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Pharmaceutics, Volume 7, Issue 2 (June 2015) – 5 articles , Pages 10-89

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1629 KiB

Open AccessReview

Endocytosis of Nanomedicines: The Case of Glycopeptide Engineered PLGA Nanoparticles

by Antonietta Vilella, Barbara Ruozi, Daniela Belletti, Francesca Pederzoli, Marianna Galliani, Valentina Semeghini, Flavio Forni, Michele Zoli, Maria Angela Vandelli and Giovanni Tosi

Pharmaceutics 2015, 7(2), 74-89; https://doi.org/10.3390/pharmaceutics7020074 - 19 Jun 2015

Cited by 50 | Viewed by 7959

Abstract

The success of nanomedicine as a new strategy for drug delivery and targeting prompted the interest in developing approaches toward basic and clinical neuroscience. Despite enormous advances on brain research, central nervous system (CNS) disorders remain the world’s leading cause of disability, in part due to the inability of the majority of drugs to reach the brain parenchyma. Many attempts to use nanomedicines as CNS drug delivery systems (DDS) were made; among the various non-invasive approaches, nanoparticulate carriers and, particularly, polymeric nanoparticles (NPs) seem to be the most interesting strategies. In particular, the ability of poly-lactide-co-glycolide NPs (PLGA-NPs) specifically engineered with a glycopeptide (g7), conferring to NPs’ ability to cross the blood brain barrier (BBB) in rodents at a concentration of up to 10% of the injected dose, was demonstrated in previous studies using different routes of administrations. Most of the evidence on NP uptake mechanisms reported in the literature about intracellular pathways and processes of cell entry is based on in vitro studies. Therefore, beside the particular attention devoted to increasing the knowledge of the rate of in vivo BBB crossing of nanocarriers, the subsequent exocytosis in the brain compartments, their fate and trafficking in the brain surely represent major topics in this field. Full article

(This article belongs to the Special Issue Drug Delivery to Brain)

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802 KiB

Open AccessCommunication

Effect of the Compaction and the Size of DNA on the Nuclear Transfer Efficiency after Microinjection in Synchronized Cells

by Hidetaka Akita, Dai Kurihara, Marco Schmeer, Martin Schleef and Hideyoshi Harashima

Pharmaceutics 2015, 7(2), 64-73; https://doi.org/10.3390/pharmaceutics7020064 - 9 Jun 2015

Cited by 22 | Viewed by 6885

Abstract

The nuclear transfer process is one of the critical rate-limiting processes in transgene expression. In the present study, we report on the effect of compaction and the size of the DNA molecule on nuclear transfer efficiency by microinjection. A DNA/protamine complex- or variously-sized naked DNA molecules were injected into the cytoplasm or nucleus of synchronized HeLa cells. To evaluate the nuclear transfer process, a nuclear transfer score (NT score), calculated based on transgene expression after cytoplasmic microinjection divided by that after nuclear microinjection, was employed. The compaction of DNA with protamine decreased the NT score in comparison with the injection of naked DNA when the N/P ratio was increased to >2.0. Moreover, when naked DNA was microinjected, gene expression increased in parallel with the size of the DNA in the following order: minicircle DNA (MC07.CMV-EGFP; 2257 bp) > middle-sized plasmid DNA (pBS-EGFP; 3992 bp) > conventional plasmid DNA (pcDNA3.1-EGFP; 6172 bp), while the level of gene expression was quite comparable among them when the DNAs were injected into the nucleus. The above findings suggest that the intrinsic size of the DNA molecule is a major determinant for nuclear entry and that minicircle DNA has a great advantage in nuclear transfer. Full article

(This article belongs to the Special Issue New Paradigm of Gene Therapy)

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2044 KiB

Open AccessArticle

Product Development Studies on Sonocrystallized Curcumin for the Treatment of Gastric Cancer

by Mohammad Ashif Khan, Nida Akhtar, Vijay Sharma and Kamla Pathak

Pharmaceutics 2015, 7(2), 43-63; https://doi.org/10.3390/pharmaceutics7020043 - 27 Apr 2015

Cited by 20 | Viewed by 7072

Abstract

Curcumin suffers from the limitation of poor solubility and low dissolution that can lead to limited applications. The investigation was aimed to substantiate the potentiality of melt sonocrystallized gastroretentive tablets of curcumin. Melt sonocrystallized curcumin (MSC CMN) was developed and its therapeutic potential was validated by in vitro cytotoxicity studies against Human oral cancer cell line KB. MSC curcumin was then formulated as floating tablet and evaluated. MSC form of CMN exhibited 2.36-fold and 2.40-fold solubility enhancement in distilled water and phosphate buffer, pH 4.5, respectively, better flow properties and intrinsic dissolution rate (0.242 ± 1.42 and 0.195 ± 1.26 mg/cm²/min) in comparison to its original form. The GI₅₀ value of MSC CMN was found to be less than 10, specifying inhibition of growth more effectively at its least concentration by 50%. The gastroretentive-floating tablet (Formulation F4) displayed controlled drug release (96.22% ± 1.43%) for over 12 h. The present study revealed melt sonocrystallization can be used to produce particles with superior biopharmaceutical properties without the use of organic solvents or the addition of other excipients, and amenable to formulation in to a pharmaceutical dosage form. Full article

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5008 KiB

Open AccessArticle

Liposomal Conjugates for Drug Delivery to the Central Nervous System

by Frieder Helm and Gert Fricker

Pharmaceutics 2015, 7(2), 27-42; https://doi.org/10.3390/pharmaceutics7020027 - 1 Apr 2015

Cited by 36 | Viewed by 9503

Abstract

Treatments of central nervous system (CNS) diseases often fail due to the blood–brain barrier. Circumvention of this obstacle is crucial for any systemic treatment of such diseases to be effective. One approach to transfer drugs into the brain is the use of colloidal carrier systems—amongst others, liposomes. A prerequisite for successful drug delivery by colloidal carriers to the brain is the modification of their surface, making them invisible to the reticuloendothelial system (RES) and to target them to specific surface epitopes at the blood–brain barrier. This study characterizes liposomes conjugated with cationized bovine serum albumin (cBSA) as transport vectors in vitro in porcine brain capillary endothelial cells (PBCEC) and in vivo in rats using fluorescently labelled liposomes. Experiments with PBCEC showed that sterically stabilized (PEGylated) liposomes without protein as well as liposomes conjugated to native bovine serum albumin (BSA) were not taken up. In contrast, cBSA-liposomes were taken up and appeared to be concentrated in intracellular vesicles. Uptake occurred in a concentration and time dependent manner. Free BSA and free cBSA inhibited uptake. After intravenous application of cBSA-liposomes, confocal fluorescence microscopy of brain cryosections from male Wistar rats showed fluorescence associated with liposomes in brain capillary surrounding tissue after 3, 6 and 24 h, for liposomes with a diameter between 120 and 150 nm, suggesting successful brain delivery of cationized-albumin coupled liposomes. Full article

(This article belongs to the Special Issue Drug Delivery to Brain)

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1371 KiB

Open AccessArticle

Effects of Mitragynine and a Crude Alkaloid Extract Derived from Mitragyna speciosa Korth. on Permethrin Elimination in Rats

by Kachamas Srichana, Benjamas Janchawee, Sathaporn Prutipanlai, Pritsana Raungrut and Niwat Keawpradub

Pharmaceutics 2015, 7(2), 10-26; https://doi.org/10.3390/pharmaceutics7020010 - 27 Mar 2015

Cited by 14 | Viewed by 8064

Abstract

Detoxification and elimination of permethrin (PM) are mediated by hydrolysis via carboxylesterase (CES). Mitragyna speciosa (kratom) contains mitragynine (MG) and other bioactive alkaloids. Since PM and MG have the same catalytic site and M. speciosa is usually abused by adding other ingredients such as pyrethroid insecticides, the effects of MG and an alkaloid extract (AE) on the elimination of PM were investigated in rats. Rats were subjected to single and multiple pretreatment with MG and AE prior to receiving a single oral dose (460 mg/kg) of PM. Plasma concentrations of trans-PM and its metabolite phenoxybenzylalcohol (PBAlc) were measured. The elimination rate constant (k_el) and the elimination half-life (t_{1/2 el}) of PM were determined, as well as the metabolic ratio (PMR). A single and multiple oral pretreatment with MG and AE altered the plasma concentration-time courses of both trans-PM and PBAlc during 8–22 h, decreased the PMRs, delayed elimination of PM, but enhanced elimination of PBAlc. Results indicated that PM–MG or AE toxicokinetic interactions might have resulted from the MG and AE interfering with PM hydrolysis. The results obtained in rats suggest that in humans using kratom cocktails containing PM, there might be an increased risk of PM toxicity due to inhibition of PM metabolism and elimination. Full article

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