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Molecular pharmaceutics [journal]
- Carboxymethylcellulose-Based and Docetaxel-Loaded Nanoparticles Circumvent P-Glycoprotein-Mediated Multidrug Resistance. [JOURNAL ARTICLE]
- Mol Pharm 2014 Mar 6.
Taxanes are a class of anticancer agents with a broad spectrum and have been widely used to treat a variety of cancer. However, its long-term use has been hampered by accumulating toxicity and development of drug resistance. The most extensively reported mechanism of resistance is the overexpression of P-glycoprotein (Pgp). We have developed a PEGylated carboxymethylcellulose conjugate of docetaxel (Cellax), which condenses into ∼120 nm nanoparticles. Here we demonstrated that Cellax therapy did not upregulate Pgp expression in MDA-MB-231 and EMT-6 breast tumor cells, whereas a significant increase in Pgp expression was measured with native docetaxel (DTX) treatment. Treatment with DTX led to 4-7-fold higher Pgp mRNA expression and 2-fold higher Pgp protein expression compared with Cellax treatment in the in vitro and in vivo system, respectively. Cellax also exhibited significantly increased efficacy compared with that of DTX in a taxane-resistant breast tumor model. Against the highly Pgp expressing EMT6/AR1 cells, Cellax exhibited a 6.5 times lower IC50 compared with that of native DTX, and in the in vivo model, Cellax exhibited 90% tumor growth inhibition, while native DTX had no significant antitumor activity.
- Inhibition of Metastatic Tumor Growth and Metastasis via Targeting Metastatic Breast Cancer by Chlorotoxin-Modified Liposomes. [JOURNAL ARTICLE]
- Mol Pharm 2014 Feb 28.
A liposome system modified with chlorotoxin (ClTx), a scorpion venom peptide previously utilized for targeting brain tumors, was established. Its targeting efficiency and antimetastasis behavior against metastatic breast cancer highly expressed MMP-2, the receptor of ClTx, were investigated. 4T1, a metastatic breast cancer cell line derived from a murine breast tumor, was selected as the cell model. As results, the ClTx-modified liposomes displayed specific binding to 4T1 as determined by flow cytometry and confocal imaging. The cytotoxicity assay revealed that the ClTx modification increased the toxicity compared with nonmodified liposomes. In addition, the modified liposomes also exhibited high in vivo targeting efficiency in the BALB/c mice bearing 4T1 tumors. Importantly, this system inhibited the growth of metastatic tumor and prevented the incidence of lung metastasis in mice bearing 4T1 tumors with only low systemic toxicity. The data obtained from the in vitro and in vivo studies confirmed that the ClTx-modified liposomes increased the drug delivery to metastatic breast cancers. This study proved that the ClTx-modified liposomes had targeting ability to metastatic breast cancer in addition to brain cancer, and displayed an obvious antimetastasis effect. Generally, it may provide a promising strategy for metastatic breast cancer therapy.
- The effects of lipiodol and cyclosporine on the hepatobiliary disposition of doxorubicin in pigs. [JOURNAL ARTICLE]
- Mol Pharm 2014 Feb 21.
Doxorubicin (DOX) emulsified in Lipiodol (LIP) is used as local palliative treatment for unresectable intermediate stage hepatocellular carcinoma. The objective of this study was to examine the poorly understood effects of the main excipient in the drug delivery system, LIP, alone or together with cyclosporin A (CsA), on the in vivo liver disposition of DOX. The advanced, multi-sampling-site, acute pig model was used; samples were collected from three blood vessels (v. portae, v. hepatica and v. femoralis), bile and urine. The four treatment groups (TI-TIV) all received two intravenous 5 min infusions of DOX into an ear vein: at 0 and 200 min. Before the second dose, the pigs received a portal vein infusion of saline (TI), LIP (TII), CsA (TIII) or LIP and CsA (TIV). Concentrations of DOX and its active metabolite doxorubicinol (DOXol) were analyzed using UPLC-MS/MS. A multi-compartment model was developed to describe the distribution of DOX and DOXol in plasma, bile and urine. LIP did not affect the pharmacokinetics of DOX or DOXol. CsA (TIII and TIV) had no effect on the plasma pharmacokinetics of DOX, but a 2-fold increase in exposure to DOXol and a significant decrease in hepatobiliary clearance of DOX and DOXol was observed. Model simulations supported that CsA inhibits 99% of canalicular biliary secretion of both DOX and DOXol, but does not affect the metabolism of DOX to DOXol. In conclusion, LIP did not interact with transporters, enzymes and/or biological membranes important for the hepatobiliary disposition of DOX.
- Synergistic Induction of Apoptosis by Methylseleninic Acid and Cisplatin, The Role of ROS-ERK/AKT-p53 Pathway. [JOURNAL ARTICLE]
- Mol Pharm 2014 Mar 3.
Cisplatin-based therapy is one of the most important chemotherapy treatments for cancers. However, its efficacy is greatly limited by drug resistance and undesirable side effects. Therefore, it is of great importance to develop chemosensitizing agents to cisplatin. In the present study, we demonstrated the strategy to use methylseleninic acid (MeSe) as a synergistic agent of cisplatin and elucidated their action mechanisms. The combination of MeSe and cisplatin exhibited synergistic anticancer efficacy and achieved greater selectivity between cancer cell and normal cell. By inducing intracellular oxidative stress, MeSe potentiated cisplatin-induced DNA damage and led to enhanced p53 phosphorylation, followed by increased activation of both mitochondrial and death receptor pathway. Down-regulation of phosphorylated AKT and ERK also played important roles in the synergistic effects of MeSe and cisplatin. Our results suggested that the strategy to apply MeSe as a synergistic agent to cisplatin could be a highly efficient way to achieve anticancer synergism by targeting the intracellular redox system. MeSe might be a candidate for clinical application as a chemosensitizer to cisplatin-based therapy for cancer treatments, especially for hepatocellular carcinoma.
- Influence of Compression Forces on the Structural Stability of Naproxen/PVP-VA 64 Solid Dispersions. [JOURNAL ARTICLE]
- Mol Pharm 2014 Feb 26.
Solid dispersions are preferentially formulated as solid dosage forms such as tablets and capsules. The structural stability of the solid dispersions has not been adequately explored during post spray drying manufacturing processes. In this paper, we describe the influence of compression forces on solid dispersions made up of naproxen and PVP-VA 64 prepared by spray drying. Compression of the solid dispersion containing 30% (w/w) of naproxen led to low intensity of the powder X-ray diffraction (PXRD) halo pattern maxima at 2θ = 16.11°, and the uncompressed samples also exhibit higher glass transition broadening than the compressed samples after 21 days storage at 75% RH at ambient temperature which indicates structural changes in the solid dispersion. The intensity of the vibration band at 1654 cm(-1) originating from the interaction between the hydrogen of the carboxylic acid moiety of NAP and the amide carbonyl moiety of PVP-VA 64 was increased for the compressed samples. The consequence of compression was further amplified after a long-term stability study (5 months) where the compressed 40 and 50% (w/w) NAP/PVP-VA 64 solid dispersions showed less crystallinity than the uncompressed samples. This suggests that compression improved the physical stability of the solid dispersions as a result of enhanced drug-polymer interactions.
- Drug-Polymer Miscibility across a Spray Dryer: A Case Study of Naproxen and Miconazole Solid Dispersions. [JOURNAL ARTICLE]
- Mol Pharm 2014 Feb 26.
The structural and physical stability of solid dispersions have not been adequately explored during spray drying manufacturing processes. In this study a wide range of compositions of naproxen/PVP-VA 64 (poly(1-vinylpyrrolidone-co-vinyl acetate)) and miconazole/PVP-VA 64 solid dispersions prepared by different laboratory spray dryers were collected from various selected locations and used to investigate the drug-polymer mixing across spray dryers. Spray-dried dispersions with 30% (w/w) naproxen collected from the transport tube of the Pro-C-epT Microspray dryer showed the narrowest glass transition width, which apparently indicates the highest degree of drug-polymer mixing compared to the other locations. The intensity of the naproxen-PVP-VA 64 interaction peak at 1654 cm(-1) of IR spectra differs for solid dispersions (SDs) from the collector and transport tube of Pro-C-epT Microspray dryer with a higher intensity for the latter. Samples with 50% (w/w) naproxen loading collected from the cyclone and the cyclone steel part of the Buchi mini spray dryer showed a melting endotherm (Tm at 112.2 ± 0.8 °C and ΔHf between 0.7 and 1.8 J/g), whereas samples from the cyclone tube to the drying chamber were devoid of crystalline material. The variations in drug-polymer mixing extend to miconazole/PVP-VA solid dispersions where 20% drug loading showed location-dependent drug-polymer mixing. This study clearly showed that the variation in drug-polymer miscibility and solid form of the drug in solid dispersions can occur across spray dryer in small-scale manufacturing processes. The optimization of formulation parameters and spray drying process parameters is imperative to diminish these variations to enhance homogeneity of solid dispersions in laboratory scale spray dryers. The same problem can occur in geometrically large spray drying manufacturing equipment, and the robustness of the processes should be carefully assessed.
- Validating Antimetastatic Effects of Natural Products in an Engineered Microfluidic Platform Mimicking Tumor Microenvironment. [JOURNAL ARTICLE]
- Mol Pharm 2014 Feb 24.
Development of new, antimetastatic drugs from natural products has been substantially constrained by the lack of a reliable in vitro screening system. Such a system should ideally mimic the native, three-dimensional (3D) tumor microenvironment involving different cell types and allow quantitative analysis of cell behavior critical for metastasis. These requirements are largely unmet in the current model systems, leading to poor predictability of the in vitro collected data for in vivo trials, as well as prevailing inconsistency among different in vitro tests. In the present study, we report application of a 3D, microfluidic device for validation of the antimetastatic effects of 12 natural compounds. This system supports co-culture of endothelial and cancer cells in their native 3D morphology as in the tumor microenvironment and provides real-time monitoring of the cells treated with each compound. We found that three compounds, namely sanguinarine, nitidine, and resveratrol, exhibited significant antimetastatic or antiangiogenic effects. Each compound was further examined for its respective activity with separate conventional biological assays, and the outcomes were in agreement with the findings collected from the microfluidic system. In summary, we recommend use of this biomimetic model system as a new engineering tool for high-throughput evaluation of more diverse natural compounds with varying anticancer potentials.
- Polymersome-mediated delivery of combination anti-cancer therapy to head and neck cancer cells: 2D and 3D in vitro evaluation. [JOURNAL ARTICLE]
- Mol Pharm 2014 Feb 17.
Polymersomes have the potential to encapsulate and deliver chemotherapeutic drugs into tumour cells, reducing off-target toxicity that often compromises anti-cancer treatment. Here we assess the ability of the pH-sensitive poly 2-(methacryloyloxy)ethyl phosphorylcholine (PMPC)- poly 2-(diisopropylamino)ethyl methacrylate (PDPA) polymersomes to encapsulate chemotherapeutic agents for effective combinational anti-cancer therapy. Polymersome uptake and ability to deliver encapsulated drugs into healthy normal oral cells and oral head and neck squamous cell carcinoma (HNSCC) cells was measured in two and three-dimensional culture systems. PMPC-PDPA polymersomes were more rapidly internalised by HNSCC cells compared to normal oral cells. Polymersome cellular up-take was found to be mediated by class B scavenger receptors. We also observed that these receptors are more highly expressed by cancer cells compared to normal oral cells, enabling polymersome-mediated targeting. Doxorubicin and paclitaxel were encapsulated into pH-sensitive PMPC-PDPA polymersomes with high efficiencies either in isolation or as a dual-load for both singular and combinational delivery. In monolayer culture, only a short exposure to drug-loaded polymersomes was required to elicit a strong cytotoxic effect. When delivered to three-dimensional tumour models, PMPC-PDPA polymersomes were able to penetrate deep into the centre of the spheroid resulting in extensive cell damage when loaded with both singular and dual-loaded chemotherapeutics. PMPC-PDPA polymersomes offer a novel system for the effective delivery of chemotherapeutics for the treatment of HNSCC. Moreover, the preferential internalisation of PMPC polymersomes by exploiting elevated scavenger receptor expression on cancer cells opens up the opportunity to target polymersomes to tumours.
- Inhalable Particles Containing Rapamycin for Induction of Autophagy in Macrophages Infected with Mycobacterium tuberculosis. [JOURNAL ARTICLE]
- Mol Pharm 2014 Feb 24.
We investigated whether particles suitable for delivery to alveolar macrophages may provide a means of targeting rapamycin, an inducer of autophagy, to alveolar macrophages as a host-directed antituberculosis agent. Inhalable particles were prepared by spray-drying and characterized using laser scattering and electron microscopy. Their aerodynamic diameter was calculated from bulk and tapped densities. In vitro drug release was studied in PBS containing 1% SDS. In vitro uptake of particles by THP-1 derived macrophages was studied by flow cytometry. Cytotoxicity of the particles toward macrophages and their efficacy against intracellular Mycobacterium tuberculosis were studied using a methyltetrazolium assay and counting bacterial colonies obtained when cell lysates were plated on agar. The encapsulation efficiency was 88.8 ± 1.13% and drug content 22 ± 4% w/w. The particles had a median diameter of 2.88 ± 0.8 μm and appeared as collapsed spheres. Their calculated aerodynamic diameter was about 1 μm. In vitro drug release from the particles was first-order and extended beyond 10 days. Flow cytometry indicated that the particles were taken up by macrophages within 3 h. Macrophages exposed to the particles or rapamycin in solution at a concentration of 100 μg/mL over a 24 h period maintained 79.37 ± 0.72% and 58.33 ± 1.39% viability, respectively. Efficacy studies concluded that particles were more effective in clearing intracellular mycobacteria than rapamycin in solution. It was concluded that the preparation was suitable for formulating as a dry powder inhalation to test efficacy of inhaled, macrophage-targeted rapamycin against TB.
- Stability Analysis of Glutamic Acid Linked Peptides Coupled to NOTA through Different Chemical Linkages. [JOURNAL ARTICLE]
- Mol Pharm 2014 Feb 24.
Glutamic acid is a commonly used linker to form dimeric peptides with enhanced binding affinity than their corresponding monomeric counterparts. We have previously labeled NOTA-Bn-NCS-PEG3-E[c(RGDyK)]2 (NOTA-PRGD2)  with [(18)F]AlF and (68)Ga for imaging tumor angiogenesis. The p-SCN-Bn-NOTA was attached to E[c(RGDyK)]2  through a mini-PEG with a thiourea linkage, and the product  was stable at radiolabeling condition of 100 °C and pH 4.0 acetate buffer. However, when the same p-SCN-Bn-NOTA was directly attached to the α-amine of E[c(RGDfK)]2 , the product NOTA-Bn-NCS-E[c(RGDfK)]2  became unstable under similar conditions and the release of monomeric c(RGDfK)  was observed. The purpose of this work was to use HPLC and LC-MS to monitor the decomposition of glutamic acid linked dimeric peptides and their NOTA derivatives. A c(RGDyK)  and bombesin (BBN)  heterodimer c(RGDyK)-E-BBN , and a dimeric bombesin E(BBN)2 , both with a glutamic acid as the linker, along with a model compound PhSCN-E[c(RGDfK)]  were also studied. All the compounds were dissolved in 0.5 M pH 4.0 acetate buffer at the concentration of 1 mg/mL, and 0.1 mL of each sample was heated at 100 °C for 10 min and the more stable compounds were heated for another 30 min. The samples at both time points were analyzed with analytical HPLC to monitor the decomposition of the heated samples. The samples with decomposition were further analyzed by LC-MS to determine the mass of products from the decomposition for possible structure elucidation. After 10 min heating, the obvious release of c(RGDfK)  was observed for NOTA-Bn-NCS-E[c(RGDfK)]2  and Ph-SCN-E[c(RGDfK)] . Little or no release of monomers was observed for the remaining samples at this time point. After further heating, the release of monomers was clearly observed for E[c(RGDyK)]2 , E[c(RGDfK)]2 , c(RGDyK)-E-BBN , and E(BBN)2 . No decomposition or little decomposition was observed for NOTA-Bn-NCS-PEG3-E[c(RGDyK)]2 , PEG3-E[c(RGDyK)]2 , NOTA-E[c(RGDyK)]2 , and NOTA-PEG3-E[c(RGDyK)]2 . The glutamic acid linked dimeric peptides with a free α-amine are labile due to the neighboring amine participation in the hydrolysis. The stability of peptides could be increased by converting the free amine into amide. The instability of thiourea derivatives formed from α-amine was caused by participation of thiol group derived from thiourea.