment epithelium cells, sHDL-Rap exhibited the abilities to efflux cholesterol, neutralize endotoxin, and suppress NF-κB activation. As an mTOR inhibitor, Rap induced autophagy and inhibited NF-κB-mediated pro-inflammatory signaling. Additionally, a greater reduction in lipofuscin accumulation and increased anti-inflammatory effects were achieved by sHDL-Rap relative to free drug or sHDL alone. In vivo studies demonstrated that sHDL reached the target retina pigment epithelium (RPE) layer following intravitreal administration in rats. These results suggest that sHDL-Rap holds potential as a treatment for AMD. Rapamycin loaded synthetic HDL (sHDL-Rap) was made by co-lyophilization and thermocycling, which resulted in uniform, 10 nm sized particles with the highest drug encapsulation efficiency (40%). These sHDL-Rap particles displayed little toxicity in ARPE-19 RPE cells and were able to modulate cholesterol homeostasis, autophagy and inflammation in RPE cells. sHDL nanoparticle was also able to target RPE layer in vivo following single intravitreal administration using fluorescently labeled DiO-sHDL nanoparticles in rats. [Display omitted] [ABSTRACT FROM AUTHOR]

Abstract: The treatment of glioma is a great challenge because of the existence of the blood-brain barrier (BBB). In order to reduce toxicity to the normal brain tissue and achieve efficient treatment, it is also important for drugs to specifically accumulate in the glioma foci and penetrate into the tumor core after entering into the brain. In this study, a specific ligand cyclic RGD peptide was conjugated to a cell penetrating peptide R8 to develop a multifunctional peptide R8-RGD. R8-RGD increased the cellular uptake of liposomes by 2-fold and nearly 30-fold compared to separate R8 and RGD respectively, and displayed effective penetration of three-dimensional glioma spheroids and BBB model in vitro. In vivo studies showed that R8-RGD-lipo could be efficiently delivered into the brain and selectively accumulated in the glioma foci after systemic administration in C6 glioma bearing mice. When paclitaxel (PTX) was loaded in liposomes, R8-RGD-lipo could induce the strongest inhibition and apoptosis against C6 cells and finally achieved the longest survival in intracranial C6 glioma bearing mice. In conclusion, all the results indicated that the tandem peptide R8-RGD was a promising ligand possessing multi functions including BBB transporting, glioma targeting and tumor penetrating. And R8-RGD-lipo was proved to be a potential anti-glioma drug delivery system. [Copyright &y& Elsevier]

Herein, we developed a hierarchical bio-composite sensing film by facile one-step electro-deposition of 0D enzyme-polymer nanoparticles (NPs) with 2D graphene oxide nanosheets as conductive supports and nanofillers, based on which an effective and robust enzymatic biosensor platform was constructed. Horseradish peroxidase (HRP) as a model enzyme was co-assembled with a photo-cross-linkable polypeptide of 2-hydroxyethyl methacrylate modified poly(γ-glutamic acid) (γ-PGA-HEMA), generating hybrid HRP@γ-PGA-HEMA nanoparticles (HRP@PGH NPs). Then HRP@PGH NPs and graphene oxide nanosheets (GO NSs) were simultaneously electrodeposited onto the electrode surface, obtaining a hierarchical 0D-2D bio-composite film. After subsequent electrochemical reduction of GO NSs into graphene nanosheets (GNSs) and following photo-cross-linking, the resultant nanostructured HRP@PGH/GNSs sensing film was successfully applied to construct an enzymatic biosensor for hydrogen peroxide (H 2 O 2). The biosensor exerted high sensitivity, fast response, and good stability for H 2 O 2 sensing. Satisfactory results were also demonstrated for its practical application in human serum samples, suggesting a promising application potential in biomedical diagnostics. The one-step generated 0D-2D bio-composite sensing film demonstrates synergetic effects from both the soft nanoparticles and hard conductive nanosheets, which would enlighten the innovative construction of composite nanomaterials and nanoarchitectonics for bio-sensing systems. A robust enzymatic biosensor platform was constructed based on a hierarchical bio-composite sensing film by facile one-step electro-deposition of photo-cross-linkable 0D enzyme-loaded bio-polymeric nanoparticles and 2D graphene oxide nanosheets. Image 1 • A hierarchical 0D-2D bio-composite sensing film was developed by facile one-step electro-deposition process. • The 0D-2D bio-composite film consisted of 0D enzyme-loaded polymeric nanoparticles decorating 2D graphene nanosheets. • A robust enzymatic biosensor platform was constructed with high sensitivity, fast response, and good stability. • Satisfactory analytical results in human serum samples suggests the sensor's applicability in biomedical diagnostics. [ABSTRACT FROM AUTHOR]

Microbially induced carbonate precipitation (MICP) is a common biomineralization method, which is often used for remediation of heavy metal pollution such as hexavalent chromium (Cr(VI)) in recent years. Calcium sources are essential for the MICP process. This study investigated the potential of MICP technology for Cr(VI) remediation under the influence of three calcium sources (CaCl 2 , Ca(CH 3 COO) 2 , Ca(C 6 H 11 O 7) 2). The results indicated that CaCl 2 was the most efficient in the mineralization of Cr(VI), and Ca(C 6 H 11 O 7) 2 could significantly promote Cr(VI) reduction. The addition of different calcium sources all promoted the urease activity of Sporosarcina saromensis W5, in which the CaCl 2 group showed higher urease activity at the same Ca2+ concentration. Besides, with CaCl 2 , Ca(CH 3 COO) 2 and Ca(C 6 H 11 O 7) 2 treatments, the final fraction of Cr species (Cr(VI), reduced Cr(III) and organic Cr(III)-complexes) were mainly converted to the carbonate-bound, cytoplasm and cell membrane state, respectively. Furthermore, the characterization results revealed that three calcium sources could co-precipitate with Cr species to produce Ca 10 Cr 6 O 24 (CO 3), and calcite and vaterite were present in the CaCl 2 and Ca(CH 3 COO) 2 groups, while only calcite was present in the Ca(C 6 H 11 O 7) 2 group. Overall, this study contributes to the optimization of MICP-mediated remediation of heavy metal contaminated soil. CaCl 2 was the more suitable calcium source than the other two for the application of MICP technology in the Cr(VI) reduction and mineralization. [Display omitted] • Ca(C 6 H 11 O 7) 2 significantly promoted Cr(VI) reduction with a reduction rate of 99.85%. • The highest mineralization capacity of Cr based on MICP of the CaCl 2 group reached 87.79 mg/kg. • CaCl 2 , Ca(CH 3 COO) 2 and Ca(C 6 H 11 O 7) 2 group promoted carbonate-bound Cr, cytoplasm Cr and cell membrane Cr, respectively. • Calcite and vaterite were detected in MICP process for Cr(VI) reduction and mineralization. [ABSTRACT FROM AUTHOR]

Graphical abstract Abstract AmBisome® is a liposomal formulation of amphotericin B (Amp B), a complex parenteral antifungal product with no US FDA approved generic version available to date. For generic Amp B liposomal product development, examination of the drug release profile is important for product quality control and analytical comparability evaluation with the reference listed drug. Yet, there is no standardized in vitro drug release (IVR) assay currently available for Amp B liposomes. In this study, we describe the development of a USP-4 apparatus-based IVR assay capable of discriminating liposomal Amp B formulations based on the drug release profile. The goal of the IVR assay development was to identify release media compositions and assay temperatures capable of facilitating 70–100% of drug release from AmBisome® in 24 h without Amp B precipitation or disruption of liposome structure. We found that an addition of 5% w/v of γ-cyclodextrin to the release media of 5% sucrose, 10 mM HEPES, and 0.01% NaN 3 (pH = 7.4) prevented Amp B precipitation and facilitated drug release. Increased IVR assay temperature led to increased drug release rate, and 55 °C was selected as the highest temperature that induced drug release close to our target without causing product precipitation. The developed IVR assay was used to discriminate between drug release rates from AmBisome® and micellar Amp B products like Fungizone® and Fungcosome. The IVR assay was also capable of discriminating between Amp B liposomes with the same composition as AmBisome® but prepared by either extrusion or homogenization processes, both of which resulted in measurable liposomal particle size heterogeneity and Amp B concentration differences. Finally, the USP-4 IVR assay was used to compare Amp B release profiles between AmBisome® and two generic products approved in India, Amphonex® (Bharat Serums and Vaccines Ltd.) (f2 = 66.3) and Phosome® (Cipla Ltd.) (f2 = 55.4). Taken together, the developed USP-4 IVR assay can be a useful tool for drug release profile characterization in generic liposomal Amp B formulation development. [ABSTRACT FROM AUTHOR]

Preeclampsia is one of the most serious pregnancy complications. Many animal models have already been developed by researchers to study the pathogenesis and treatment of preeclampsia. However, most of these animal models were established by systemic administration or by surgery in the uterine cavity, which could lead to unwanted systemic toxicity or operative wounds and affect the accuracy of the results. Because of the high expression level of integrin αvβ3 on the placenta, arginine-glycine-aspartic acid peptide (RGD) modified PEGylated cationic liposome (RGD-Lip) was designed as a novel gene delivery system to target the placenta safely and efficiently, and a new animal model of preeclampsia was established through targeting of long noncoding RNA (lncRNA). The results of cellular uptake and endosomal localization showed that RGD-Lip enhanced cellular uptake and endosomal escape of small interfering RNA (siRNA) on HTR-8/SVneo. In vivo imaging revealed that RGD-Lip was selectively delivered to the placenta. Additionally, H19x siRNA was efficiently transferred into the placenta of C57BL/6 mice via the injection of H19x siRNA-loaded RGD-Lip, which could result in the occurrence of preeclampsia-like symptoms. In summary, RGD-Lip provided a platform to efficiently deliver siRNA to the placenta, and a new preeclampsia-like mouse model was developed targeting placenta enriched/specific genes, including noncoding RNAs. [ABSTRACT FROM AUTHOR]

Autophagy is a lysosomal degradation pathway that acts as a cytoprotective mechanism causing treatment resistance in various cancer cells. Recent studies showed that hydroxychloroquine can inhibit the latter step of autophagy and therefore enhance the anti-glioma efficiency of ZD6474, a tyrosine kinase inhibitor. However, the nonselective distribution of ZD6474 in vivo and the low penetrating ability of hydroxychloroquine when crossing the blood-brain barrier restrict their clinical use in glioma therapy. Here we coencapsulated ZD6474 and hydroxychloroquine into R6dGR peptide-modified liposomes (R6dGR-Lip) which can specifically recognize both integrin αvβ3 and neuropilin-1 receptors that are highly expressed on the endothelial cells and glioma cells. R6dGR significantly enhanced the brain targeting and overcame the blood-brain barrier. Our results confirmed that loading hydroxychloroquine into R6dGR-Lip blocked autophagic flux more efficiently than free hydroxychloroquine in glioma cells and significantly sensitized glioma cells to ZD6474-induced cell death in vitro and in vivo . The coencapsulated R6dGR-modified liposomes (ZD6474/HCQ-R6dGR-Lip) prolonged the medium survival time of intracranial C6 glioma bearing mice by 1.2-fold compared with ZD6474-R6dGR-Lip, 1.5-fold compared with free ZD6474/HCQ, and 1.8-fold compared with free ZD6474, exhibiting a synergistic therapeutic effect. Therefore, ZD6474/HCQ-R6dGR-Lip is presented as a potential strategy which could be further used for efficient anti-glioma therapy. [ABSTRACT FROM AUTHOR]

[Display omitted] Exparel is a bupivacaine multivesicular liposomes (MVLs) formulation developed based on the DepoFoam technology. The complex composition and the unique structure of MVLs pose challenges to the development and assessment of generic versions. In the present work, we developed a panel of analytical methods to characterize Exparel with respect to particle size, drug and lipid content, residual solvents, and pH. In addition, an accelerated in vitro drug release assay was developed using a rotator-facilitated, sample-and-separate experimental setup. The proposed method could achieve over 80% of bupivacaine release within 24 h, which could potentially be used for formulation comparison and quality control purposes. The batch-to-batch variability of Exparel was examined by the established analytical methods. Four different batches of Exparel showed good batch-to-batch consistency in drug content, particle size, pH, and in vitro drug release kinetics. However, slight variation in lipid contents were observed. [ABSTRACT FROM AUTHOR]

C1q-tumor necrosis factor-related protein 3 (CTRP3), an adipokine, has been reported to be closely related to cardiovascular diseases (CVDs). However, the effect of CTRP3 on heart failure (HF) remains dimness. This study was to explore the role of CTRP3 in HF and its potential interaction mechanism. Heart failure model was established by inducing ischemia myocardial infarction (MI) through ligation of the left anterior descending artery in Sprague-Dawley rats. Four weeks later, the rats were detected by transthoracic echocardiography and masson staining. Atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), cardiac troponin I (cTnI) levels, creatine kinase-MB (CK-MB) and oxidative stress levels were recorded. The level of CTRP3 was reduced in the cardiomyocytes (CMs) treated with oxygen-glucose deprivation (OGD) and in the heart of MI rats. CTRP3 overexpression alleviated cardiac dysfunction, attenuated the cardiac fibrosis, and inhibited the increases of ANP, BNP, cTnI and CK-MB in the serum of MI rats. The increases of ANP and BNP in the CMs, and the collagen I and collagen III in the cardiac fibroblasts (CFs) induced by OGD were inhibited by CTRP3 overexpression. The enhancement of oxidative stress in the heart of MI rats was inhibited by CTRP3 overexpression. These results indicated that overexpression of CTRP3 could improve cardiac function and the related cardiac fibrosis in MI-induced HF rats via inhibition of oxidative stress. Upregulation of CTRP3 may be a strategy for HF therapy in the future. • Overexpression of CTRP3 could improve cardiac function of heart failure. • CTRP3 upregulation attenuated cardiac fibrosis of heart failure. • CTRP3 upregulation alleviated heart failure via inhibition of oxidative stress. [ABSTRACT FROM AUTHOR]

Abstract: Tumor-oriented nanocarrier drug delivery approaches with pH-sensitivity have been drawing considerable attentions over the years. Here we described a liposomal delivery system modified with pH-responsive cell penetrating peptide TH (TH-Lip). Conventional cell penetrating peptide (CPP)-related drug delivery tactics sometimes seemed limited due to the extensive in vivo penetration and the lack of proper selectivity of conventional CPPs. In this study, TH (AGYLLGHINLHHLAHL(Aib)HHIL-NH2), an engineered α-helical cell penetrating peptide originated from peptide TK (AGYLLGKINLKKLAKL(Aib)LLIL-NH2), was endowed pH-responsiveness after complete replacement of all lysines in the sequence of TK into histidines, and was introduced onto the surface of liposomes. Accordingly, TH-Lip could benefit from the unique property of TH, as the cell penetrating capacity of TH was concealed during the blood circulation and in normal tissues because of the neutral pH under those conditions. However, when TH-Lip reached the tumor, and as pH declined, histidines in TH peptide protonated and the surface charge of TH-Lip converted from negative to positive, initiating activated cell penetrating capacity and leading to enhanced cellular and tumor spheroid uptake. The endocytosis inhibition assay demonstrated that the endocytosis of TH-Lip was influenced by the positively charged surface of the liposomes in acidic environment and was mediated by clathrin, and the intracellular trafficking study suggested that the liposomes were mainly accumulated in endoplasmic reticulum and Golgi apparatus. After systemic administration in mice, TH-Lip could be internalized into tumor cells efficaciously. When it comes to the delivery of paclitaxel (PTX), the pH-responsiveness of TH-Lip led to strong inhibition against tumor cell growth which occurred both in vitro (under pH 6.3) and in vivo, and the tumor inhibition rate reached 86.3% on C26 tumor-bearing mice for PTX-loaded TH-Lip. Therefore, TH-Lip proved itself to be a promising pH-responsive strategy for drug delivery within acidified tumor microenvironment. [Copyright &y& Elsevier]

[Display omitted] Surgery combined with postoperative treatment is a widely accepted therapeutic strategy against breast cancer. Macrophage-based carriers have been proved to be an effective postoperative drug delivery system due to their inflammatory tendency. However, the slow and incomplete release of the cargo and the postoperative inflammation remain to be solved. Here, we described a macrophage-mediated photothermal therapy combined with anti-inflammatory strategy to inhibit breast cancer postoperative relapse. The anti-inflammatory resveratrol and photothermal agent indocyanine green (ICG) were loaded in octaarginine (R8)-modified liposomes, then ingested by macrophages to form the macrophage-based drug delivery system (Res/ICG-R8-Lip@MP). Res/ICG-R8-Lip@MP showed effective tumor-targeting ability via inflammatory tropism of macrophages and excellent near-infrared (NIR) photothermal performance. In vitro experiments showed that the carrier could not only trigger drug release though inflammation, but also utilize the photothermal conversion property to destroy the macrophage-based carrier at the local tumor to maximize drug release. In vivo experiments indicated that Res/ICG-R8-Lip@MP ablated residual tumor tissues and reduced the postoperative inflammation, and at the same time achieved significant effect of inhibiting tumor postoperative relapse. This synergistic photothermal and anti-inflammatory strategy has great potential in postoperative treatment of breast cancer. [ABSTRACT FROM AUTHOR]