- Terpolymer Micelles for the Delivery of Arsenic to Breast Cancer Cells: The Effect of Chain Sequence on Polymeric Micellar Characteristics and Cancer Cell Uptake. [Journal Article]
- MPMol Pharm 2016 Nov 4
- In this study, we developed a micellar platform composed of terpolymers for the encapsulation of inorganic arsenite or arsenous acid (As(III)). For this purpose, a series of terpolymers composed of p...
In this study, we developed a micellar platform composed of terpolymers for the encapsulation of inorganic arsenite or arsenous acid (As(III)). For this purpose, a series of terpolymers composed of poly(ethylene oxide) (PEO, block A), poly(α-carboxylate-ε-carprolactone) (PCCL, block B), and poly(ε-caprolactone) (PCL, block C) with either a blocked, i.e., BC or CB, or random, i.e., (B/C)ran block copolymer sequence in the polyester segment was synthesized. The COOH groups on block B were further modified with mercaptohexylamine for As(III) encapsulation. We then investigated how sequence of terpolymers can affect the stability and surface charge of micelles as well as the cellular uptake of their cargo, i.e., As(III), by MDA-MB-435 cancer cells. (1)H NMR spectroscopy in D2O and CDCl3 was also used to study the structure of different terpolymer micelles. Our results showed micelles with ABC sequence to have better stability over those of ACB and A(B/C)ran as reflected by a lower critical micellar concentration. The As(III)-loaded ABC micelles were less negatively charged on the surface than the other two types of terpolymer micelles. In line with this observation, ABC micelles showed a substantially enhanced uptake of As(III) by MDA-MB-435 cancer cells. Stability and surface charge are key parameters that can influence the performance of polymeric micelles as nanodrug carriers. Based on these results, we suggest ABC micelles to have improved characteristics for As(III) delivery compared to ACB and A(B/C)ran micelles.
- Preparation of reductant-responsive N-maleoyl-functional chitosan/poly(vinyl alcohol) nanofibers for drug delivery. [Journal Article]
- MPMol Pharm 2016 Nov 3
- Chitosan/polyvinyl alcohol (CS/PVA) hybrid nanofibers via electrospinning have been extensively used as wound dressing materials. However, there are still several drawbacks associated with their proc...
Chitosan/polyvinyl alcohol (CS/PVA) hybrid nanofibers via electrospinning have been extensively used as wound dressing materials. However, there are still several drawbacks associated with their processing procedures and material properties, including the necessity of using acid solutions as spinning solvents, the need of employing highly toxic cross-linkers, and the lack of stimuli-responsive functions. In this context, water soluble N-maleoyl functional chitosan (MCS) was successfully synthesized and well characterized. Using neutral de-ionized water as a spinning solvent, MCS/PVA nanofibers were prepared via electrospinning under the optimal operating conditions. Instead of using conventional cross-linking methodologies, the MCS/PVA nanofibers were further cross-linked by UV-irradiation with allyl disulfide as a cross-linker. The resulting disulfide cross-linked MCS/PVA (ss-MCS/PVA) nanofibers have demonstrated great water stability, high water regain ability, insignificant cytotoxicity and reductant-responsive functions. With a successful loading of an antibiotic Tetracycline hydrochloride (TCH) and those favorable material features, ss-MCS/PVA nanofibers are capable of being exploited as a potential wound dressing to promote the healing of various types of wounds.
- Development of a physiologically relevant population pharmacokinetic in vitro-in vivo correlation approach for designing extended-release oral dosage formulation. [Journal Article]
- MPMol Pharm 2016 Nov 3
- Establishing a level A in vitro-in vivo correlation (IVIVC) for a drug with complex absorption kinetics is challenging. The objective of the present study was to develop an IVIVC approach based on po...
Establishing a level A in vitro-in vivo correlation (IVIVC) for a drug with complex absorption kinetics is challenging. The objective of the present study was to develop an IVIVC approach based on population pharmacokinetic (POP-PK) modeling that incorporated physiologically relevant absorption kinetics. To prepare three extended release (ER) tablets of loxoprofen, three types of hydroxypropyl methylcellulose (HPMC 100, 4000, and 15000 cps) were used as drug release modifiers, while lactose and magnesium stearate were used as the diluent and lubricant, respectively. An in vitro dissolution test in various pH conditions showed that loxoprofen dissolution was faster at higher pH. The in vivo pharmacokinetics of loxoprofen was assessed following oral administration of the different loxoprofen formulations to beagle dogs (n=22 in total). Secondary peaks or shoulders were observed in many of the individual plasma concentration vs. time profiles after ER tablet administration, which may result from secondary absorption in the intestine due to a dissolution rate increase under intestinal pH compared to that observed at stomach pH. In addition, in vivo oral bioavailability was found to decrease with prolonged drug dissolution, indicating site-specific absorption. Based on the in vitro dissolution and in vivo absorption data, a POP-PK IVIVC model was developed using S-ADPAT software. pH-dependent biphasic dissolution kinetics, described using modified Michaelis-Menten kinetics with varying Vmax, and site-specific absorption, modeled using a changeable absorbed fraction parameter, were applied to the POP-PK IVIVC model. To experimentally determine the biphasic dissolution profiles of the ER tablets, another in vitro dissolution test was conducted by switching dissolution medium pH based on an in vivo estimate of gastric emptying time. The model estimated, using linear regression, that in vivo initial maximum dissolution rate (Vmax(0)in vivo) was highly correlated (r2> 0.998) with in vitro (Vmax(0)in vitro), indicating that in vivo dissolution profiles obtained from POP-PK modeling could be converted to in vitro dissolution profiles and vice versa. Monte Carlo simulations were performed for model validation, and prediction errors for Cmax and AUC were all within the acceptable range (90 to 110%) according to the FDA guidelines. The developed model was successfully applied for the prediction of in vivo pharmacokinetics of a loxoprofen double-layered tablet using the in vitro dissolution profile. In conclusion, a level A IVIVC approach was developed and validated using population modeling that accounted for pH-dependent dissolution and site-specific absorption. Excellent correlations were observed between in vitro and in vivo dissolution profiles. This new approach holds great promise for the establishment of IVIVCs for drug and formulation development where absorption kinetics strongly depend on complex physiologically absorption processes.
- Predicting passive permeability of drug-like molecules from chemical structure: where are we? [Journal Article]
- MPMol Pharm 2016 Nov 2
- Intestinal absorption in human is routinely predicted in drug discovery using in vitro assays such as permeability in the MDCK cell line. In silico models trained on these data are used in drug disco...
Intestinal absorption in human is routinely predicted in drug discovery using in vitro assays such as permeability in the MDCK cell line. In silico models trained on these data are used in drug discovery efforts to prioritize novel chemical targets for synthesis, however their proprietary nature and the limited validation available, which is usually restricted to predicting in vitro permeability, is a barrier to wide-spread adoption. Due to the categorical nature of the in vitro permeability assay, intrinsic assay variability, and the challenges often encountered when translating in vitro data to an in vivo drug property, validation based solely on in vitro data might not be a good characterization of the usefulness of the in silico tool. In this work we analyze the performance of three different in silico models in predicting the in vitro and in vivo permeability of 300 marketed drugs and 86 discovery compounds. The models differ in their approach (mechanistic vs QSAR) and the degree of complexity; one of them is a linear equation based on seven simple physico-chemical descriptors and is presented for the first time in this work. Results show that in silico models can be successfully used to complement the discovery toolbox for characterizing in vivo intestinal permeability, defined using fraction of dose absorbed in human (Fa) and human jejunal permeability (Peff). While the in vitro permeability models outperformed the in silico approach at predicting each of the in vivo endpoints explored, the gap in predictivity between the in vitro and the in vivo data was generally comparable to the gap between in silico and in vitro data. The in vitro and in silico approaches shared many of the same outliers, which can often be explained by the route of drug absorption (paracellular vs transcellular, active vs passive). Data suggest that the discovery process can greatly benefit from an early adoption of in silico models for predicting permeability as well as from a careful analysis of the in silico to in vivo disconnects.
- Single and Combinational siRNA Therapy of Cancer Cells: Probing Changes in Targeted and non-Targeted Mediators after siRNA Treatment. [Journal Article]
- MPMol Pharm 2016 Nov 1
- Cancer cells are known to be heterogeneous and plastic, which imparts innate and acquired abilities to resist molecular targeting by short interfering RNA (siRNA). Not all cancer cells in a populatio...
Cancer cells are known to be heterogeneous and plastic, which imparts innate and acquired abilities to resist molecular targeting by short interfering RNA (siRNA). Not all cancer cells in a population would show a similar responsiveness to targeting of genes critical for their survival and, even the responders could quickly transform and switch to alternative mechanism(s) for their survival. This study was designed to look at this phenomenon by analyzing the effect of siRNA silencing of selected protein mRNAs involved in cell survival and proliferation on other protein mRNAs that could contribute to cell survival. We compared the gene expression profile of the initial population after siRNA silencing to the sub-population that survived the siRNA silencing, to identify potential over-expressions that might explain the cell survival. Our studies show that silencing well-selected protein mRNAs simultaneously could offer advantages compared to individual siRNA silencing due to an additional impact on the expression level of certain protein mRNAs. We also demonstrate that over-expression of certain protein mRNAs could explain the innate un-responsiveness of a sub-population of cells. These observations could be a stepping stone for further investigation of the possibility of significant synergistic effect for this combinational RNA interference strategy.
- Salt Disproportionation in the Solid State: Role of Solubility and Counterion Volatility. [Journal Article]
- MPMol Pharm 2016 Nov 2
- Disproportionation propensity of salts (HCl, HBr, heminapadisylate) and adipic acid cocrystal of corticotropin releasing hormone receptor-1 antagonist was studied using model free kinetics. Using the...
Disproportionation propensity of salts (HCl, HBr, heminapadisylate) and adipic acid cocrystal 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 cocrystal 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 cocrystal 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 cocrystal or heminapadisylate 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 was quite different. The HCl salt highlighted the important role that volatility of the counterion plays in the physical stability of the formulations. Solution state stability (i.e., in dissolution medium) of salts and cocrystal was also assessed and compared with solid state stability, by determining their solubility at different pH's, and intrinsic dissolution rate.
- Tenofovir Containing Thiolated Chitosan Core/Shell Nanofibers: In Vitro and in Vivo Evaluations. [Journal Article]
- MPMol Pharm 2016 Nov 1
- It is hypothesized that thiolated chitosan (TCS) core/shell nanofibers (NFs) can enhance the drug loading of tenofovir, a model low molecular weight and highly water-soluble drug molecule, and improv...
It is hypothesized that thiolated chitosan (TCS) core/shell nanofibers (NFs) can enhance the drug loading of tenofovir, a model low molecular weight and highly water-soluble drug molecule, and improve its mucoadhesivity and in vivo safety. To test this hypothesis, poly(ethylene oxide) (PEO) core with TCS and polylactic acid (PLA) shell NFs are fabricated by a coaxial electrospinning technique. The morphology, drug loading, drug release profiles, cytotoxicity and mucoadhesion of the NFs are analyzed using scanning and transmission electron microscopies, liquid chromatography, cytotoxicity assays on VK2/E6E7 and End1/E6E7 cell lines and Lactobacilli crispatus, fluorescence imaging and periodic acid colorimetric method, respectively. In vivo safety studies are performed in C57BL/6 mice followed by H&E and immunohistochemical (CD45) staining analysis of genital tract. The mean diameters of PEO, PEO/TCS, and PEO/TCS-PLA NFs are 118.56, 9.95, and 99.53 nm, respectively. The NFs exhibit smooth surface. The drug loading (13%-25%, w/w) increased by 10-fold compared to a nanoparticle formulation due to the application of the electrospinning technique. The NFs are noncytotoxic at the concentration of 1 mg/mL. The PEO/TCS-PLA core/shell NFs mostly exhibit a release kinetic following Weibull model (r(2) = 0.9914), indicating the drug release from a matrix system. The core/shell NFs are 40-60-fold more bioadhesive than the pure PEO based NFs. The NFs are nontoxic and noninflammatory in vivo after daily treatment for up to 7 days. Owing to their enhanced drug loading and preliminary safety profile, the TCS core/shell NFs are promising candidates for the topical delivery of HIV/AIDS microbicides such as tenofovir.
- Biodistribution of Self-Assembling Polymer-Gemcitabine Conjugate after Systemic Administration into Orthotopic Pancreatic Tumor bearing Mice. [Journal Article]
- MPMol Pharm 2016 Oct 31
- Therapeutic efficacy of gemcitabine (GEM) is severely limited due to its rapid metabolism by enzymatic deamination in vivo. We recently determined its therapeutic efficacy before (F-GEM) and after co...
Therapeutic efficacy of gemcitabine (GEM) is severely limited due to its rapid metabolism by enzymatic deamination in vivo. We recently determined its therapeutic efficacy before (F-GEM) and after conjugation to poly(ethylene glycol)-block-poly(2-methyl-2-carboxyl-propylene carbonate) (mPEG-b-PCC-g-GEM-g-DC, abbreviated as P-GEM) in subcutaneous and orthotopic pancreatic tumor bearing mice. In this study, pharmacokinetic (PK) parameters and biodistribution profiles of F-GEM and P-GEM were determined after intravenous injection into orthotopic pancreatic tumor bearing NSG mice. To assess the short-term toxicity, the levels of hematological, hepatic and renal injury markers were measured after 24 h post-administration into these mice. P-GEM was distributed to all the major organs, with higher accumulation in the liver, spleen and tumor compared to F-GEM. Area under the curve (AUC), elimination half-life (t1/2) and mean residence time (MRT) of P-GEM treated group were significantly higher compared to those of F-GEM treated group: 246,425±1605 vs 83,591±1844 ng/mL×h as AUC, 5.77 ± 2.02 vs 1.99 ± 0.09 h as t1/2 and 4.45 ± 0.15 vs. 1.12 ± 0.13 h as MRT. Further, P-GEM exhibited negligible systemic toxicity as evidenced by almost similar alanine aminotransferase (ALT) and aspartate aminotransferase (AST) values for both P-GEM and F-GEM. These results suggest that P-GEM protects GEM from degradation and provides sustained drug release, resulting in enhanced GEM delivery to the tumor by more than 2.5-fold compared to F-GEM. Hence, P-GEM is a promising gemcitabine conjugated polymeric micelles for treating pancreatic cancer.
- CD44 Receptor Targeting and Endosomal pH-Sensitive Dual Functional Hyaluronic Acid Micelles for Intracellular Paclitaxel Delivery. [Journal Article]
- MPMol Pharm 2016 Oct 31
- A novel CD44 receptor targeting and endosome pH-sensitive dual functional hyaluronic acid-deoxycholic acid-histidine (HA-DOCA-His) micellar system was designed for intracellular paclitaxel (PTX) deli...
A novel CD44 receptor targeting and endosome pH-sensitive dual functional hyaluronic acid-deoxycholic acid-histidine (HA-DOCA-His) micellar system was designed for intracellular paclitaxel (PTX) delivery. The HA-DOCA-His micelles exhibited desirable endosome pH (5.0-6.0)-induced aggregation and deformation behavior verified by size distribution, critical micellar concentration, and zeta potential changes. The HA-DOCA-His micelles presented excellent encapsulation efficiency and loading capacity of 90.0% and 18.9% for PTX, respectively. The PTX release from HA-DOCA-His micelles was pH-dependent, with more rapid PTX release at pH 6.0 and 5.0 than those at pH 7.4 and 6.5. The cellular uptake performance of HA-DOCA-His micelles was enhanced comparing with pH-insensitive HA-DOCA micelles by qualitative and quantitative measurements. HA-DOCA-His micelles could be taken up via CD44-receptor mediated endocytosis, transported into endosomes, and triggered drug release to cytoplasm. In vitro cytotoxicity study exhibited PTX-loaded HA-DOCA-His micelles were more active in tumor cell growth inhibition in MCF-7 cells at pH 5.8 than those at pH 6.8 and pH 7.4. A superior antitumor efficacy was demonstrated with HA-DOCA-His micelles in a MCF-7 breast tumor model. These indicated that the dual functional HA-DOCA-His micelles combined targeted intracellular delivery and endosomal release strategies could be developed as a promising nanocarrier for anticancer efficacy improvement of PTX.
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- Self-Targeted Polysaccharide Prodrug Suppresses Orthotopic Hepatoma. [Journal Article]
- MPMol Pharm 2016 Oct 31
- Self-targetability is an emerging targeting strategy for polymer nanocarriers with facile preparation and high targeting efficiency. An acid-sensitive dextran-doxorubicin prodrug (Dex-g-DOX) has been...
Self-targetability is an emerging targeting strategy for polymer nanocarriers with facile preparation and high targeting efficiency. An acid-sensitive dextran-doxorubicin prodrug (Dex-g-DOX) has been synthesized and used as a self-targeted drug delivery system for the treatment of orthotopic hepatoma. The polysaccharide prodrug exhibits ultraselective accumulation in cancerous liver tissue, acid-sensitive DOX release within cells, and high antitumor efficacy in vitro and in vivo. Therefore, Dex-g-DOX demonstrates great potential for chemotherapy of orthotopic hepatoma.