Enhanced Water Solubility Research Articles

A Novel D-π-A Type Fluorescent Probe for Cu2+ Based on Styryl-Pyridinium Salts Conjugating Di-(2-picolyl)amine (DPA) Units.

A novel D-π-A type fluorescent probe L(NO3) for Cu (II) sensing was designed and fully characterized. The probe consists of a styryl-pyridine cation fluorescent group and a di-(2-picolyl)amine (DPA) receptor unit, which are linked by a phenyl group to form an electron donor-π-acceptor (D-π-A) conjugate system, especially the introduction of a nitrate counter anion for significantly enhanced water solubility of the probe. Fluorescence titration studies of the probe L(NO3) showed a higher selectivity for Cu2+ than other metal ions, and the emission spectrum was strongly quenched upon binding. The competitive binding assay and the low detection limit (0.932 µM) showed that the probe L(NO3) had strong anti-interference ability and excellent Cu2+ detection performance. The binding ratio of probe L(NO3) and Cu2+ was determined from Job's plot to be 1:1, which is consistent with the results obtained from X-ray crystal structures. Meanwhile, the probe showed instantaneous chemical reversibility when titrated with EDTA solution, indicating potential recycling properties of the probe. In addition, the design of inexpensive fluorescent test strips can perform the on-site and real-time detection Cu2+ with a color recognition application.

Nanoparticles Based on Chondroitin Sulfate from Tuna Heads and Chitooligosaccharides for Enhanced Water Solubility and Sustained Release of Curcumin.

This study aimed to separate chondroitin sulfate (CS) from the heads of skipjack tuna (Katsuwonus pelamis) and yellowfin tuna (Thunnus albacares), by-products derived from canned tuna processing, via a biological process. The use of 1% w/w papain and an incubation time of 48 h resulted in a degree of hydrolysis of 93.75 ± 2.94% and a CS content of 59.53 ± 1.77 mg/100 g. The FTIR spectra of extracted CS products exhibited identical functional groups found in commercially available CS. The molecular weights of CS extracted from skipjack and yellowfin tuna heads were 11.0 kDa and 7.7 kDa, respectively. Subsequently, a CH:CS ratio of 3:2 for CS and chitooligosaccharides (CH) was chosen as the optimal ratio for the preparation of spherical nanoparticles, with %EE, mean particle size, PDI, and zeta potential values of 50.89 ± 0.66%, 128.90 ± 3.29 nm, 0.27 ± 0.04, and -12.47 ± 2.06, respectively. The CU content was enhanced to 127.21 ± 1.66 μg/mL. The release of CU from this particular nanosystem involved mainly a drug diffusion mechanism, with a burst release in the first 3 h followed by a sustained release of CU over 24 h. The DPPH and ABTS scavenging activity results confirmed the efficient encapsulation of CU into CHCS nanoparticles. This study will provide a theoretical basis for CS derived from tuna head cartilages to be used as a functional component with specific functional properties in food and biomedical applications.

Synthesis of Alpha-Linked Glucosides from Soybean Isoflavone Aglycones Using Amylosucrase from Deinococcus geothermalis.

Soybean isoflavone aglycones (SIAs) have many biological activities but are poorly water-soluble in the human body. Glycosylation provides structural diversity to SIAs and can alter their physicochemical properties, including water solubility. An alpha-linked glucosylation of SIA was achieved using amylosucrase from Deinococcus geothermalis. A total of 13 alpha-linked glucosyl SIAs were obtained, and their colors in solution were confirmed. The structures of the isolated compounds were identified by mass spectrometry and multidimensional nuclear magnetic resonance spectroscopy. The amylosucrase transglycosylation formed new isoflavone glycosides with alpha glycosidic bonds at C-7 and/or C-4' of SIAs, followed by the production of isoflavone glycosides with alpha (1 → 6) glycosidic bonds. The products with a glucosyl moiety attached to the C-4' of SIAs were found to be more water-soluble than their counterparts attached to the C-7 and/or beta-linkages. This study suggests a strategy for the synthesis of bioactive compounds with enhanced water solubility through alpha-linked glucosylation.

Optimizing Axial and Peripheral Substitutions in Si-Centered Naphthalocyanine Dyes for Enhancing Aqueous Solubility and Photoacoustic Signal Intensity.

Photoacoustic imaging using external contrast agents is emerging as a powerful modality for real-time molecular imaging of deep-seated tumors. There are several chromophores, such as indocyanine green and IRDye800, that can potentially be used for photoacoustic imaging; however, their use is limited due to several drawbacks, particularly photostability. There is, therefore, an urgent need to design agents to enhance contrast in photoacoustic imaging. Naphthalocyanine dyes have been demonstrated for their use as photoacoustic contrast agents; however, their low solubility in aqueous solvents and high aggregation propensity limit their application. In this study, we report the synthesis and characterization of silicon-centered naphthalocyanine dyes with high aqueous solubility and near infra-red (NIR) absorption in the range of 850-920 nm which make them ideal candidates for photoacoustic imaging. A series of Silicon-centered naphthalocyanine dyes were developed with varying axial and peripheral substitutions, all in an attempt to enhance their aqueous solubility and improve photophysical properties. We demonstrate that axial incorporation of charged ammonium mesylate group enhances water solubility. Moreover, the incorporation of peripheral 2-methoxyethoxy groups at the α-position modulates the electronic properties by altering the π-electron delocalization and enhancing photoacoustic signal amplitude. In addition, all the dyes were synthesized to incorporate an N-hydroxysuccinimidyl group to enable further bioconjugation. In summary, we report the synthesis of water-soluble silicon-centered naphthalocyanine dyes with a high photoacoustic signal amplitude that can potentially be used as contrast agents for molecular photoacoustic imaging.

Redox-Responsive Hyaluronic Acid-Tacrolimus Conjugate: Synthesis, Characterization, and In Vitro Immunosuppressive Activity.

A redox-responsive macromolecular prodrug of tacrolimus, HA-ss-Tac, was constructed by conjugation of tacrolimus (TAC, FK506) through its succinate ester to cystamine-modified hyaluronic acid (HA-Cys), and its physicochemical properties and immunosuppressive activity were studied. The synthesized HA-ss-TAC was determined to contain 8% of chemically loaded TAC with significantly enhanced water solubility. The release study showed a sustained release of drug through slow degradation of linker-drug bonds. In vitro inhibition of proliferation of T- and B-lymphocytes was almost comparable to that of TAC, implying that the biologically active compound could be released from the conjugate. The polymeric prodrug lacks obvious cytotoxicity on Raw 264.7 macrophages and significantly suppressed the production of inflammatory cytokines IL-2 and IL-1β by LPS-activated cells. Additionally, the cellular uptake study of the FITC-labeled conjugate confirmed the HA receptor-mediated internalization of the conjugate into targeted cells, thus avoiding systemic side effects. Taken together, the HA-ss-TAC prodrug could be an optimal prodrug for intravenous administration based on this preliminary data and can be expected to have improved therapeutic efficacy.

Silver-promoted solid-phase guanidinylation enables the first synthesis of arginine glycosylated Samoamide A cyclopeptide analogue.

Cyclization and glycosylation serve as effective approaches for enhancing the drug properties of peptides. Distinct from typical glycosylation, atypical arginine N-glycosylation has drawn increasing attention due to its fundamental role in various cellular procedures and signaling pathways. We previously developed a robust strategy for constructing arginine N-glycosylated peptides characterized by silver-promoted solid-phase guanidinylation. Modeled after cyclic octapeptide Samoamide A, an antitumor peptide composed of eight hydrophobic amino acids extracted from cyanobacteria, herein we first performed arginine scanning to determine an optimal position for replacement with arginine. Consequently, the first synthesis of arginine glycosylated Samoamide A cyclopeptide analogue was described combining solid-phase glycosylation with solution-phase cyclization. The resultant SA-HH-TT displayed enhanced water solubility compared with the non-glycosylated SA-HH-TT. Notably, our method provides a universal strategy for synthesizing arginine N-glycosylated cyclopeptides.

Design and synthesis of atorvastatin derivatives with enhanced water solubility, hepatoselectivity and stability.

Statins are effective 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG-R) inhibitors, which are successfully used for cardiovascular disease treatment. Statins' side effects are generally attributed to poor bioavailability and hepatoselectivity, which are closely related to their high lipophilicity. Targeted delivery of statins to the liver is considered as a way to reduce unwanted side effects. Herein we report on synthesis and evaluation of atorvastatin conjugates targeting the galactose-specific hepatic asialoglycoprotein receptor (ASGPR). The prepared conjugates showed greater water solubility compared to unmodified atorvastatin. The synthesised compounds demonstrated potent binding to the ASGPR with submicromolar K D values. The conjugates with an amide bond connecting atorvastatin and the targeting moiety displayed the optimal stability under model conditions, as they underwent hydrolysis only when incubated with the intracellular protease. The hydrolysis products effectively inhibited HMG-R activity. The results suggest that the designed amide-based compounds have the potential to be further developed as orally administered prodrugs of atorvastatin.

Development of a novel sialic acid-conjugated camptothecin prodrug for enhanced cancer chemotherapy.

Camptothecin (CPT) is an attractive natural drug for cancer chemotherapy. However, the poor water solubility, non-targeting feature, and adverse side effects of CPT are significant obstacles to developing an effective anticancer drug. Here, for the first time, 9-thiol-sialic acid (9-SH-Sia) is coupled to CPT by forming a disulfide releasable carbonate linkage, resulting in a novel CPT prodrug (CPT-ss-Sia) that self-assembles into nanostructures in an aqueous solution. Strikingly, CPT-ss-Sia exhibited excellent in vitro properties, including enhanced water solubility, glutathione (GSH)-triggered CPT release, and increased E-lactone ring stability. Furthermore, CPT-ss-Sia had good cancer cell-killing ability comparable to CPT. Intravenous administration of CPT-ss-Sia significantly inhibited the growth of multiple types of tumors. Histological analysis showed that CPT-ss-Sia treatment significantly reduced lesions in tumor-bearing mice compared to CPT treatment. Notably, CPT-ss-Sia treatment did not adversely affect the body weight of the mice. This is the first report of the 9-SH-Sia conjugate-based prodrug. Overall, CPT-ss-Sia has broad clinical application prospects.

Metal Complexes of a 5-Nitro-8-Hydroxyquinoline-Proline Hybrid with Enhanced Water Solubility Targeting Multidrug Resistant Cancer Cells.

Multidrug resistance (MDR) in cancer is one of the major obstacles of chemotherapy. We have recently identified a series of 8-hydroxyquinoline Mannich base derivatives with MDR-selective toxicity, however with limited solubility. In this work, a novel 5-nitro-8-hydroxyquinoline-proline hybrid and its Rh(η5-C5Me5) and Ru(η6-p-cymene) complexes with excellent aqueous solubility were developed, characterized, and tested against sensitive and MDR cells. Complex formation of the ligand with essential metal ions was also investigated using UV-visible, circular dichroism, 1H NMR (Zn(II)), and electron paramagnetic resonance (Cu(II)) spectroscopic methods. Formation of mono and bis complexes was found in all cases with versatile coordination modes, while tris complexes were also formed with Fe(II) and Fe(III) ions, revealing the metal binding affinity of the ligand at pH 7.4: Cu(II) > Zn(II) > Fe(II) > Fe(III). The ligand and its Rh(III) complex displayed enhanced cytotoxicity against the resistant MES-SA/Dx5 and Colo320 human cancer cell lines compared to their chemosensitive counterparts. Both organometallic complexes possess high stability in solution, however the Ru(II) complex has lower chloride ion affinity and slower ligand exchange processes, along with the readiness to lose the arene ring that is likely connected to its inactivity.

Utilization of Hydrotropic Solubilisation Technique for Quantitative Studies of Dexamethasone in Pharmaceutical preparations

Solubility is a crucial characteristic for achieving the appropriate drug concentration in the systemic circulation and demonstrating pharmacological response. Poor water solubility can severely limit drug efficacy, and some medications can even cause negative effects as a result of their poor solubility. Enhancing water solubility can be done through several of methods. Increased water solubility can thus be a beneficial technique for enhancing therapeutic effectiveness and/or reducing side effects. This is true for solutions that are given intravenously, topically, or orally. Increasing the aqueous solubility of drugs that are weakly water soluble can be done in a variety of techniques. Hydrotropy is a solubility enhancement technique that uses hydrotropes such as sodium benzoate, sodium salicylate, sodium citrate, urea, ibuprofen sodium, and niacin amide to improve the solubility of poorly water-soluble drugs. Hydrotropic solubilization was employed in this study to solubilize weakly water-soluble drug like Dexamethasone utilizing hydrotropic agents like sodium benzoate (2M) and sodium salicylate (2M). Dexamethasone has maximum absorbance at 272.05nm, when sodium benzoate is used as a hydrotropic agent. In the 5-25 µg/ml concentration range, this substance follows the beers law. Dexamethasone shows maximum absorbance at 317.10nm, when sodium salicylate is used as a hydrotropic agent. In the concentrations ranging from 5 to 25µg/ml, this substance follows the beers law. The findings of studies have been statistically confirmed, as well as by re-examination studies. According to the ICH guidelines, validation parameters such as linearity, range, and assay were investigated.

Polysaccharide dextran-based conjugate for selective co-delivery of two synergistic drugs docetaxel and docosahexaenoic acid to tumor cells

Most chemotherapeutic agents are nonspecific distribution and cause systemic toxicities. Polysaccharide-based conjugates are promising strategies to overcome these drawbacks. To this end, two synergistic drugs docetaxel (DTX) and docosahexaenoic acid (DHA) were independently covalently bonded through individual linkers to dextran (100 kDa) to produce a novel dual-drug conjugate dextran–DHA–DTX. The single-drug conjugates dextran–DHA and dextran–DTX were also prepared for comparison. Fluorescent dye Cy7.5-based conjugates dextran–Cy7.5 and dextran–DHA–Cy7.5 were synthesized for cellular uptake study. The dual-drug conjugate dextran–DHA–DTX self-assembled into nanoparticles with the diameter of 102.3 ± 8.3 nm and demonstrated enhanced water solubility and improved pharmacokinetic profiles. Cellular uptake results showed that the dual-drug conjugate entered cells more than the parent DTX by determining the intracellular DTX contents via HPLC/MS analysis and by determining the fluorescent intensity of dextran-Cy7.5 and dextran–DHA–Cy7.5. Importantly, the dual-drug conjugate dextran–DHA–DTX significantly accumulated in tumor tissues and dramatically reduced the DTX concentrations in normal tissues. The dual-drug conjugate completely eradicated all the MCF-7 xenograft tumors without obvious side effects and showed more superior antitumor activity than parent DTX and single-drug conjugate dextran–DTX and dextran–DHA. Both in vitro and in vivo studies showed that DHA enhanced the antitumor activity of dextran–DTX. The polysaccharide dextran-based dual-drug conjugates may represent an effective way to improve the chemotherapeutic agents.

Enhanced triclosan biodegradation by a biphasic bioreactor

Triclosan (TCS), an antiseptic agent that facilitates the formation of microbial resistances, has been widely used and is therefore ubiquitously detectable in wastewater. However, structure and low water solubility limit both microbial transformation kinetic and removal efficiency of TCS. Therefore, the use of solubilizers or non-aqueous phases (NAP) appears to be a suitable approach for rapid, complete, and cost-effective treatment of highly contaminated TCS point sources such as sports clubs, hospitals, industrial wastewater treatment plants or synthesis effluents without dilution effects.The mixed culture TCSmix100 previously isolated and characterized, and able to completely mineralize TCS at stoichiometric chloride release, was investigated in presence or absence of solubilizers in lab-scale well stirred batch reactors. While TCS conversion was limited in solubilizer-free tests due to limited solubility of TCS crystals within the aqueous phase, solubilizers enhanced water solubility, mass transport and microbial kinetics. Thus, TCS transformation rate at initial 1.45 g TCS L−1 was further increased from a high level of 155–172 mg L−1d−1 without solubilizers to 399 mg L−1d−1 or to 888 mg L−1 d-1 providing β-pinene or α-pinene as NAPs, i.e., by a factor of 2.3–5.2, exceeding kinetic parameters of other strains described in literature by at least two orders of magnitude. These results clearly demonstrate the high TCS mineralization capacity of this biphasic treatment technologies and its applicability in treatment of highly contaminated TCS point-sources to eliminate recalcitrant contaminants at high levels before getting diluted.

Water-soluble trehalose glycolipids show superior Mincle binding and signaling but impaired phagocytosis and IL-1β production.

The tremendous potential of trehalose glycolipids as vaccine adjuvants has incentivized the study of how the structures of these ligands relate to their Mincle-mediated agonist activities. Despite this, structure-activity work in the field has been largely empirical, and less is known about how Mincle-independent pathways might be affected by different trehalose glycolipids, and whether Mincle binding by itself can serve as a proxy for adjuvanticity. There is also much demand for more water-soluble Mincle ligands. To address this need, we prepared polyethylene glycol modified trehalose glycolipids (PEG-TGLs) with enhanced water solubility and strong murine Mincle (mMincle) binding and signaling. However, only modest cytokine and chemokine responses were observed upon the treatment of GM-CSF treated bone-marrow cells with the PEG-TGLs. Notability, no IL-1β was observed. Using RNA-Seq analysis and a representative PEG-TGL, we determined that the more water-soluble adducts were less able to activate phagocytic pathways, and hence, failed to induce IL-1β production. Taken together, our data suggests that in addition to strong Mincle binding, which is a pre-requisite for Mincle-mediated cellular responses, the physical presentation of trehalose glycolipids in colloidal form is required for inflammasome activation, and hence, a strong inflammatory immune response.

Nanocomplexation is a promising strategy to enhance the solubility and anti-Ichthyophthirius multifiliis activity of magnolol

The protozoan parasite Ichthyophthirius multifiliis infects a wide range of freshwater fish species worldwide and causes Ichthyophthiriasis, also called white spot disease, resulting in mass mortality and great economic losses to global aquaculture. Despite more and more chemotherapeutic drugs being found effective against I. multifiliis, the native poorly solubility for most hydrophobic compounds including natural products caused activity decline and even loss, limiting the further application in the control of aquatic animal diseases. The concern about water-insoluble drugs accentuates the urgent need for solubilization technologies and methods. Here we propose a nano-complexation technology to overcome the concerns of natural products' insolubility. Based on this technology, the magnolol-nanocomplexes were successfully prepared with various mass ratios of magnolol to peptone. The data of particle size and PDI revealed that magnolol particle size was decreased from micro to nanoscale after complexation with peptone, with enhanced water solubility. Images obtained from transmission electron microscopy (TEM) visually displayed the morphological characteristics of magnolol nanoparticles after complexation with peptone and the average particle size was calculated as 63.69–82.84 nm using the ImageJ software. Furthermore, differential scanning calorimetry (DSC) and Fourier Transform Infrared (FTIR) spectroscopy were employed to investigate the complexation mechanism, which suggested that the hydrogen bond interactions were formed between magnolol and peptone that contributed to the stabilization for magnolol-nanocomplex. Lastly, the antiparasitic efficacy of magnolol-nanocomplex was both significantly improved after complexation with peptone against I. multifiliis infection at all life stages in vitro and in vivo. These findings indicated that animal proteins, peptone, could be used as a nanocarrier to improve the water solubility and antiparasitic effects of natural product magnolol. Altogether, this study first proposes a promising strategy to enhance the solubility and activity of hydrophobic drugs against aquatic animal diseases, which might be hoping to be further applicate in the aquaculture industry.

Selection of bionic Co-former improves the dissolution of Neohesperidin via Co-amorphous solid dispersion with Naringin

The co-amorphous solid dispersion (c-ASD) is a useful method to enhance water solubility of poorly soluble drugs. The objective of this study was to improve the dissolution of Neohesperidin (NE) via binary c-ASD which, to the best of our knowledge, has not yet been reported. Since NE and Naringin (NA) co-exist abundantly in Chinese herbal medicine Fructus Aurantii Immaturus, it was hypothesised that NA served as a co-former of NE-NA c-ASD to improve the dissolution profile of NE. Hence, NA was selected to prepare c-ASD with NE at a weight ratio of 4:10, 10:10, 10:4 by lyophilisation. They were characterised according to thermal properties, molecular interactions, dissolution properties and physical stability. We found that the 10:10 ratio was the most potent in enhancing the dissolution behaviour of NE; whereby NE and NA are highly synchronous in pair-wise solvation process. A molecular mixture was achieved through the intermolecular H-bond and pi-pi stacking force formed between NE and NA and was stable for 7 -months. We concluded that the NE-NA co-amorphous binary system is a promising strategy to improve the dissolution behaviour and stabilise the amorphous state of NE. Bionic co-former selection may be an innovative and effective way to accurately determine the appropriate co-former of poorly water soluble substances.

Enhanced Water Solubility and Anti-Tumor Activity of Oleanolic Acid through Chemical Structure Modification.

Cancer has been a major health problem in the world in the past decades. It is urgent to develop new, effective and safe drugs for the treatment of cancer. There are many pentacyclic triterpenoids with positive anti-tumor activity and safety in nature. Oleanolic acid (OA), as one of the pentacyclic triterpenoids, also has broad biological activities including liver protection, anti-inflammatory, hypoglycemic, antiviral and anti-tumor. Therefore, to investigate its anti-tumor activity and mechanism, many OA derivatives have been developed. Some derivatives are less toxic to normal hepatocytes, which may be due to the strong liver protection ability of OA. However, the poor water solubility of OA is one of the main reasons for the weak anti-tumor activity. It is reported that some OA derivatives could enhance solubility by chemically linking some hydrophilic groups to improve anti-tumor activity. This review not only summarizes the highly water-soluble OA derivatives that can improve anti-tumor activity reported in recent years, but also introduces their possible anti-tumor mechanisms.

Shifting the Triangle-Square Equilibrium of Self-Assembled Metallocycles by Guest Binding with Enhanced Photosensitization.

Shifting a triangle-square equilibrium in one direction is an important problem in supramolecular self-assembly. Reaction of a benzothiadiazole-based diimidazole donor with a cis-Pt(II) acceptor yielded an equilibrium mixture of a triangle ([C18H24N10O6S1Pt1]3≡ PtMCT) and a square ([C18H24N10O6S1Pt1]4≡ PtMCS). We report here the shifting of such equilibrium toward a triangle using a guest (pyrene aldehyde, G1). While both benzothiadiazole and pyrene aldehyde can form reactive oxygen species (ROS) in organic solvents, their therapeutic use in water is restricted due to aqueous insolubility. The enhanced water solubility of the benzothiadiazole unit and G1 by macrocycle formation and host-guest complexation, respectively, enabled enhanced ROS generation by the host-guest complex (G1' ⊂ PtMCT) in water (G1' = hydrated form of G1). The guest-encapsulated metallacycle (G1' ⊂ PtMCT) has shown synergistic antibacterial activity compared to the mixture of macrocycles upon white-light irradiation due to enhanced ROS generation. The mechanism for such enhanced activity was established by measuring the oxidative stress and relative internalization of PtMCs and G1' ⊂ PtMCT.

A Novel Dextran-Based Dual Drug Conjugate Targeted Tumors with High Biodistribution Ratio of Tumors to Normal Tissues.

PurposeMost chemotherapeutic agents possess poor water solubility and show more significant accumulations in normal tissues than in tumor tissues, resulting in serious side effects. To this end, a novel dextran-based dual drug delivery system with high biodistribution ratio of tumors to normal tissues was developed.MethodsA bi-functionalized dextran was developed, and several negatively charged dextran-based dual conjugates containing two different types of drugs, docetaxel and docosahexaenoic acid (DTX and DHA, respectively) were synthesized. The structures of these conjugates were characterized using nuclear magnetic resonance and liquid chromatography/mass spectrometry (1H-NMR and LC/MS, respectively) analysis. Cell growth inhibition, apoptosis, cell cycle distribution, and cellular uptake were measured in vitro. Drug biodistribution and pharmacokinetics were investigated in mice bearing 4T1 tumors using LC/MS analysis. Drug biodistribution was also explored by in vivo imaging. The effects of these conjugates on tumor growth were evaluated in three mice models.ResultsThe dextran–docosahexaenoic acid (DHA)– docetaxel (DTX) conjugates caused a significant enhancement of DTX water solubility and improvement in pharmacokinetic characteristics. The optimized dextran–DHA–DTX conjugate A treatment produced a 2.1- to 15.5-fold increase in intra-tumoral DTX amounts for up to 96 h compared to parent DTX treatment. Meanwhile, the concentrations of DTX released from conjugate A in normal tissues were much lower than those of the parent DTX. This study demonstrated that DHA could lead to an improvement in the efficacy of the conjugates and that the conjugate with the shortest linker displayed more activity than conjugates with longer linkers. Moreover, conjugate A completely eradicated all MCF-7 xenograft tumors without causing any obvious side effects and totally outperformed both the conventional DTX formulation and Abraxane in mice.ConclusionThese dextran-based dual drug conjugates may represent an innovative tumor targeting drug delivery system that can selectively deliver anticancer agents to tumors.

Antifungal Activity of Angelica gigas with Enhanced Water Solubility of Decursin and Decursinol Angelate by Hot-Melt Extrusion Technology against Candida albicans

Hot-melt extrusion (HME) has been an alternative technique to improve the solubility and bioavailability of active molecules with low water solubility. In this study, HME-Angelica gigas Nakai (AGN) was prepared to increase the aqueous solubility of decursin (D) and decursinol angelate (DA), the active ingredients of AGN. Compared with unprocessed AGN, HME-AGN showed enhanced water solubility of D and DA. The HME-AGN exhibited improved antioxidant activity by the DPPH radical scavenging method. The antifungal activity was confirmed against Candida albicans (C. albicans). There was a decrease in CFU in the plate treated with the HME-AGN extract compared with the plate treated with the AGN extract, and F2 showed the highest antifungal activity.

Demonstrating Tumor Vascular Disrupting Activity of the Small-Molecule Dihydronaphthalene Tubulin-Binding Agent OXi6196 as a Potential Therapeutic for Cancer Treatment.

Simple SummaryVascular-disrupting agents promise significant therapeutic efficacy against solid tumors by selectively damaging tumor-associated vasculature. Following administration of the phosphate prodrug OXi6197, dynamic bioluminescence imaging revealed dose-responsive vascular shutdown in MDA-MB-231 human breast tumor xenografts and for the first time murine RENCA kidney tumors. Rapid vascular disruption was observed, which continued over 24 h. Histology showed vascular congestion, hemorrhage and necrosis. Twice-weekly doses of OXi6197 caused a significant growth delay in MDA-MB-231 breast tumors and many RENCA kidney tumors growing orthotopically in mice.The vascular disrupting activity of a promising tubulin-binding agent (OXi6196) was demonstrated in mice in MDA-MB-231 human breast tumor xenografts growing orthotopically in mammary fat pad and syngeneic RENCA kidney tumors growing orthotopically in the kidney. To enhance water solubility, OXi6196, was derivatized as its corresponding phosphate prodrug salt OXi6197, facilitating effective delivery. OXi6197 is stable in water, but rapidly releases OXi6196 in the presence of alkaline phosphatase. At low nanomolar concentrations OXi6196 caused G2/M cell cycle arrest and apoptosis in MDA-MB-231 breast cancer cells and monolayers of rapidly growing HUVECs underwent concentration-dependent changes in their morphology. Loss of the microtubule structure and increased bundling of filamentous actin into stress fibers followed by cell collapse, rounding and blebbing was observed. OXi6196 (100 nM) disrupted capillary-like endothelial networks pre-established with HUVECs on Matrigel®. When prodrug OXi6197 was administered to mice bearing orthotopic MDA-MB-231-luc tumors, dynamic bioluminescence imaging (BLI) revealed dose-dependent vascular shutdown with >80% signal loss within 2 h at doses ≥30 mg/kg and >90% shutdown after 6 h for doses ≥35 mg/kg, which remained depressed by at least 70% after 24 h. Twice weekly treatment with prodrug OXi6197 (20 mg/kg) caused a significant tumor growth delay, but no overall survival benefit. Similar efficacy was observed for the first time in orthotopic RENCA-luc tumors, which showed massive hemorrhage and necrosis after 24 h. Twice weekly dosing with prodrug OXi6197 (35 mg/kg) caused tumor growth delay in most orthotopic RENCA tumors. Immunohistochemistry revealed extensive necrosis, though with surviving peripheral tissues. These results demonstrate effective vascular disruption at doses comparable to the most effective vascular-disrupting agents (VDAs) suggesting opportunities for further development.