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Molecular pharmaceutics [journal]
- On the physical stability of the amorphous anti-cholesterol agent (ezetimibe) - the role of molecular mobility. [JOURNAL ARTICLE]
- Mol Pharm 2014 Oct 13.
The purpose of this paper is to examine the role of molecular mobility in the recrystallization process from the amorphous state of the anti-cholesterol drug - ezetimibe. Both the molecular dynamics and crystallization kinetics have been studied using various experimental techniques, such as broadband dielectric spectroscopy (BDS), differential scanning calorimetry (DSC), and X-ray diffraction (XRD). Our investigations have shown that ezetimibe easily recrystallizes from the disordered state, both below and above its glass transition temperature (Tg = 336 K). Moreover, we found that an only slightly elevated pressure (5 MPa) significantly accelerates the recrystallization process at T>Tg. We predict that the structural relaxation time of amorphous ezetimibe at 293 K (storage temperature) and ambient pressure is only 22 days. This result corresponds to the characteristic time, determined from XRD measurements, for amorphous ezetimibe to recrystallize during storage at Troom = 298 K. It leads to the conclusion that the molecular mobility reflected in structural relaxation of ezetimibe is mainly responsible for devitrification of this drug. Finally, we determined a relatively easy way to improve the physical stability of the drug by preparing a binary amorphous ezetimibe-soluplus mixture. Ezetimibe in an amorphous mixture with 20% wt. soluplus has a much better (over six times) solubility than the pure crystalline material.
- Distinct subcellular trafficking resulting from monomeric vs. multimeric targeting to endothelial ICAM-1: implications for drug delivery. [JOURNAL ARTICLE]
- Mol Pharm 2014 Oct 9.
Ligand-targeted, receptor-mediated endocytosis is commonly exploited for intracellular drug delivery. However, cells-surface receptors may follow distinct endocytic fates when bound by monomeric vs. multimeric ligands. Our purpose was to study this paradigm using ICAM-1, an endothelial receptor involved in inflammation, to better understand its regulation and potential for drug delivery. Our procedure involved fluorescence microscopy of human endothelial cells to determine the endocytic behavior of unbound ICAM-1 vs. ICAM-1 bound by model ligands: monomeric (anti-ICAM) vs. multimeric (anti-ICAM biotin-streptavidin conjugates or anti-ICAM coated onto 100-nm nanocarriers). Our findings suggest that both monomeric and multimeric ligands undergo a similar endocytic pathway sensitive to amiloride (~50% inhibition), but not inhibitors of clathrin-pits or caveoli. After 30 min, ~60-70% of both ligands co-localized with Rab11a-compartments. By 3-5 h, ∼65-80% of multimeric anti-ICAM co-localized with perinuclear lysosomes with ∼60-80% degradation, while 70% of monomeric anti-ICAM remained associated with Rab11a at the cell periphery and recycled to and from the cell-surface with minimal (<10%) lysosomal co-localization and minimal (≤15%) degradation. In the absence of ligands, ICAM-1 also underwent amiloride-sensitive endocytosis with peripheral distribution, suggesting that monomeric (not multimeric) anti-ICAM follows the route of this receptor. In conclusion, ICAM-1 can mediate different intracellular itineraries, revealing new insight into this biological pathway and alternative avenues for drug delivery.
- Influence of copolymer composition on the phase behavior of solid dispersions. [JOURNAL ARTICLE]
- Mol Pharm 2014 Oct 8.
The incorporation of poorly-soluble active pharmaceutical ingredients (APIs) into excipients (e.g. polymers) to formulate an amorphous solid dispersion is a promising strategy to improve the oral bioavailability of the API. The application of copolymer excipients allows access to combination of different monomers and thus to the design of excipients to improve solid-dispersion properties. In this work, the thermodynamic phase behavior of solid dispersions was investigated as function of API, type of monomers, and copolymer composition. The glass-transition temperatures and API solubilities in the solid dispersions of naproxen and indomethacin in polyvinyl pyrrolidone, polyvinyl acetate, and copolymers with different weight fractions of vinyl pyrrolidone and vinyl actetate were investigated. It could be shown that the thermodynamic phase behavior of API/copolymer solid dispersions is a function of monomer type and copolymer composition. This effect was also predicted by using the Perturbed-Chain Statistical Associating Fluid Theory (PC-SAFT). The glass-transition temperature of the solid dispersions was calculated with the Gordon-Taylor equation.
- Cetuximab Reduces the Accumulation of Radiolabeled Bevacizumab in Cancer Xenografts without Decreasing VEGF Expression. [JOURNAL ARTICLE]
- Mol Pharm 2014 Oct 17.
Bevacizumab and cetuximab are approved for the treatment of cancer. However, in advanced colorectal cancer, addition of cetuximab to chemotherapy with bevacizumab did not improve survival. The reason for the lack of activity remains unclear. The aim of this study was to determine the effect of cetuximab on VEGF expression and targeting of bevacizumab to the tumor. Mice with subcutaneous SUM149 or WiDr xenografts were treated with cetuximab, bevacizumab, or a combination of the two. Before the start of cetuximab treatment and after 7 and 21 days of treatment, the uptake of radiolabeled bevacizumab in the tumor was measured by immunoSPECT/CT. Tumor growth of SUM149 xenografts was significantly inhibited by cetuximab, bevacizumab, or their combination, whereas growth of WiDr xenografts was not affected. Cetuximab caused a significant reduction of bevacizumab uptake in SUM149 xenografts, whereas tumor-to-blood ratios in mice with WiDr xenografts did not change. Biodistribution studies with an irrelevant antibody in the SUM149 model also showed significantly reduced tumor-to-blood ratios. Cetuximab treatment did not decrease VEGF expression. Without decreasing VEGF levels, cetuximab reduces tumor targeting of bevacizumab. This could, at least partly, explain why the combination of bevacizumab and cetuximab does not result in improved therapeutic efficacy.
- Tracking targeted bimodal nanovaccines: immune responses and routing in cells, tissue and whole organism. [JOURNAL ARTICLE]
- Mol Pharm 2014 Oct 7.
Dendritic cells (DCs) are the most potent antigen-presenting cells (APCs), involved in the induction of immunity and currently exploited for anti-tumor immunotherapies. An optimized non-invasive imaging modality capable of determining and quantifying DC-targeted nanoparticle (NP) trajectories could provide valuable information regarding therapeutic vaccine outcome. Here, targeted poly(D, L-lactide-co-glycolide) nanoparticles (PLGA NPs) recognizing DC receptors were equipped with superparamagnetic iron oxide particles (SPIO) or gold nanoparticles with fluorescently labeled antigen. The fluorescent label allowed for rapid analysis and quantification of DC-specific uptake of targeted PLGA NPs in comparison to uptake by other cells. Transmission electron microscopy (TEM) showed that a fraction of the encapsulated antigen reached the lysosomal compartment of DCs, where SPIO and gold were already partially released. However, part of the PLGA NPs localized within the cytoplasm, as confirmed by confocal microscopy. DCs targeted with NPs carrying SPIO or fluorescent antigen were detected within lymph nodes as early as 1 h after injection by magnetic resonance imaging (MRI). Despite the fact that targeting did not markedly affect PLGA NP biodistribution on organism and tissue level, it increased delivery of NPs to DCs residing in peripheral lymph nodes and resulted in enhanced T cell proliferation. In conclusion, two imaging agents within a single carrier allows tracking of targeted PLGA NPs at the subcellular, cellular and organismal level, thereby facilitating the rational design of in vivo targeted vaccination strategies.
- Gambogic Acid-Loaded Electrosprayed Particles for Site-Specific Treatment of Hepatocellular Carcinoma. [JOURNAL ARTICLE]
- Mol Pharm 2014 Oct 7.
This study aims to assess the targeted effect and antitumor efficacy of Gambogic-acid-loaded particles (GA-Ps). GA-Ps with uniform particle sizes of 69.8 ± 17.8 nm (GA-P1), 185.6 ± 33.8 nm (GA-P2), 357.8 ± 81.5 nm (GA-P3), and 7.56 ± 0.95 μm (GA-P4) were prepared using an electrospray technique and exhibited extremely high entrapment efficiency. As the particle size increased from the nano- to microscale, the in vitro GA release rate sharply decreased. After tail-vein injection in mice, GA-P samples GA-P1, GA-P2, GA-P3, and GA-P4 improved the uptake of GA 1.67-times in the liver, 1.78-times in the liver, 2.18-times in the spleen, and 2.35-times in the lung, respectively, compared with GA solution (GA-S). The antitumor efficacy of GA-P2, with an 82.51% targeting efficiency (Te) for the liver, was examined in hepatocellular carcinoma (HCC) model mice. After 2 weeks of administration, HCC mice in the GA-P2 group exhibited a lower degree of tumor invasion and cell lesions in hepatic tissue, recovered liver function, and significantly prolonged survival time, compared with mice in the model, GA-S, and normal saline (NS) groups. Pharmacokinetic studies indicated that the superior antitumor efficacy of GA-P2 was attributed not only to tissue targeting but also to low clearance, extended retention, high bioavailability in plasma, and increased GA stability.
- Beyond the great wall: recent advances in molecular pharmaceutics research in china. [Journal Article]
- Mol Pharm 2014 Oct 6; 11(10):3231-2.
- Sequence-Specific Formation of d-Amino Acids in a Monoclonal Antibody during Light Exposure. [JOURNAL ARTICLE]
- Mol Pharm 2014 Oct 17.
The photoirradiation of a monoclonal antibody 1 (mAb1) at λ = 254 nm and λmax = 305 nm resulted in the sequence-specific generation of d-Val, d-Tyr, and potentially d-Ala and d-Arg, in the heavy chain sequence [95-101] YCARVVY. d-Amino acid formation is most likely the product of reversible intermediary carbon-centered radical formation at the (α)C-positions of the respective amino acids ((α)C(•) radicals) through the action of Cys thiyl radicals (CysS(•)). The latter can be generated photochemically either through direct homolysis of cystine or through photoinduced electron transfer from Trp and/or Tyr residues. The potential of mAb1 sequences to undergo epimerization was first evaluated through covalent H/D exchange during photoirradiation in D2O, and proteolytic peptides exhibiting deuterium incorporation were monitored by HPLC-MS/MS analysis. Subsequently, mAb1 was photoirradiated in H2O, and peptides, for which deuterium incorporation in D2O had been documented, were purified by HPLC and subjected to hydrolysis and amino acid analysis. Importantly, not all peptide sequences which incorporated deuterium during photoirradiation in D2O also exhibited photoinduced d-amino acid formation. For example, the heavy chain sequence [12-18] VQPGGSL showed significant deuterium incorporation during photoirradiation in D2O, but no photoinduced formation of d-amino acids was detected. Instead this sequence contained ca. 22% d-Val in both a photoirradiated and a control sample. This observation could indicate that d-Val may have been generated either during production and/or storage or during sample preparation. While sample preparation did not lead to the formation of d-Val or other d-amino acids in the control sample for the heavy chain sequence [95-101] YCARVVY, we may have to consider that during hydrolysis N-terminal residues (such as in VQPGGSL) may be more prone to epimerization. We conclude that the photoinduced, radical-dependent formation of d-amino acids requires not only the intermediary formation of a (α)C(•) radical but also sufficient flexibility of the protein domain to allow both pro-chiral faces of the (α)C(•) radical to accept a hydrogen atom.
- The crystallographic textures and morphologies of solution cast ibuprofen composite films at solid surfaces. [JOURNAL ARTICLE]
- Mol Pharm 2014 Oct 2.
The preparation of thin composite layers has promising advantages in a variety of applications like transdermal, buccal or sublingual patches. Within this model study the impact of the matrix material on the film forming properties of Ibu - matrix composite films is investigated. As matrix materials polystyrene, methyl cellulose or hydroxyl-ethyl cellulose were used. The film properties were either be varied by the preparation route, i.e. spin coating or drop casting, or via change in the relative ratio of the Ibuprofen to the matrix material. The resulting films were investigated via x-ray diffraction and atomic force microscope and experiments. The results show preferred textures can be induced via spin coating while the drop casting results in a powder like behavior. The film morphology of the films is strongly impacted by the Ibu amount rather than the preparation method. A comparison of the various matrix materials in terms of their impact on the dissolution properties show the fastest release is obtained for methyl cellulose followed by polystyrene. The slowest rate was observed within the hydroxyl ethyl cellulose as the film is affected by swelling. The investigation shows a simple way to understand the formation of layer material which can be easily extended to other material combinations.
- pH-Triggered Echogenicity and Contents Release from Liposomes. [JOURNAL ARTICLE]
- Mol Pharm 2014 Oct 1.
Liposomes are representative lipid nanoparticles, and are widely used for delivering anticancer drugs, DNA fragments or siRNA to cancer cells. Upon targeting, various internal and external triggers have been used to increase the rate of contents release from the liposomes. Amongst the internal triggers, the decrease in pH within the cellular lysosomes has been successfully used to enhance the rate of contents release. However, imparting pH-sensitivity to liposomes requires the synthesis of specialized lipids whose structures are substantially modified at reduced pH. Herein, we report an alternative strategy to render liposomes pH-sensitive by encapsulating a precursor which generates gas bubbles in situ in response to acidic pH. The disturbance created by the escaping gas bubbles leads to the rapid release of the encapsulated contents from the liposomes. Atomic force microscopic studies indicate that the liposomal structure is destroyed at reduced pH. The gas bubbles also render the liposomes echogenic - allowing ultrasound imaging. In order to demonstrate the applicability of this strategy, we have successfully targeted doxorubicin-encapsulated liposomes to the pancreatic ductal carcinoma cells overexpressing the folate receptor on the surface. In response to the decreased pH in the lysosomes, the encapsulated anticancer drug is efficiently released. Contents release from these liposomes is further enhanced by the application of (1 MHz) continuous wave ultrasound, resulting in substantially reduced viability for the pancreatic cancer cells (14%).