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Molecular pharmaceutics [journal]
- Mathematical modeling of PLGA microparticles: from polymer degradation to drug release. [JOURNAL ARTICLE]
- Mol Pharm 2014 Sep 17.
The here presented work is focused on the development and the validation of a mechanistic model describing the degradation of drug-loaded polylactic-co-glycolic acid microparticles and the drug release process from such devices. Microparticles degradation is described through mass conservation equations; the application of population balances allows a detailed description of the hydrolysis kinetics, which also takes into account the autocatalytic behavior that characterizes bulk eroding polymers. Drug release considers both drug dissolution and the diffusion of dissolved active principle through the polymeric matrix. Oligomers, water and drug diffusion is assumed to follow a Fickian behavior; the use of effective diffusion coefficients allows to take into account the diffusivity increase due to polymer hydrolysis. The model leads to a system of partial differential equation, solved by means of the method of lines and then numerically integrated. The satisfactorily matching with different sets of experimental data taken from the literature indicates that the here presented model, despite its simplicity, is able to describe the key phenomena governing the device behavior.
- Design of PLGA based nanoparticles for Imaging Guided applications. [JOURNAL ARTICLE]
- Mol Pharm 2014 Sep 16.
An amphiphilic Gd(III) complex has been efficiently loaded in polylactic-co-glycolic acid nanoparticles (PLGA-NP) to yield a novel, high sensitive MRI contrast agent for imaging guided drug delivery applications. As the Gd(III) complex is soluble in organic solvents, the nanoparticles were prepared as oil/water emulsions. PLGA-NP were stable, in buffer, for more than one week without any release of the incorporated agents. The millimolar relaxivity of the Gd(III) complex incorporated in the particles (140 nm diameter) was of 21.7 mM-1 s-1 at 21.5 MHz, a value that is about 5 times higher than that observed with the commercially available contrast agents used in clinic. The relaxometric efficiency of these particles resulted inversely proportional to the particle size measured by dynamic light scattering. The high stability and sensitivity of PLGA-NP allowed their accumulation "in vivo" in murine melanoma xenograft as shown in the corresponding MR images. Once loaded with drug and contrast agents, PLGA nanoparticles can be proposed as efficient theranostic MRI agents.
- Poly(amidoamine) Dendrimer-Methotrexate Conjugates: The Mechanism of Interaction with Folate Binding Protein. [JOURNAL ARTICLE]
- Mol Pharm 2014 Sep 15.
Generation 5 poly(amidoamine) (G5 PAMAM) methotrexate (MTX) conjugates employing two small molecular linkers, G5-(COG-MTX)n, G5-(MFCO-MTX)n were prepared along with the conjugates of the G5-G5 (D) dimer, D-(COG-MTX)n, D-(MFCO-MTX)n. The monomer G5-(COG-MTX)n conjugates exhibited only a weak, rapidly reversible binding to folate binding protein (FBP) consistent with monovalent MTX binding. The D-(COG-MTX)n conjugates exhibited a slow onset, tight-binding mechanism in which the MTX first binds to the FBP, inducing protein structural rearrangement, followed by polymer-protein van der Waals interactions leading to tight-binding. The extent of irreversible binding is dependent on total MTX concentration and no evidence of multivalent MTX binding was observed.
- Involvement of carrier-mediated transport in the retinal uptake of clonidine at the inner blood-retinal barrier. [JOURNAL ARTICLE]
- Mol Pharm 2014 Sep 15.
In the present study, the blood-to-retina transport across the inner BRB was investigated for clonidine, a compound which is expected to exhibit a neuroprotective effect for the treatment of the severe retinal diseases. In the in vivo study, the integration plot analysis for [3H]clonidine exhibited an apparent influx permeability clearance of 457 μL/(min•g retina) in the retina. The in vivo inhibition study suggests that the blood-to-retina transport of clonidine at the BRB is organic cation-sensitive since clonidine, pyrilamine and propranolol, at a concentration of 40 mM, significantly reduced the retinal uptake index (RUI) of [3H]clonidine, and an inhibitory effect on the RUI was also exhibited by verapamil, at a concentration of 3 mM. The in vitro study with TR-iBRB2 cells, an in vitro model cell line of the inner BRB, suggests that carrier-mediated transport is involved in the blood-to-retina transport of clonidine at the inner BRB since the results obtained demonstrated time-, temperature-, pH- and concentration-dependent [3H]clonidine uptake, with a Km of 286 μM. In the in vitro inhibition study, the [3H]clonidine uptake was significantly reduced by several organic cations, such as clonidine, verapamil, pyrilamine and propranolol, and was competitively inhibited by 200 μM verapamil, in spite of slight or no significant alteration being produced with organic anions. Furthermore, the typical substrates and inhibitors of well-known organic cation transporters had no significant effect on the uptake of [3H]clonidine to suggest the involvement of novel transporter molecules in the transport of clonidine across the inner BRB. These results suggest that the blood-to-retina transport of clonidine across the inner BRB involves carrier-mediated transport manner, suggesting the contribution of a novel organic cation transporter expressed by the retinal capillary endothelial cells.
- Nitric oxide-releasing D-α-tocopheryl polyethylene glycol succinate (TPGS) for enhancing antitumor activity of doxorubicin. [JOURNAL ARTICLE]
- Mol Pharm 2014 Sep 15.
Nitric oxide (NO) has attracted much attention for its antitumor activity and synergistic effects when co-delivered with anticancer agents. However, due to its chemical instability and short half-life, delivering gaseous NO directly to tumors is still challenging. Herein, we synthesized a NO releasing polymer, nitrate functionalized D-α-tocopheryl polyethylene glycol succinate (TNO3). TNO3 was able to self-assemble into stable micelles in physiological condition, accumulate in tumors and release ~ 90% of NO content in cancer cells for 96 h. It further exhibited significant cancer cell cytotoxicity and apoptosis compared with nitroglycerine (GTN). Notably, TNO3 could also serve as an enhancer for the common chemotherapeutic drug, Doxorubicin (DOX). Co-delivering TNO3 with DOX to hepatocarcinoma HepG2 cancer cells strengthened the cellular uptake of DOX and enabled the synergistic effect between NO and DOX to induce higher cytotoxicity (~6.25-fold lower IC50). Moreover, for DOX-based chemotherapy in tumor-bearing mice, co-administration with TNO3 significantly extended the blood circulation time of DOX (14.7-fold t1/2, 6.5-fold mean residence time (MRT), and 13.7-fold area under curve (AUC)) and enhanced its tumor accumulation and penetration, thus resulting in better antitumor efficacy. In summary, this new NO donor, TNO3, may provide a simple but effective strategy to enhance the therapeutic efficacy of chemotherapeutic drugs.
- Novel free-paclitaxel-loaded redox-responsive nanoparticles based on a disulfide-linked poly(ethylene glycol)-drug conjugate for intracellular drug delivery: Synthesis, characterization, and antitumor activity in vitro and in vivo. [JOURNAL ARTICLE]
- Mol Pharm 2014 Sep 10.
To address the obstacles of cancer chemotherapeutics, including toxicity, side effects, water insolubility, and lack of tumor selectivity, a novel stimuli-responsive drug-delivery system was developed based on paclitaxel-loaded poly(ethylene glycol)-disulfide-paclitaxel conjugate nanoparticles (PEG-SS-PTX/PTX NPs). The formulation emphasizes several benefits, including polymer-drug conjugates/prodrugs, self-assembled NPs, a high drug content, redox-responsibility, and programed drug release. The PTX-loaded, self-assembled NPs, with a uniform size of 103 nm, characterized by DLS, TEM, XRD, DSC and 1H-NMR, exhibited excellent drug-loading capacity (15.7%) and entrapment efficiency (93.3%). PEG-SS-PTX/PTX NPs were relatively stable under normal conditions but disassembled quickly under reductive conditions, indicated by the triggered-aggregation phenomena and drug-release profile in the presence of dithiothreitol (DTT), a reducing agent. What's more, by taking advantages of difference in drug releasing rates between physical-loaded and chemical-conjugated drugs, the "programmed drug release" phenomenon was observed, which attributed to higher concentration and longer action-time of drugs. The influence of PEG-SS-PTX/PTX NPs on in vitro cytotoxicity, the cell cycle, and cellular apoptosis was determined in MCF-7 cell lines, and the NPs demonstrated a superior anti-proliferation activity associated with PTX-induced cell arrest in the G2/M phase and apoptosis over their nonresponsive counterparts. Moreover, the redox-responsive NPs were more efficacious than both free PTX and the non-redox-responsive formulation at equivalent doses of PTX in the breast cancer xenograft mouse model. This redox-responsive PTX drug delivery system is promising and can be explored in effective intracellular drug delivery.
- Transport pathways of solid lipid nanoparticles across MDCK epithelial cell monolayer. [JOURNAL ARTICLE]
- Mol Pharm 2014 Sep 8.
An understanding of drug delivery system transport across epithelial cell monolayer is very important for improving the absorption and bioavailability of the drug payload. The mechanisms of epithelial cell monolayer transport for various nanocarriers may differ significantly due to their variable components, surface properties or diameter. Solid lipid nanoparticles (SLNs), conventionally formed by lipid materials, have gained increasing attention in recent years due to their excellent biocompatibility and high oral bioavailability. However, there have been few reports about the mechanisms of SLNs transport across epithelial cell monolayer. In this study, the molecular mechanisms utilized by SLNs of approximately 100 nm in diameter crossing intestinal epithelial monolayer were carefully studied using a simulative intestinal epithelial monolayer formed by Madin-Darby canine kidney (MDCK) epithelial cells. The results demonstrated that SLNs transportation did not induce a significant change on tight junction structure. We found that the endocytosis of SLNs into the epithelial cells was energy-dependent and was significantly greater than nanoparticle exocytosis. The endocytosis of SLNs was found to be rarely mediated via macropinocytosis, as confirmed by the addition of 5-(N-ethyl-N-isopropyl)-amiloride (EIPA) as an inhibitory agent, and mainly depended on lipid raft/caveolae- and clathrin-mediated pathways. After SLNs was internalized into MDCK cells, lysosome was one of the main destinations for these nanoparticles. The exocytosis study indicated that the endoplasmic reticulum, Golgi complex and microtubules played important roles in the transport of SLNs out of MDCK cells. The transcytosis study indicated that only approximately 2.5 % of the total SLNs was transported from the apical side to the basolateral side. For SLNs transportation in MDCK cell monolayer, greater transport (approximately 4-fold) was observed to the apical side than to the basolateral side. Our findings may present a more comprehensive understanding on the transport of SLNs across epithelial cell monolayer.
- Rational design of artificial β-strand forming antimicrobial peptides with biocompatible properties. [JOURNAL ARTICLE]
- Mol Pharm 2014 Sep 5.
The control and treatment of bacterial infections are major concerns in today's human health care. Since the intensive use of antibiotic has led to a large variety of resistant bacterial strains, therapeutic measures have become increasingly more challenging. In order to ensure the reliable handling and treatment of diseases, alternative antimicrobial agents need to be explored. In this context, antimicrobial peptides that are part of the innate immune system were discussed as novel bioactive molecules. However, naturally occurring peptides are limited in their applicability due to high manufacturing cost and poor pharmacokinetic properties. Therefore, the investigation focuses on the construction of optimized peptides with antimicrobial and biocompatible properties. Consequently, the design of antimicrobial peptides featuring two flanking cationic regions and a hydrophobic center is presented. This conformation leads to distinct antimicrobial activity in the same order of magnitude as naturally occurring reference peptides but with less cytotoxic or cytostatic drawbacks. Furthermore, a deletion and substitution library revealed a β-strand motif as a characteristic 3D structure of the peptides. This structural motif was pivotal for antimicrobial activity. Consequently, an optimized peptide sequence with antimicrobial and biocompatible properties was derived and its application demonstrated in a mixed culture experiment. Thus, it was shown that the optimized artificial antimicrobial peptide is suitable as a therapeutic agent and may be used as template for the development of new antimicrobial peptides with unique secondary structures.
- Overexpression of human ABCB1 in cancer cells leads to reduced activity of GSK461364, a specific inhibitor of polo-like kinase 1. [JOURNAL ARTICLE]
- Mol Pharm 2014 Sep 5.
Polo-like kinase 1 (Plk1) is a serine/threonine kinase involved in the regulation of mitosis, and is overexpressed in many tumor types. Inhibition of Plk1 leads to cell cycle arrest, onset of apoptosis and cell death, thus Plk1 has emerged as an important target for cancer treatment. GSK461364 is a potent inhibitor of Plk1that inhibits the proliferation of multiple human cancer cell lines by promoting G2/M cell cycle arrest at low concentrations. However, alike many therapeutic drugs, the risk of developing drug resistance to GSK461364 can present a therapeutic challenge to clinicians. Since the overexpression of ATP-binding cassette (ABC) drug transporter ABCB1 is one of the most common mechanisms of drug resistance, we aimed to investigate the effect of ABCB1 on the cellular efficacy of GSK461364. In this study, we observed a significantly reduced activity of GSK461364 in cells overexpressing human ABCB1. We showed that GSK461364 stimulates the ABCB1 ATPase activity and competitively inhibits ABCB1-mediated efflux of calcein-AM in a concentration-dependent manner. Moreover, as a way to assess the impact of ABCB1 on the efficacy of GSK461364, we evaluated the G2/M cell cycle arrest and apoptosis induced by GSK461364. We discovered that by inhibiting the function of ABCB1, the reduced G2/M cell cycle arrest, apoptosis and sensitivity to GSK461364 treatment in ABCB1-overexpressing cells can be significantly restored. In conclusion, in order to achieve a better therapeutic outcome, combination therapy of GSK461364 with a modulator of ABCB1 should be further investigated as a potential treatment approach.
- Beyond Overton's rule - Quantitative Modeling of Passive Permeation Through Tight Cell Monolayers. [JOURNAL ARTICLE]
- Mol Pharm 2014 Sep 4.
One of the great challenges in pharmacokinetics is to find a means to optimize the transport across cell barriers. In this work, permeation across a cell monolayer, such as the tight endothelia in the Blood Brain Barrier, was modeled using a homologous series of amphipatic molecules, NBD-labeled alkyl chain amphiphiles, (NBD-Cn, n = 2 to 16), to obtain rules that relate permeant structure to permeability. The amphiphile enters the system from the serum, equilibrated with serum albumin and lipoproteins, and its sequestration by serum components, interaction with the endothelium and accumulation in the tissue is followed over time. The dependence of the permeability coefficient on the number of carbons of the amphiphile's alkyl chain has a "parabolic like" shape. After a threshold value, an increase in the hydrophobicity of the amphiphile, along the homologous series, results in a decrease in the characteristic rate of permeation to the tissue. A sensitivity analysis was performed and the rate limiting steps for permeation of each amphiphile were identified. Sequestration in the serum and rate of interaction with the endothelium, particularly the rate of desorption, were found to be the determinant processes for some amphiphiles, while for others translocation was the rate limiting step. Additionally, for some amphiphiles a single rate limiting step could not be identified, with several steps contributing significantly to the overall permeation. Finally, we derived analytical equations that adequately describe the rate of amphiphile accumulation in the tissue for the cases where permeation is controlled by a single rate limiting step.