Amphiphilic Carrier Research Articles

Comparative clinical outcomes of amphilimus-eluting stents in diabetic versus non-diabetic patients

Abstract Background Patients with diabetes mellitus (DM) are at an increased risk of experiencing adverse events following percutaneous coronary intervention (PCI). The Cre8 EVO stent, which releases a formulation of sirolimus with an amphiphilic carrier from laser-dug wells, has demonstrated clinical benefits specifically in diabetic populations. We aimed to explore the impact of DM on clinical outcomes in a large, real-world registry of all-comer patients treated with Cre8 and Cre8 EVO stents. Methods We did an investigator-initiated, prospective, single-arm observational trial at 28 sites in South Korea. The primary endpoint was a composite of cardiac death, target vessel-related myocardial infarction (MI), and clinically-driven repeat revascularization at 12 months. All-cause mortality was a key secondary endpoint. Results A total of 2,045 patients (66.0 ± 11.5 years of age; 76.2% male) were analyzed. Diabetic patients (n = 774; 37.8%) were more likely to be older, female, and have hypertension, dyslipidemia, or chronic kidney disease. There were 39 cases of primary events, 17 (2.5%) in the DM group and 22 (1.9%) in the non-DM group (hazard ratio, 1.34; 95% confidence interval, 0.74–2.41; log-rank p = 0.33). Overall, the primary endpoint occurred in 2.1% of patients, with a cardiac death rate of 0.4%, a target vessel-related MI rate of 0.3%, and a clinically driven TLR rate of 1.8%. Among the secondary endpoints, the DM group exhibited a significantly higher all-cause mortality rate compared to the non-DM group (2.0% vs. 0.9%; hazard ratio, 2.20; 95% confidence interval, 1.04–4.65). Conclusion In this real-world registry, diabetic patients treated with amphilimus-eluting stents demonstrated excellent safety and effectiveness at 12 months, with a similar occurrence of MACE compared to non-diabetics. These results underscore the potential for amphilimus-eluting stents to become a preferred option for PCI in diabetic patients, prompting further investigation into their long-term benefits and mechanisms of action.

Utilizing phospholipid as an amphiphilic carrier for solid dispersion of ambrisentan: formulation and evaluation

ABSTRACT: The partial water solubility of ambrisentan poses a challenge to its oral administration despite being the second oral endothelin A-receptor antagonist approved in the United States. In this study, we aimed to improve ambrisentan’s solubility and bioavailability using an amphiphilic phospholipid carrier. Phospholipids, with their glycerol-bound, phosphorus-containing amphiphilic nature, are known to prolong drug lifespan by facilitating drug penetration across cell membranes through hydrogen bonds or van der Waals interactions. Moreover, phospholipid compounds have been shown to significantly enhance drug solubility, permeability, and bioavailability in various studies. We optimized the ratios of ambrisentan and phospholipid carriers (1:1, 1:3, and 1:5) based on saturation and phase solubility experiments. Solid dispersion was prepared using the solvent evaporation technique. Differential scanning calorimetry (DSC), X-ray diffraction (XRD), and scanning electron microscopy (SEM) analyses confirmed the conversion of ambrisentan from a crystalline to an amorphous form in the solid dispersion. The solubility of ambrisentan in the solid dispersion increased by 13-fold with a 1:5 ratio of ambrisentan to phospholipid carrier. The release profile indicated rapid release of the active substance within the first 15 min, corresponding to the peak phospholipid concentration. Pharmacokinetic studies demonstrated higher bioavailability of the medicine compared to the pure drug. This study suggests that phospholipids can effectively enhance drug solubility and bioavailability in solid dispersion systems.

Liposomes in Medicine: An In-depth Analysis of Preparation Methods and Applications

Liposomes are the targeted drug administration system that offers the potential to improve the medicinal value of drugs by boosting the concentration of medication the duration of time in intended cells, thereby reducing side effects. Liposomes, which are sphere-shaped vesicles built from phospholipids and cholesterol, are being investigated extensively as a means of increasing the bioavailability and delivery of therapeutic medications. Liposomes have both hydrophilic head and hydrophobic tail and exhibit eminent properties, including reduced toxicity, better biocompatibility, easily biodegradable, easy to function and enhanced sustained release of drugs with increased therapeutic efficacy. Liposomes are said to be an ideal drug-carrier system as they enhance the delivery of anticancer drugs at the tumor site. Since liposomes are amphiphilic carriers that may be modified to have various functional characteristics, they are seen as a potential technology for a range of pharmacological and industrial uses. As a potential way to carry drug delivery across cell membranes, liposomes help medications to target specific disease sites. Liposomes are employed to deliver genetic material, such as DNA fragments, to specified cells so they may synthesize certain proteins. Thus, liposomes are investigated as adaptable nano-vesicular vehicles with potential medical applications for medicinal and diagnostic purposes. The future of liposomal formulations is projected to be a multipurpose use of imaging capabilities and medicinal components in a single liposome for diagnostic and actual-time therapy. The most promising approach for topical administration is liposomal drug delivery since it is compatible with living systems and can accommodate simultaneously hydrophobic and hydrophilic medicated substances because of the amphipathic feature of phospholipids.

Preparation and characterization of a novel amphiphilic nanocarrier based on enzymatic polymerization-derived α-1,3-glucan for efficient quercetin encapsulation

Biodegradable nanocarriers based on polysaccharide-derived amphiphilic copolymers are promising candidates to enhance drug solubility and stability. This study aimed to design a novel amphiphilic carrier based on enzymatic polymerization-derived exopolysaccharides, α-1,3-glucan. Glycosyltransferase I from Streptococcus mutans was used to synthesize α-1,3-glucan, and the amphiphilic α-1,3-glucan-graft-poly(ε-caprolactone) (Glucan-g-PCL) copolymer was synthesized via a homogeneous ring-opening polymerization (ROP) in ionic liquid, 1-butyl-3-methylimidazolium chloride. The chemical structures and physical properties of Glucan-g-PCL copolymer were characterized by FT-IR, 1H NMR, XRD, and TGA. The self-assembly behavior of the amphiphilic α-1,3-glucan derivative was investigated by fluorescence probe. The results showed that Glucan-g-PCL exhibited a low critical aggregation concentration (CAC) and formed core-shell structured nanostructure via self-assembly. Quercetin (Qu), a hydrophobic active component, was successfully encapsulated within the Glucan-g-PCL micelle-like nanostructure, showing efficient encapsulation and dispersion in water. Qu/Glucan-g-PCL micelle-like nanostructure (Qu/M) was characterized by DLS, TEM, FT-IR, and XRD. FT-IR and XRD analyses showed that Qu was present in an amorphous state in the formulation and without any chemical reactions during the sample preparation procedures. In addition, the antioxidant properties of the Qu/M were investigated using the 2,2-diphenyl-1-picrylhydrazyl (DPPH) method, and significantly improved antioxidant activity was observed for Qu/M compared to Qu/water. The utilization of Glucan-g-PCL nanostructure encapsulation opens up new possibilities for enhancing and expanding the practical applications of quercetin and α-1,3-glucan.Graphic

Chemical Evolution of Amphiphilic Xenopeptides for Potentiated Cas9 Ribonucleoprotein Delivery.

The introduction of the CRISPR/Cas9 system in the form of Cas9/sgRNA ribonucleoproteins (RNP) is an efficient, straightforward strategy for genome editing, and potent RNP carriers are in high demand. Here, we report a series of artificial peptides based on novel ionizable amino acids that are able to deliver Cas9 RNP into cells very efficiently. Systematic variation of hydrophobic properties revealed a relationship between the xenopeptide logD7.4 and genome editing potency. By correlating the physicochemical properties with biological activity, individual optima were found for different xenopeptide sequence architectures. The optimized amphiphilic carriers enable ∼88% eGFP knockout at an RNP dose of only 1 nM and up to 40% homology-directed repair (HDR) in eGFP/BFP switchable reporter cells by co-delivery with an ssDNA template. Mechanistic studies demonstrated that hydrophobically balanced xenopeptides are more resistant to ionic stress as well as concentration-dependent dissociation and promote endocytosis by both clathrin- and macropinocytosis-mediated pathways. The systematic study develops a versatile and adjustable carrier platform and highlights impactful structure-activity relationships, providing a new chemical guide for the design and optimization of nonviral Cas9 RNP nanocarriers.

Dendrobium officinale polysaccharide-based carrier to enhance photodynamic immunotherapy

Photodynamic therapy (PDT) eradicates tumors via the generation of toxic reactive oxygen species (ROS) by activation of a photosensitizer (PS) with appropriate light. Local PDT toward tumors can trigger the immune response to inhibit distant tumors, but the immune response is usually insufficient. Herein, we used a biocompatible herb polysaccharide with immunomodulatory activity as the carrier of PS to enhance the immune inhibition of tumors after PDT. The Dendrobium officinale polysaccharide (DOP) is modified with hydrophobic cholesterol to serve as an amphiphilic carrier. The DOP itself can promote dendritic cell (DC) maturation. Meanwhile, TPA-3BCP are designed to be cationic aggregation-induced emission PS. The structure of one electron-donor linking to three electron-acceptors endows TPA-3BCP with high efficiency to produce ROS upon light irradiation. And the nanoparticles are designed with positively charged surfaces to capture antigens released after PDT, which can protect the antigens from degradation and improve the antigen-uptake efficiency by DCs. The combination of DOP-induced DC maturation and antigen capture-increased antigen-uptake efficiency by DCs significantly improves the immune response after DOP-based carrier-mediated PDT. Since DOP is extracted from the medicinal and edible Dendrobium officinale, the DOP-based carrier we designed is promising to be developed for enhanced photodynamic immunotherapy in clinic.

Ru-Ni Alloy Nanoparticles Loaded on N-Doped Amphiphilic Mesoporous Hollow Carbon@silica Spheres as Catalyst for the Hydrogenation of α-Pinene to cis-Pinane.

N-doped mesoporous carbon spheres (NHMC@mSiO2 ) encapsulated in silica shells were prepared by emulsion polymerization and domain-limited carbonization using ethylenediamine as the nitrogen source, and Ru-Ni alloy catalysts were prepared for the hydrogenation of α-pinene in the aqueous phase. The internal cavities of this nanomaterial are lipophilic, enhancing mass transfer and enrichment of the reactants, and the hydrophilic silica shell enhances the dispersion of the catalyst in water. N-doping allows more catalytically active metal particles to be anchored to the amphiphilic carrier, enhancing its catalytic activity and stability. In addition, a synergistic effect between Ru and Ni significantly enhances the catalytic activity. The factors influencing the hydrogenation of α-pinene were investigated, and the optimum reaction conditions were determined to be as follows: 100 °C, 1.0 MPa H2 , 3 h. The high stability and recyclability of the Ru-Ni alloy catalyst were demonstrated through cycling experiments.

Glycolipids improve the stability of liposomes: The perspective of bilayer membrane structure

The storage and thermal stability of liposomes, which are amphiphilic carriers, cause very large challenges. However, glycolipid modification may be a potential method to improve the stability of liposomes. In this study, the mechanism by which tilapia head glycolipids improve the stability of liposomes was studied. The head groups of glycolipids and liposomes have a strong interaction (Ka = 633.650 M−1), mainly due to hydrogen bonds, which promote the formation of microstructure domains between glycolipids and liposomes. In addition, glycolipids caused the bilayer structure of liposomes to rearrange, resulting in an increase in the phase transition temperature, tight arrangement of membrane molecules, and increase in membrane thickness (from 2.4 nm to 3.5 nm). Novelty, the formation of microstructure domains helped prevent the liposomes membrane structure from being disrupted during storage and heat. Therefore, glycolipid modification improved the stability of liposomes. This study can provide new insights into the development of high-stability liposomes.

Boron clusters as broadband membrane carriers

The membrane translocation of hydrophilic substances constitutes a challenge for their application as therapeutic compounds and labelling probes1–4. To remedy this, charged amphiphilic molecules have been classically used as carriers3,5. However, such amphiphilic carriers may cause aggregation and non-specific membrane lysis6,7. Here we show that globular dodecaborate clusters, and prominently B12Br122−, can function as anionic inorganic membrane carriers for a broad range of hydrophilic cargo molecules (with molecular mass of 146–4,500 Da). We show that cationic and neutral peptides, amino acids, neurotransmitters, vitamins, antibiotics and drugs can be carried across liposomal membranes. Mechanistic transport studies reveal that the carrier activity is related to the superchaotropic nature of these cluster anions8–12. We demonstrate that B12Br122− affects cytosolic uptake of different small bioactive molecules, including the antineoplastic monomethyl auristatin F, the proteolysis targeting chimera dBET1 and the phalloidin toxin, which has been successfully delivered in living cells for cytoskeleton labelling. We anticipate the broad and distinct delivery spectrum of our superchaotropic carriers to be the starting point of conceptually distinct cell-biological, neurobiological, physiological and pharmaceutical studies.

Antibacterial and antioxidant chitosan nanoparticles improve the preservation effect for donor kidneys in vitro

Hypothermic machine perfusion (HMP) is a preferable measure to preserve kidneys from donation after cardiac death (DCD), while the current standard perfusate is imperfect. We synthesized amphiphilic chitosan, N-alkylated-O-(2-hydroxyl) propyl-3-trimethyl ammonium chitosan chloride (N-alkyl-O-HTCC) as additive in the perfusate, which can self-assembly into micelles in water (size 133 ± 8.48 nm) (ζ-potential 43.9 ± 2.06 mV), with good antibacterial activity for Escherichia coli and Staphylococcus aureus. The derivates can also deliver hydrophobic drug Alda-1 into kidneys through HMP, with drug loading ratio (~42.14%). The delivery system specifically activated mitochondrial acetaldehyde dehydrogenase 2 in kidneys and reduced the ischemic injury. What's more, the addition of N-alkyl-O-HTCC in HMP also activated mitochondria superoxide dismutase 2, presented nice antioxidant activity. These all helped to improve the quality of DCD kidneys. This study provides a feasible amphiphilic carrier for hydrophobic drugs, and provides efficient guidance for perfusate improvement.

Novel ROS-responsive marine biomaterial fucoidan nanocarriers with AIE effect and chemodynamic therapy

Chemodynamic therapy (CDT) has been widely used in the treatment of many kinds of tumors, which can effectively induce tumor cell apoptosis by using produced reactive oxygen species (ROS). In this paper, ROS-sensitive multifunctional marine biomaterial natural polysaccharide nanoparticles were designed. Aggregation-induced emission (AIE) molecules tetraphenylethylene (TPE) labeled and caffeic acid (CA) modified fucoidan (FUC) amphiphilic carrier material (CA-FUC-TK-TPE, CFTT) was fabricated, in which the thioketal bond(TK) was used as the linkage arm between TPE and fucoidan chain, giving the CFTT material ROS sensitivity. In addition, amphiphilic carrier material (FUC-TK-VE, FTVE) composed of thioketal-linked vitamin E and fucoidan was synthesized. The mixed carrier material CFTT and FTVE self-assembled in water to form nanoparticles (CFTT – FTVE@PTX-Fe3+) loaded with PTX and Fe3+. The CDT effect was combined with the chemotherapeutic drug PTX to achieve tumor inhibition. In vitro cell studies have proved that CT/PTX nanoparticles have excellent cell permeability and tumor cytotoxicity. In vivo antitumor experiments confirmed effective antitumor activity and reduced side effects.

Amphilimus- vs. zotarolimus-eluting stents in patients with diabetes mellitus and coronary artery disease: the SUGAR trial.

AimPatients with diabetes mellitus are at high risk of adverse events after percutaneous revascularization, with no differences in outcomes between most contemporary drug-eluting stents. The Cre8 EVO stent releases a formulation of sirolimus with an amphiphilic carrier from laser-dug wells, and has shown clinical benefits in diabetes. We aimed to compare Cre8 EVO stents to Resolute Onyx stents (a contemporary polymer-based zotarolimus-eluting stent) in patients with diabetes.Methods and resultsWe did an investigator-initiated, randomized, controlled, assessor-blinded trial at 23 sites in Spain. Eligible patients had diabetes and required percutaneous coronary intervention. A total of 1175 patients were randomly assigned (1:1) to receive Cre8 EVO or Resolute Onyx stents. The primary endpoint was target-lesion failure, defined as a composite of cardiac death, target-vessel myocardial infarction, and clinically indicated target-lesion revascularization at 1-year follow-up. The trial had a non-inferiority design with a 4% margin for the primary endpoint. A superiority analysis was planned if non-inferiority was confirmed. There were 106 primary events, 42 (7.2%) in the Cre8 EVO group and 64 (10.9%) in the Resolute Onyx group [hazard ratio (HR): 0.65, 95% confidence interval (CI): 0.44–0.96; Pnon-inferiority < 0.001; Psuperiority = 0.030]. Among the secondary endpoints, Cre8 EVO stents had significantly lower rate than Resolute Onyx stents of target-vessel failure (7.5% vs. 11.1%, HR: 0.67, 95% CI: 0.46–0.99; P = 0.042). Probable or definite stent thrombosis and all-cause death were not significantly different between groups.ConclusionIn patients with diabetes, Cre8 EVO stents were non-inferior to Resolute Onyx stents with regard to target-lesion failure composite outcome. An exploratory analysis for superiority at 1 year suggests that the Cre8 EVO stents might be superior to Resolute Onyx stents with regard to the same outcome.Clinical trial registrationClinicalTrials.gov: NCT03321032.

Next Generation Immunotherapies – Emerging Strategies for Immune Modulation against Cancer, Infections, and Beyond

Next Generation Immunotherapies – Emerging Strategies for Immune Modulation against Cancer, Infections, and Beyond

Cyclic RGDfK- and Sulfo-Cy5.5-functionalized mPEG-PCL theranostic nanosystems for hepatocellular carcinoma

Sorafenib (SF) is a standard, clinically-recognized therapy for treating hepatocellular carcinoma (HCC) patients. However, as a multikinase inhibitor, SF causes a systemic side effect. Therefore, there is an urgent need to selectively deliver the optimum dose of SF to the tumor site. The present study aimed to selectively target SF to HCC using a biocompatible drug carrier to increase the therapeutic efficacy, in turn, minimize the adverse effects. To this end, methoxy polyethylene glycol-polycaprolactone (mPEG-PCL) di-block copolymer was selected as an amphiphilic carrier for SF that hydrophobic PCL core can encapsulate SF through self-assembly. Cyclic RGDfK (cRGD) was conjugated to the end of PEG-PCL (cRGD-PEG-PCL) for HCC targeting. Sulfo-Cyanine5.5 (S-Cy5.5) was also incorporated to PEG-PCL (S-Cy5.5-PEG-PCL) for near-infrared fluorescence (NIRF) imaging. The composition, morphology and size distribution of nanoparticles (NPs) were characterized by 1H NMR, transmission electron microscopy (TEM) and dynamic light scattering (DLS), respectively. In addition, the ability of the integrin-mediated targeting of NPs for the selective delivery of SF was systemically investigated with Hep3B cell line and a nude mouse xenograft model. Consequently, it was found that S-Cy5.5-cRGD-PEG-PCL leads to the selective accumulation of SF into the tumor site and improve anticancer activity against HCC.

A novel self-assembled micelles based on stearic acid modified schizophyllan for efficient delivery of paclitaxel

This study was aimed to design a novel amphiphilic carrier based on schizophyllan (SPG) exopolysacharide for drug delivery. Stearic acid (SA) was used for the esterification of SPG with two degrees of substitutions (SA-SPG0.5 and SA-SPG1). The H NMR and FTIR spectroscopies verified the succesfull esterification of SPG. The polymeric micelles easily self-assembled into nanomicelles by ultrasound method. Fluorescence spectroscopy showed that the critical micelle concentrations (CMCs) of SA-SPG0.5 and SA-SPG1 micelles were 0.068 mg/mL and 0.027 mg/mL, respectively. DLS analyses showed that nanomicelles were ranged from 156 to 175 nm. SEM and TEM images showed that nanomicelles were mostly spherical. Paclitaxel (PTX) as a drug model was successfully loaded into SA-SPG nanomicelles with three different drug/polymer weight ratios of 0.1, 0.2 and 0.3. The highest encapsulation efficiency (75 %) was obtained when the PTX/SA-SPG weight ratio was 0.1. The in vitro release of PTX from SA-SPG micelles represented the sustained release profile over 144 h. MTT assay showed that the PTX-loaded SA-SPG nanomicelles had the higher cytotoxicity against MCF-7 cells than free PTX. These results revealed that the synthesized SA-SPG nanomicelles had a promising potential as a new carrier for efficient delivery of hydrophobic drugs.

Effect of Non Ionic Surfactant Concentration on Pterostilbene Niosome Characteristics

Excessive radiation from UV light can cause skin damage to melanoma, especially UVB rays. Chronic effects from exposure of excessive UVB rays can induce gene mutations because the exposure of excessive UVB rays directly causes damage to cellular DNA by producing ROS in the epidermis, dermis, and skin epithelium cells. The use of sunscreen is very necessary to prevent skin damage. Sunscreen containing antioxidants are highly recommended to protect the skin from free radicals UVB rays. Pterostilbene is one of the phenolic compounds, which has the pharmacological activity of antioxidants and UV filters to be one of the recommended compounds for sunscreen components. A good delivery system is needed to be formulated to improve the pharmacological effects of pterostilbene on topical use. Niosomes are non-ionic surfactant vesicles which are one of the amphiphilic carrier systems which can carry hydrophobic active ingredients such as pterostilbene, which are expected to increase the pharmacological effect by increasing the penetration of pterostilbene into the skin. Pterostilbene niosome using non-ionic surfactant (span 80 and span 60) by thin layer hydration method. The research aimed to examine the effect of surfactant concentration (span 80 and span 60) 2, 4, and 6 g toward the characterization of niosome pterostilbene and determine the optimum formulation by particle size. The results of the study showed that the particle size was smaller with an increase in span concentration. Based on these results, the optimum formulation of pterostilbene niosomes is obtained using span 60 with a concentration of 6 g.

Intracellular microtubules as nano-scaffolding template self-assembles with conductive carbon nanotubes for biomedical device.

Cellular bilayer and its membrane have been mimicked and for decades, e.g., to synthesize amphiphilic carriers for controlled release. Here we report using nanosized cellular microtubules (MT) as scaffolding template and amphiphilic cytomembrane fragment to self-assemble with hydrophobic carbon nanotubes (MWNT). The hybrid was then cross-linked to form a conductive scaffold. Polyaniline (PANI) was finally added to the nanocomposite to enhance conductivity. Being an electrode, the obtained cell-based conductive gel raise interfacial surface area, increase the conductivity of the material, and enhance the energy density and power density of the material with a relatively low MWNTs concentration (less than 4.8wt%). The cell-based supercapacitor reaches a specific capacitance of 209.2F/g and thus the fabricated cell-based electrode achieves a conductivity of 38Scm-1. The cellular electric device exhibits great potential for future implantable bio-device and bio-electronic interface applications.

Novel dual ROS-sensitive and CD44 receptor targeting nanomicelles based on oligomeric hyaluronic acid for the efficient therapy of atherosclerosis

Although the clinical usage of drugs administration was raising, the application of nanoparticles encapsulating the hydrophobic drugs with plummy efficiency was very scarce for atherosclerosis (AS) treatment. In this work, a novel dual ROS-sensitive and CD44 receptors targeting amphiphilic carrier material, oligomeric hyaluronic acid-2′-[propane-2,2-diyllbls (thio)] diacetic acl-hydroxymethylferrocene (oHA-TKL-Fc), named HASF, was synthesized and characterized by 1H-NMR spectra. Then, we combined curcumin (Cur) with HASF into nano-micelles (HASF@Cur micelles) by self-assembling method. The resulting HASF@Cur micelles had the average size of 150.8 nm and zeta potential of -35.04 mV to maintain the will-defined spheroidal structure and stability. Importantly, the HASF@Cur micelles had ultrahigh entrapment efficiency (about 51.41 %). Moreover, in vitro release study, Cur release from HASF@Cur micelles was effective in the reactive oxygen species (ROS) condition, and the release rate was interrelated with the concentration of hydrogen peroxide (H2O2). Further, fluorescence imaging showed that the HASF@Cur micelles could more selective access to Raw 264.7 cells than free Cur via oHA-receptor mediated endocytosis. The MTT assay attested the safety of amphiphilic carrier material HASF. Additionally, the results of in vivo Oil red O lipid staining studies showed that the lesion area of the aorta was reduced to 47.3±3.4 % with HASF@Cur micelles, compared with the lesion area of Cur group (63.2±2.7 %), HASF@Cur micelles had the more remarkable effect in reducing lesion area (*P < 0.05). Consequently, the novel dual ROS-sensitive and CD44 receptors targeting drug delivery system would become a promising strategy for atherosclerosis.

Improved solubility, dissolution, and oral bioavailability for atorvastatin-Pluronic® solid dispersions.

Despite the status of atorvastatin (AT) as one of the top selling statins for prophylaxis against primary and secondary cardiovascular diseases, its limited oral absorption limits its full therapeutic benefits. Herein, formulations of AT with amphiphilic carriers (Pluronic F127® and Pluronic F68®) were developed in the form of hard capsules to improve in vitro solubility and dissolution, as well as in vivo oral bioavailability. Prepared formulas were characterized by assessing solubility improvements in the carrier solution and examining the FTIR, DSC, and X-RPD profiles for each formula. The dissolution rate and absorption were also examined after oral administration to New Zealand rabbits. The solubility of AT was improved by the incorporation of either Pluronic F127® or Pluronic F68®. No chemical changes or interactions were detected using X-RPD, DSC, and FTIR characterization. Dissolution profiles revealed an increase in the rate and maximum amount of dissolved AT and showed that up to 93% of the AT content was dissolved within 30min. In vivo absorption of the tested formula (Cmax=1146ng/ml and AUC0-12 to 9,993.4ng.h/ml) was greater than Lipitor® (Cmax=642.3ng/ml and AUC0-12=4427.4ng.h/ml) and AT (Cmax=517.6ng/ml and AUC0- 12=2,473.7ng.h/ml). In conclusion, the formulation of AT with Pluronics® profoundly augments the dissolution behavior and absorption of AT and may serve as a useful approach for improving AT therapeutic and clinical efficacy.

Synergistic anticancer activity by co-delivered nanosized dual therapeutic agents and siRNA in colon cancer

Co-delivery of anticancer drugs and nucleic acid can improve therapeutic potential by modulating apoptosis pathways for the treatment of cancer. We synthesized an amphiphilic carrier to encapsulate two drugs and one siRNA for co-delivering nanoparticles (NPs) to colon cancer cells. NPs carrying multiple drugs along with siRNA is challenging and thus, rare in literature. Therefore, anticancer efficacy and synergy between multiple drugs and siRNA are important to study. Specifically, in this study, NP containing doxorubicin (DOX), aspirin (Asp) and siRNA targeting BCL-2 were prepared and characterized. The NPs demonstrated enhanced anticancer activity against the colon cancer cell line (HCT-116) compared to other cancer cell lines. Multiple drugs (DOX and Asp) and BCL-2 siRNA loaded NPs synergistically induced apoptosis in HCT-116 cells as evident by an increase in G2/M phase cells and decrease in mitochondrial membrane potential (MMP). Chou-Talalay analysis revealed strong synergistic interaction in all doses of NPs. Therefore, multiple drugs and siRNA loaded NPs significantly inhibited HCT-116 cell growth and hence could be a potential candidate for the treatment of colon cancer.