- A Redox-Sensitive and RAGE-Targeting Nanocarrier for Hepatocellular Carcinoma Therapy. [Journal Article]
- MPMol Pharm 2016 Oct 21
- Hepatocellular carcinoma (HCC) is an aggressive malignancy and the second leading cause of cancer death worldwide. Most current therapeutic agents lack the tumor-targeting efficiency and result in a ...
Hepatocellular carcinoma (HCC) is an aggressive malignancy and the second leading cause of cancer death worldwide. Most current therapeutic agents lack the tumor-targeting efficiency and result in a nonselective biodistribution in the body. In our previous study, we identified a peptide Ala-Pro-Asp-Thr-Lys-Thr-Gln (APDTKTQ) that can selectively bind to the receptor of advanced glycation end-products (RAGE), an immunoglobulin superfamily cell surface molecule overexpressed during HCC malignant progression. Here, we report the design of a mixed micelles system modified with this peptide to target HCC cells. Specifically, we modified Pluronic F68 (F68) with APDTKTQ (F68-APDTKTQ), and we conjugated d-α-tocopheryl polyethylene glycol succinate (TPGS) with poly(lactic-co-glycolic acid) (PLGA) by a disulfide linker (TPGS-S-S-PLGA). We mixed TPGS-S-S-PLGA and F68-APDTKTQ (TSP/FP) to form a micelle, followed by the loading of oridonin (ORI). The prepared micelles showed a homogeneously spherical shape without aggregation, triggered an increased cellular uptake, and induced apoptosis in more cells than did the free ORI. Taken together, these results demonstrate the potential of this APDTKTQ-modified ORI-loaded TSP/FP mixed micelle system as a promising strategy for HCC-targeting therapy.
- Salt Disproportionation in the Solid-State: role of solubility and counter-ion volatility. [Journal Article]
- MPMol Pharm 2016 Oct 21
- Disproportionation propensity of salts (HCl, HBr, hemi-napadisylate) and adipic acid co-crystal of corticotropin releasing hormone receptor-1 antagonist, was studied using model free kinetics. Using ...
Disproportionation propensity of salts (HCl, HBr, hemi-napadisylate) and adipic acid co-crystal of corticotropin releasing hormone receptor-1 antagonist, was studied using model free kinetics. Using thermogravimetic weight loss profile or heat flow curves from differential scanning calorimetry, an activation energy plot for salts and co-crystal was generated based on model free kinetics. This activation energy of disproportionation provided qualitative information about the solid state salt stability. To ensure the stability throughout the shelf life, "prototype" formulations of salts and co-crystal in tablet form, were stored at 40 °C and several water vapor pressures. Disproportionation kinetics were studied in these prototype tablet formulations using two-dimensional X-ray diffractometry. Formulations containing the adipic acid co-crystal or hemi-napadisylate salt did not show disproportionation of API when stored at 40 °C/ 75% RH, for 300 days. On the other hand, formulations containing HCl or HBr salt disproportionated. Though isostructural, the disproportionation propensity of HBr and HCl salts were quite different. The HCl salt highlighted the important role that volatility of the counter-ion plays in the physical stability of the formulations. Solution state stability (i.e. in dissolution medium) of salts and co-crystal was also assessed and compared with solid state stability, by determining their solubility at different pH's, and intrinsic dissolution rate.
- Nrf2 Knockdown Disrupts the Protective Effect of Curcumin on Alcohol-Induced Hepatocyte Necroptosis. [Journal Article]
- MPMol Pharm 2016 Oct 20
- It has emerged that hepatocyte necroptosis plays a critical role in chronic alcoholic liver disease (ALD). Our previous study has identified that the beneficial therapeutic effect of curcumin on alco...
It has emerged that hepatocyte necroptosis plays a critical role in chronic alcoholic liver disease (ALD). Our previous study has identified that the beneficial therapeutic effect of curcumin on alcohol-caused liver injury might be attributed to activation of nuclear factor (erythroid-derived 2)-like 2 (Nrf2), whereas the role of curcumin in regulating necroptosis and the underlying mechanism remain to be determined. We firstly found that chronic alcohol consumption triggered obvious hepatocyte necroptosis, leading to increased expression of receptor-interacting protein 1, receptor-interacting protein 3, high-mobility group box 1, and phosphorylated mixed lineage kinase domain-like in murine livers. Curcumin dose-dependently ameliorated hepatocyte necroptosis and alleviated alcohol-caused decrease in hepatic Nrf2 expression in alcoholic mice. Then Nrf2 shRNA lentivirus was introduced to generate Nrf2-knockdown mice. Our results indicated that Nrf2 knockdown aggravated the effects of alcohol on liver injury and necroptosis and even abrogated the inhibitory effect of curcumin on necroptosis. Further, activated Nrf2 by curcumin inhibited p53 expression in both livers and cultured hepatocytes under alcohol stimulation. The next in vitro experiments, similar to in vivo ones, revealed that although Nrf2 knockdown abolished the suppression of curcumin on necroptosis of hepatocytes exposed to ethanol, p53 siRNA could clearly rescued the relative effect of curcumin. In summary, for the first time, we concluded that curcumin attenuated alcohol-induced hepatocyte necroptosis in a Nrf2/p53-dependent mechanism. These findings make curcumin an excellent candidate for ALD treatment and advance the understanding of ALD mechanisms associated with hepatocyte necroptosis.
- Bioimaging of Intravenous Polymeric Micelles Based on Discrimination of Integral Particles Using an Environment-Responsive Probe. [Journal Article]
- MPMol Pharm 2016 Oct 19
- One of the biggest challenges in bioimaging of nanoparticles is how to identify integral particles from bulk signals of probes. Signals of free probes are always mistakenly counted into total signals...
One of the biggest challenges in bioimaging of nanoparticles is how to identify integral particles from bulk signals of probes. Signals of free probes are always mistakenly counted into total signals of particles. In this study, in vivo fate of intravenous polymeric micelles (PMs, mPEG2.5k-PDLLA2.5k) was explored using a highly sensitive near-infrared environment-responsive fluorescent probe. This probe is able to emit fluorescence when embedded in nanocarriers but quench spontaneously and absolutely upon release into water, based on the aggregation-caused quenching effect, which means that the interference generated by free probes can be completely diminished. Analysis of blood-borne fluorescence reveals rapid clearance of PMs from blood following a tri-compartmental pharmacokinetic model. Live imaging shows pervasive distribution of PMs throughout the body, and a tendency of accumulation to extremities with fluorescence density 3-5 times higher than the trunk. Ex vivo examination reveals that most PMs are found in vital organs following an order of lung > liver > spleen > heart > kidney in concentration, but an order of liver > lung > spleen > heart ≈ kidney in total amount. The distribution to other organs and tissues is even lower, and to brain negligible. It is concluded that the biodistribution of PMs to vital organs and extremities warns of potential toxicity and can be translated to explain the toxicity of its commercial counterpart with similar chain lengths.
- Permeability profiles and intestinal toxicity assessment of hydrochlorothiazide and its inclusion complex with β-cyclodextrin loaded into chitosan nanoparticles. [Journal Article]
- MPMol Pharm 2016 Oct 18
- Here, a novel drug delivery system was developed for the hydrochlorothiazide (HCT):β-cyclodextrin (βCD) inclusion complex loaded into chitosan (CS) nanoparticles (NPs)[CS/HCT:βCD NPs]. It was found, ...
Here, a novel drug delivery system was developed for the hydrochlorothiazide (HCT):β-cyclodextrin (βCD) inclusion complex loaded into chitosan (CS) nanoparticles (NPs)[CS/HCT:βCD NPs]. It was found, for the first time, that exposure of the intestinal mucosa to free HCT resulted in an increased and abnormal intestinal permeability associated with several injuries to the intestinal epithelium. Nevertheless, the HCT delivery system obtained ameliorated the damage of the intestinal epithelium induced by HCT. Furthermore, we found that the corresponding permeability profiles for both the free HCT and the CS/HCT:βCD NPs were exponential and lineal, respectively. We propose that the increased intestinal uptake and severe tissue injury of HCT to the intestinal epithelium could be directly related to possible effects of this drug on the ionoregulatory Na+/K+-ATPase channel. Thus, it is postulated that the CS/HCT:βCD NPs may increase the gastrointestinal retention of the HCT, which would provide increased adherence to the mucus barrier that lines the intestinal epithelium, consequently, this would act as a slow HCT release delivery system and maintain lower drug levels of luminal gut in comparison with the administration of free HCT, leading to less severe local injury.
- Dependence of intestinal absorption profile of insulin on carrier morphology composed of β-cyclodextrin-grafted chitosan. [Journal Article]
- MPMol Pharm 2016 Oct 17
- The effect of carrier morphology on the intestinal absorption of insulin was investigated using a morphology-tunable polymeric carrier, β-cyclodextrin-grafted chitosan (BCC). The insulin-BCC complexe...
The effect of carrier morphology on the intestinal absorption of insulin was investigated using a morphology-tunable polymeric carrier, β-cyclodextrin-grafted chitosan (BCC). The insulin-BCC complexes were prepared either in acetate and citrate buffer solutions, followed by dilution with phosphate buffer for the administration. The complex had a molecular network structure in the acetate buffer, whereas nanoparticles formed in the citrate buffer. The network structure in the acetate buffer was maintained even after dilution with a phosphate buffer, but the nanoparticles in the citrate buffer caused aggregation after dilution. Both complexes enhanced the intestinal absorption of insulin. Interestingly, their absorption profiles were totally different; prompt absorption was observed for the complex prepared in acetate buffer, whereas sustained absorption was observed for the complex prepared in citrate buffer. The difference in the absorption patterns was attributed to the difference in the complex morphology. Next, penetratin, a cell-penetrating peptide, was grafted to BCC to find further improvement in the absorption behavior. A simple mixture of penetratin and BCC was also effective. An oral administration study was also conducted in mice to observe effective suppression of glucose levels, which was further enhanced by coadministration of penetratin. Thus, BCC was proven to be an effective carrier for enhancing oral absorption of peptide drugs and it is suggested that the carrier morphology is also an important factor that influences the absorption profile.
- Optimization of curcumin loaded-PEG-PLGA nanoparticles by GSH functionalization. Investigation of the internalization pathway in neuronal cells. [Journal Article]
- MPMol Pharm 2016 Oct 15
- One major challenge in the field of nanotherapeutics is to increase the selective delivery of cargo to targeted cells. Using Poly Lactic-co-Glycolic Acid (PLGA), we recently highlighted the importanc...
One major challenge in the field of nanotherapeutics is to increase the selective delivery of cargo to targeted cells. Using Poly Lactic-co-Glycolic Acid (PLGA), we recently highlighted the importance of polymer composition in the biological fate of the nanodrug delivery systems. However the route of internalisation of polymeric nanoparticles (NPs) is another key component to consider in the elaboration of modern and targeted devices. For that purpose, herein, we effectively synthesized and characterised glutathione- functionalized PLGA-nanoparticles (GSH-NPs) loaded with curcumin (GSH-NPs-Cur), using thiol-maleimide click reaction and determined their physicochemical properties. We found that GSH- functionalization did not affect the drug loading efficiency (DLE), the size, the polydispersity index (PDI), the zeta potential, the release profile and the stability of the formulation. While being non-toxic, the presence of GSH on the surface of the formulations exhibits a better neuroprotective property against acrolein. The neuronal internalisation of GSH-NPs-Cur was higher than with free curcumin. In order to track the intracellular localisation of the formulations, we used a covalently attached Rhodamine (PLGA-Rhod), into our GSH-functionalized matrix. We found that GSH-functionalized matrix could easily be taken up by neuronal cells. Furthermore, we found that GSH-conjugation modifies the route of internalisation enabling them to escape the uptake through macropinocytosis and therefore avoiding the lysosomal degradation. Taken together, GSH-functionalization increases the uptake of formulations and modifies the route of internalization towards a safer pathway. This study shows that the choice of ideal ligand to develop NPs-targeting devices is a crucial step when designing innovative strategy for neuronal cells delivery.
- Synthesis and Monkey-PET Study of (R)- and (S)-18F-Labeled 2-Arylbenzoheterocyclic Derivatives as Amyloid Probes with Distinctive in vivo Kinetics. [Journal Article]
- MPMol Pharm 2016 Oct 15
- This study describes an effective strategy to improve pharmacokinetics of Aβ imaging agents, offering a novel class of (R)- and (S)-18F-labeled 2-arylbenzoheterocyclic derivatives which bear an addit...
This study describes an effective strategy to improve pharmacokinetics of Aβ imaging agents, offering a novel class of (R)- and (S)-18F-labeled 2-arylbenzoheterocyclic derivatives which bear an additional chiral hydroxyl group on the side chain. These ligands displayed binding abilities toward Aβ aggregates with Ki values varying from 3.2 to 195.6 nM. Chirality-related discrepancy was observed in biodistribution and (S)-2-phenylbenzoxazole enantiomers exhibited vastly improved brain clearance with washout ratios higher than 20. Notably, (S)-[18F]28 possessed high binding affinity (Ki = 7.6 nM) and excellent brain kinetics (9.46% ID/g at 2 min, brain2 min/brain60 min = 27.8) that is superior to well-established [18F]AV45. The excellent pharmacokinetics and low nonspecific binding of (S)-[18F]28 were testified by dynamic PET/CT scans in monkey brains. In addition, (S)-[18F]28 clearly labeled Aβ plaques both in vitro and ex vivo. These results suggest (S)-[18F]28 to be a promising PET probe for detecting Aβ plaques with high signal-to-noise ratio.
- One-step self-assembling nanomicelles for pirarubicin delivery to overcome multidrug resistance in breast cancer. [Journal Article]
- MPMol Pharm 2016 Oct 15
- Tumor cells can acquire multidrug resistance (MDR) as a result of drug efflux mediated by P-glycoprotein (P-gp). Here we report a targeted delivery system to carry pirarubicin (THP) to MDR breast can...
Tumor cells can acquire multidrug resistance (MDR) as a result of drug efflux mediated by P-glycoprotein (P-gp). Here we report a targeted delivery system to carry pirarubicin (THP) to MDR breast cancer both in vitro and in vivo. PEG-derivatized vitamin E (PAMV6) amphiphiles loaded with THP were self-assembled in a single step. The PAMV6 micelles showed unimodal size distribution and high drug loading efficiency. Cytotoxicity of PAMV6/THP was higher than that of free THP on MCF-7/ADR cells but comparable to that of THP on MCF-7 cells. PAMV6/THP was able to reverse MDR more than free THP in MCF-7/ADR cells, likely reflecting the remarkably higher intracellular THP concentration in micelle-treated cells and PAMV6-mediated inhibition of P-gp activity. PAMV6/THP micelles were internalized into MCF-7/ADR cells via macropinocytosis and caveolin-mediated endocytosis, further avoiding P-gp-mediated efflux. Mechanistic studies revealed that blank PAMV6 micelles inhibited P-gp activity but not affected P-gp expression, by significantly reducing mitochondrial membrane potential and slightly decreasing intracellular ATP levels. In a nude mouse xenograft model, PAMV6/THP led to much greater THP accumulation in tumors and much slower tumor growth than free THP. At the same time, PAMV6/THP was associated with significantly less severe bone marrow suppression and organ toxicity than free THP. Our results indicate that this PAMV6-based micelle system holds promise for combating MDR in cancer therapy.
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- Oral Delivery of a Nanocrystal Formulation of Schisantherin A with Improved Bioavailability and Brain Delivery for the Treatment of Parkinson's Disease. [Journal Article]
- MPMol Pharm 2016 Oct 14
- Schisantherin A (SA) is a promising anti-Parkinsonism Chinese herbal medicine but with poor water solubility and challenges to be delivered to the brain. We formulated SA as nanocrystals (SA-NC), aim...
Schisantherin A (SA) is a promising anti-Parkinsonism Chinese herbal medicine but with poor water solubility and challenges to be delivered to the brain. We formulated SA as nanocrystals (SA-NC), aiming to improve its solubility, pharmacokinetic profile and thus provide a potential therapeutic agent for the treatment of Parkinson's disease (PD). The rod-shaped SA-NC had a particle size of ~160 nm with 33.3% drug loading, and the nanocrystals exhibited a fast dissolution rate in vitro. The intact drug nanocrystals could be internalized into Madin-Darby canine kidney (MDCK) cells, which were followed by rapid intracellular release, and most of the drug was transported to the basolateral side in its soluble form. Following oral administration of the SA-NC or an SA suspension, the accumulated concentration of the SA-NC in the plasma and brain was considerably higher than that observed for the SA suspension, but the drug targeting efficiency was similar. The SA-NC significantly reversed the 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP)-induced dopaminergic (DA) neuronal loss and locomotion deficiency in zebrafish, as well as the 1-methyl-4-phenylpyridinium ion (MPP+)-induced damage of neuronal cell culture model. Further western blot analysis demonstrated that the stronger neuroprotective effect of SA-NC may be partially mediated by the activation of the protein kinase B (Akt)/glycogen synthase kinase-3β (Gsk3β) pathway. Taken together, these data provide solid evidence that the nanocrystal formulation has the potential to improve the bioavailability and brain concentration of this Biopharmaceutics Classification System (BCS) Class II compound, SA, for the treatment of PD.