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Molecular pharmaceutics [journal]
- D-α-tocopherol polyethylene glycol succinate based Redox-sensitive Paclitaxel Prodrug for Overcoming Multidrug Resistance in Cancer Cells. [JOURNAL ARTICLE]
- Mol Pharm 2014 Aug 7.
To overcome the multidrug resistance (MDR) of P-glycoprotein (P-gp) substrate anticancer drugs, such as paclitaxel (PTX), a novel dual-functional prodrug, D-α-tocopherol polyethylene glycol succinate (TPGS) based PTX prodrug (TPGS-S-S-PTX), was synthesized here to fulfil the synergistic effect of P-gp inhibiting and intracellular redox-sensitive release. The prodrug could self-assemble into stable micelles in physiological environment with a diameter of ~140 nm, while it disassociated in reductive condition and released PTX and TPGS active derivatives rapidly. High cell cytotoxicity in PTX-resistant human ovarian cell line A2780/T was observed with enhanced PTX accumulation due to the P-gp inhibition by the TPGS moiety. The IC50 of TPGS-S-S-PTX was 55% and 91% more effective than that of Taxol (clinical formulation of PTX) and uncleavable TPGS-C-C-PTX prodrug, respectively. This was found to be related with the increased apoptosis/necrosis and cell arrest in G2/M phase. In vivo evaluation of the TPGS-S-S-PTX prodrug exhibited an extended half-life, increased AUC (area under the concentration-time curve), enhanced tumor distribution and significant tumor growth inhibition with reduced side effects as compared to Taxol and TPGS-C-C-PTX. This prodrug has great potential in improving efficiency in the treatment of MDR tumors.
- Apamin-Mediated Actively Targeted Drug Delivery for Treatment of Spinal Cord Injury: More Than Just a Concept. [JOURNAL ARTICLE]
- Mol Pharm 2014 Aug 18.
Faced with the complex medical challenge presented by spinal cord injuries (SCI) and considering the lack of any available curative therapy, the development of a novel method of delivering existing drugs or candidate agents can be perceived to be as important as the development of new therapeutic molecules. By combining three ingredients currently in clinical use or undergoing testing, we have designed a central nervous system targeted delivery system based on apamin-modified polymeric micelles (APM). Apamin, one of the major components of honey bee venom, serves as the targeting moiety, poly(ethylene glycol) (PEG) distearoylphosphatidylethanolamine (DSPE) serves as the drug-loaded material, and curcumin is used as the therapeutic agent. Apamin was conjugated with NHS (N-hydroxysuccinimide)-PEG-DSPE in a site-specific manner, and APM were prepared by a thin-film hydration method. A formulation comprising 0.5 mol % targeting ligand with 50 nm particle size showed strong targeting efficiency in vivo and was evaluated in pharmacodynamic assays. A 7-day treatment by daily intravenous administration of low doses of APM (corresponding to 5 mg/kg of curcumin) was performed. Significantly enhanced recovery and prolonged survival was found in the SCI mouse model, as compared to sham-treated groups, with no apparent toxicity. A single dose of apamin-conjugated polymers was about 700-fold lower than the LD50 amount, suggesting that APM and apamin have potential for clinical applications as spinal cord targeting ligand for delivery of agents in treatment of diseases of the central nervous system.
- Synthetic Biology for Therapeutic Applications. [JOURNAL ARTICLE]
- Mol Pharm 2014 Aug 13.
Synthetic biology is a relatively new field with the key aim of designing and constructing biological systems with novel functionalities. Today, synthetic biology devices are making their first steps in contributing new solutions to a number of biomedical challenges, such as emerging bacterial antibiotic resistance and cancer therapy. This review discusses some synthetic biology approaches and applications that were recently used in disease mechanism investigation and disease modeling, drug discovery and production, as well as vaccine development and treatment of infectious diseases, cancer, and metabolic disorders.
- FRET Imaging Approaches for in Vitro and in Vivo Characterization of Synthetic Lipid Nanoparticles. [JOURNAL ARTICLE]
- Mol Pharm 2014 Aug 13.
DiI and DiD, two fluorophores able to interact by FRET (Förster resonance energy transfer), were coencapsulated in the core of lipid nanocapsules (LNCs) and nanoemulsions (LNEs), lipophilic reservoirs for the delivery of drugs. The ability of FRET imaging to provide information on the kinetics of dissociation of the nanoparticles in the presence of bovine serum albumin (BSA) or whole serum, or after incubation with cancer cells, and after systemic administration in tumor-bearing mice, was studied. Both microscopic and macroscopic imaging was performed to determine the behavior of the nanostructures in a biological environment. When 2 mg/mL FRET LNEs or LNCs were dispersed in buffer, in the presence of unloaded nanoparticles, BSA, or in whole serum, the presence of serum was the most active in destroying the particles. This occurred immediately with a diminution of 20% of FRET, then slowly, ending up with still 30% intact nanoparticles at 24 h. LNCs were internalized rapidly in cultured cells with the FRET signal decreasing within the first minutes of incubation, and then a plateau was reached and LNCs remained intact during 3 h. In contrast, LNEs were poorly internalized and were rapidly dissociated after internalization. Following their iv injection, LNCs appeared very stable in subcutaneous tumors implanted in mice. Intact particles were found using microscopic FRET determination on tumor sections 24 h after injection, that correlated well with the 8% calculated noninvasively on live animals. FRET investigations showed the potential to determine valid and reliable information about in vitro and in vivo behavior of nanoparticles.
- [(18)F](2S,4S)-4-(3-Fluoropropyl)glutamine as a Tumor Imaging Agent. [JOURNAL ARTICLE]
- Mol Pharm 2014 Aug 11.
Although the growth and proliferation of most tumors is fueled by glucose, some tumors are more likely to metabolize glutamine. In particular, tumor cells with the upregulated c-Myc gene are generally reprogrammed to utilize glutamine. We have developed new 3-fluoropropyl analogs of glutamine, namely [(18)F](2S,4R)- and [(18)F](2S,4S)-4-(3-fluoropropyl)glutamine, 3 and 4, to be used as probes for studying glutamine metabolism in these tumor cells. Optically pure isomers labeled with (18)F and (19)F (2S,4S) and (2S,4R)-4-(3-fluoropropyl)glutamine were synthesized via different routes and isolated in high radiochemical purity (≥95%). Cell uptake studies of both isomers showed that they were taken up efficiently by 9L tumor cells with a steady increase over a time frame of 120 min. At 120 min, their uptake was approximately two times higher than that of l-[(3)H]glutamine ([(3)H]Gln). These in vitro cell uptake studies suggested that the new probes are potential tumor imaging agents. Yet, the lower chemical yield of the precursor for 3, as well as the low radiochemical yield for 3, limits the availability of [(18)F](2S,4R)-4-(3-fluoropropyl)glutamine, 3. We, therefore, focused on [(18)F](2S,4S)-4-(3-fluoropropyl)glutamine, 4. The in vitro cell uptake studies suggested that the new probe, [(18)F](2S,4S)-4-(3-fluoropropyl)glutamine, 4, is most sensitive to the LAT transport system, followed by System N and ASC transporters. A dual-isotope experiment using l-[(3)H]glutamine and the new probe showed that the uptake of [(3)H]Gln into 9L cells was highly associated with macromolecules (>90%), whereas the [(18)F](2S,4S)-4-(3-fluoropropyl)glutamine, 4, was not (<10%). This suggests a different mechanism of retention. In vivo PET imaging studies demonstrated tumor-specific uptake in rats bearing 9L xenographs with an excellent tumor to muscle ratio (maximum of ∼8 at 40 min). [(18)F](2S,4S)-4-(3-fluoropropyl)glutamine, 4, may be useful for testing tumors that may metabolize glutamine related amino acids.
- Evaluation of N-[(11)C]Methyl-AMD3465 as a PET Tracer for Imaging of CXCR4 Receptor Expression in a C6 Glioma Tumor Model. [JOURNAL ARTICLE]
- Mol Pharm 2014 Aug 18.
The chemokine receptor CXCR4 and its ligand CXCL12 play an important role in tumor progression and metastasis. CXCR4 receptors are expressed by many cancer types and provide a potential target for treatment. Noninvasive detection of CXCR4 may aid diagnosis and improve therapy selection. It has been demonstrated in preclinical studies that positron emission tomography (PET) with a radiolabeled small molecule could enable noninvasive monitoring of CXCR4 expression. Here, we prepared N-[(11)C]methyl-AMD3465 as a new PET tracer for CXCR4. N-[(11)C]Methyl-AMD3465 was readily prepared by N-methylation with [(11)C]CH3OTf. The tracer was obtained in a 60 ± 2% yield (decay corrected), the purity of the tracer was >99%, and specific activity was 47 ± 14 GBq/μmol. Tracer stability was tested in vitro using liver microsomes and rat plasma; excellent stability was observed. The tracer was evaluated in rat C6 glioma and human PC-3 cell lines. In vitro cellular uptake of N-[(11)C]methyl-AMD3465 was receptor mediated. The effect of transition metal ions (Cu(2+), Ni(2+), and Zn(2+)) on cellular binding was examined in C6 cells, and the presence of these ions increased the cellular binding of the tracer 9-, 7-, and 3-fold, respectively. Ex vivo biodistribution and PET imaging of N-[(11)C]methyl-AMD3465 were performed in rats with C6 tumor xenografts. Both PET and biodistribution studies demonstrated specific accumulation of the tracer in the tumor (SUV 0.6 ± 0.2) and other CXCR4 expressing organs, such as lymph node (1.5 ± 0.2), liver (8.9 ± 1.0), bone marrow (1.0 ± 0.3), and spleen (1.0 ± 0.1). Tumor uptake was significantly reduced (66%, p < 0.01) after pretreatment with Plerixafor (AMD3100). Biodistribution data indicates a tumor-to-muscle ratio of 7.85 and tumor-to-plasma ratio of 1.14, at 60 min after tracer injection. Our data demonstrated that N-[(11)C]methyl-AMD3465 is capable of detecting physiologic CXCR4 expression in tumors and other CXCR4 expressing tissues. These results warrant further evaluation of N-[(11)C]methyl-AMD3465 as a potential PET tracer for CXCR4 receptor imaging.
- 68Ga-PRGD2 PET/CT in the evaluation of glioma: a prospective study. [JOURNAL ARTICLE]
- Mol Pharm 2014 Aug 5.
Integrin αvβ3 is over-expressed in both neovasculature and glioma cells. We aimed to evaluate 68Gallium-BNOTA-PRGD2 (68Ga-PRGD2) as a new reagent for noninvasive integrin αvβ3 imaging in glioma patients. With informed consent, 12 patients with suspicious brain glioma, as diagnosed by enhanced magnetic resonance imaging (MRI) scanning, were enrolled to undergo 68Ga-PRGD2 PET/CT and 18F-FDG PET/CT scans before surgery. The preoperative images were compared and correlated with the pathologically determined WHO grade. Next, the expression of integrin αvβ3, CD34, and Ki-67 were determined by immunohistochemical staining of the resected brain tumor tissue. Our findings demonstrated that 68Ga-PRGD2 specifically accumulated in the brain tumors that were rich of integrin αvβ3 and other neovasculature markers, but not in the brain parenchyma other than the choroid plexus. Therefore, 68Ga-PRGD2 PET/CT was able to evaluate the glioma demarcation more specifically than 18F-FDG PET/CT. The maximum standardized uptake values (SUVmax) of 68Ga-PRGD2, rather than those of 18F-FDG, were significantly correlated with the glioma grading. The maximum tumor-to-brain ratios (TBRmax) of both tracers were significantly correlated with glioma grading, whereas 68Ga-PRGD2 seemed to be more superior to 18F-FDG in differentiating high-grade glioma (HGG) from low-grade glioma (LGG). Moreover, 68Ga-PRGD2 PET/CT showed different accumulation patterns for HGG of WHO grades III and IV. This is the first non-invasive integrin imaging study, to the best of our knowledge, conducted in preoperative patients with different grades of glioma, and it preliminarily indicated the effectiveness of this novel method for evaluating glioma grading and demarcation.
- Insights into Pharmaceutical Nanocrystal Dissolution: A Molecular Dynamics Simulation Study on Aspirin. [JOURNAL ARTICLE]
- Mol Pharm 2014 Aug 11.
The presented molecular dynamics simulations are the first simulations to reveal dynamic dissolution of a pharmaceutical crystal in its experimentally determined shape. Continuous dissolution at constant undersaturation of the surrounding medium is ensured by introducing a plane of sticky dummy atoms into the water slab. These atoms have a strong interaction potential with dissolved aspirin molecules, but interactions with water are excluded from the calculations. Thus, the number of aspirin molecules diffusing freely in solution is kept at a low value and continuous dissolution of the aspirin crystal is monitored. Further insight into face-specific dissolution is drawn. The dissolution mechanism of receding edges is found for the (001) plane. These findings are in good agreement with experimental results. While the proposed dissolution mechanism for the (100) plane is terrace sinking on a rough surface, no pronounced dissolution of the perfectly flat face is seen in the present work. Molecular simulations of pharmaceuticals in their experimentally obtained structure therefore have shown to be especially suited for the investigation of dissolving faces, where the edges have a pronounced effect. In contrast to previous studies a propagation of the dissolution front into the crystal face is reported, and the crystal bulk is stable over the whole simulation time of 150 ns.
- Drug Delivery and Reversal of MDR. [Journal Article]
- Mol Pharm 2014 Aug 4; 11(8):2493-4.
- Cell-Penetrating Apoptotic Peptide/p53 DNA Nanocomplex as Adjuvant Therapy for Drug-Resistant Breast Cancer. [JOURNAL ARTICLE]
- Mol Pharm 2014 Aug 13.
Drug resistance becomes a formidable challenge against effective cancer therapy. Defective apoptosis in cancer cells is a key factor responsible for chemoresistance or radioresistance. Promoting apoptosis is an important method to sensitize the resistant cells, thereby achieving successful treatment for MDR cancer. We present a strategy of codelivery of apoptotic AVPI peptide and p53 DNA as apoptosis-induction adjuvant therapy for combating the resistant breast cancer. AVPI tetrapeptide is poorly cell-permeable, thereby with very limited value for therapeutic use. Cell-penetrating chimeric AVPI derivative was developed by modification with an octa-arginine sequence (R8). The AVPIR8 is able to not only efficiently penetrate into tumor cells but also work as a vector for gene delivery by forming nanocomplexes based on its cationic R8 moiety. The combination of AVPIR8/p53 DNA was selected for targeting apoptotic pathways, thereby sensitizing the cancer cells to chemotherapeutics. The anti-MDR effect was demonstrated both in vitro and in vivo. The synergistic use of AVPIR8/p53 significantly increased the sensitivity of the resistant tumor cells to the cytotoxic agent doxorubicin by inducing apoptosis, as demonstrated in the cellular studies. Importantly, the treatment improvement was also observed in the animal studies with resistant breast tumor model. Coadministration of AVPIR8/p53 enabled a full arrest of tumor growth combined with a reduced DOX dose, yielding a productive and safe cancer treatment.