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International Journal of Nanomedicine 2021The purpose of this study was to investigate the suitability of nanostructured lipid carriers (NLCs) loaded with miltefosine (HePC) as an anticancer drug for the...
BACKGROUND
The purpose of this study was to investigate the suitability of nanostructured lipid carriers (NLCs) loaded with miltefosine (HePC) as an anticancer drug for the treatment of breast cancer.
METHODS
HePC-NLCs were prepared using a microemulsion technique and then evaluated for particle size, polydispersity index (PDI), incorporation efficiency, in vitro release of entrapped drug, and hemolytic potential. Furthermore, pharmacokinetic, biodistribution, and liver toxicity analyses were performed in Sprague-Dawley rats, and antitumor efficacy was evaluated in Michigan Cancer Foundation-7 (MCF-7) and squamous cell carcinoma-7 (SCC-7) cells in vitro and in tumour-bearing BALB/c mice in vivo. Advanced analyses including survival rate, immunohistopathology, and terminal deoxynucleotidyl transferase dUTP nick end labelling (TUNEL) assays were performed to evaluate apoptosis in vivo.
RESULTS
The average particle size of the HePC-NLCs was 143 ± 16 nm, with a narrow PDI (0.104 ± 0.002), and the incorporation efficiency was found to be 91 ± 7%. The NLCs released HePC in a sustained manner, and this release was significantly lower than that of free drug. The in vitro hemolytic assay demonstrated a significantly reduced hemolytic potential (~9%) of the NLCs compared to that of the test formulations. The HePC-NLCs demonstrated enhanced pharmacokinetic behaviour over free drug, including extended blood circulation and an abridged clearance rate in rats. Furthermore, the HePC-NLCs exhibited higher cytotoxicity than the free drug in MCF-7 and SCC-7 cells. Moreover, the HePC-NLCs showed significantly enhanced ( < 0.005) antitumor activity compared to that of the control and free drug-treated mouse groups. Tumour cell apoptosis was also confirmed, indicating the antitumor potential of the HePC-NLCs.
CONCLUSION
These findings demonstrate the ability of NLCs as a drug delivery system for enhanced pharmacokinetic, antitumor, and apoptotic effects, most importantly when loaded with HePC.
Topics: Animals; Antineoplastic Agents; Apoptosis; Drug Carriers; Humans; Lipids; MCF-7 Cells; Male; Mice; Mice, Inbred BALB C; Nanostructures; Particle Size; Phosphorylcholine; Rats; Rats, Sprague-Dawley; Tissue Distribution
PubMed: 34012260
DOI: 10.2147/IJN.S299443 -
Biomaterials Science Sep 2021Poly(ethylene glycol) (PEG) is frequently used for liposomal surface modification. However, as PEGylated liposomes are cleared rapidly from circulation upon repeated...
Synthesis of poly(2-methacryloyloxyethyl phosphorylcholine)-conjugated lipids and their characterization and surface properties of modified liposomes for protein interactions.
Poly(ethylene glycol) (PEG) is frequently used for liposomal surface modification. However, as PEGylated liposomes are cleared rapidly from circulation upon repeated injections, substitutes of PEG are being sought. We focused on a water-soluble polymer composed of 2-methacryloyloxyethyl phosphorylcholine (MPC) units, and synthesized poly(MPC) (PMPC)-conjugated lipid (PMPC-lipid) with degrees of MPC polymerization ranging from 10 to 100 (calculated molecular weight: 3 to 30 kDa). In addition, lipids with three different alkyl chains, myristoyl, palmitoyl, and stearoyl, were applied for liposomal surface coating. We studied the interactions of PMPC-lipids with plasma albumin, human complement protein C3 and fibrinogen using a quartz crystal microbalance with energy dissipation, and found that adsorption of albumin, C3 and fibrinogen could be suppressed by coating with PMPC-lipids. In particular, the effect was more pronounced for PMPC chains with higher molecular weight. We evaluated the size, polydispersity index, surface charge, and membrane fluidity of the PMPC-lipid-modified liposomes. We found that the effect of the coating on the dispersion stability was maintained over a long period (98 days). Furthermore, we also demonstrated that the anti-PEG antibody did not interact with PMPC-lipids. Thus, our findings suggest that PMPC-lipids can be used for liposomal coating.
Topics: Humans; Lipids; Liposomes; Methacrylates; Phosphorylcholine; Polymethacrylic Acids; Surface Properties
PubMed: 34286724
DOI: 10.1039/d1bm00570g -
PloS One 2021Wound healing after Ahmed glaucoma valve (AGV) implantation often entails fibrosis as a foreign body reaction to the silicone plate. Poly(2-methacryloyloxyethyl...
PURPOSE
Wound healing after Ahmed glaucoma valve (AGV) implantation often entails fibrosis as a foreign body reaction to the silicone plate. Poly(2-methacryloyloxyethyl phosphorylcholine) (PMPC) forms an antifouling surface that inhibits fibrosis during wound healing. In this study, we aimed to compare the effects of the implantation of AGV coated with PMPC (wPMPC) versus AGV without PMPC (woPMPC) in rabbits.
METHODS
Six New Zealand White rabbit does underwent AGV implantation in both eyes. For each rabbit, one eye was randomly selected for implantation of AGV wPMPC and a conventional AGV (woPMPC) was implanted in the contralateral eye. Gross conjunctival vascularity was compared between the two groups at the first, second, and fourth weeks after surgery. The eyes were enucleated in four weeks and subjected to staining with hematoxylin and eosin and Masson's trichrome stain. The fibrosis and inflammation status among the eye samples were compared by measuring the thickness of the fibrotic walls and counting the number of chronic inflammatory cells around the AGV. Counting of inflammatory cells and measuring fibrotic wall thickness were done in a blinded method to eliminate observer bias. Statistical analysis was performed using the Mann-Whitney U test.
RESULTS
Gross and histological examinations revealed no toxic effects of PMPC. There were no apparent differences in overall conjunctival vascularity between the two groups at weeks 1, 2, and 4 after surgery. The average inflammatory cell counts were 14.3 ± 5.8 per slide and 27.3 ± 8.6 per slide in the wPMPC and woPMPC groups, respectively (p = 0.037). The average thicknesses of the fibrotic wall were 57.9 ± 11.3 μm and 81.5 ± 21.3 μm in the wPMPC and woPMPC groups, respectively (p = 0.025).
CONCLUSION
Compared to the woPMPC group, the number of inflammatory cells and fibrosis were significantly decreased in the wPMPC group.
Topics: Animals; Eye; Eye Foreign Bodies; Fibrosis; Foreign-Body Reaction; Glaucoma Drainage Implants; Models, Animal; Phosphorylcholine; Polymethacrylic Acids; Rabbits; Silicones; Wound Healing
PubMed: 34048489
DOI: 10.1371/journal.pone.0252467 -
Organic & Biomolecular Chemistry Jan 2020Phosphocholine is a small haptenic molecule that is both a precursor and degradation product of choline. Phosphocholine decorates a number of biologics such as lipids...
Phosphocholine is a small haptenic molecule that is both a precursor and degradation product of choline. Phosphocholine decorates a number of biologics such as lipids and oligosaccharides. In this study, an air and bench stable phosphocholine donor has been developed and evaluated with a number of alcohol acceptors. Using a one-pot, three-step sequence, (phosphitylation, oxidation, and phosphate deprotection) phosphocholine derivatives are synthesized in high yields. Of particular interest is the synthesis of miltefosine, the lone oral drug approved to treat leishmaniasis. Due to its prohibitive expense ($1500 per g), miltefosine is not accesable for the majority of the world's patients. Based on the described reaction sequence, this drug can be produced for $25 per g.
Topics: Alcohols; Antiprotozoal Agents; Indicators and Reagents; Models, Chemical; Oxidation-Reduction; Phosphorylcholine
PubMed: 31912847
DOI: 10.1039/c9ob02582k -
Biophysical Journal May 2019The dynamics of phosphocholine and maltoside micelles, detergents frequently used for membrane protein structure determination, were investigated using electron...
The dynamics of phosphocholine and maltoside micelles, detergents frequently used for membrane protein structure determination, were investigated using electron paramagnetic resonance of spin probes doped into the micelles. Specifically, phosphocholines are frequently used detergents in NMR studies, and maltosides are frequently used in x-ray crystallography structure determination. Beyond the structural and electrostatic differences, this study aimed to determine whether there are differences in the local chain dynamics (i.e., fluidity). The nitroxide probe rotational dynamics in longer chain detergents is more restricted than in shorter chain detergents, and maltoside micelles are more restricted than phosphocholine micelles. Furthermore, the micelle microviscosity can be modulated with mixtures, as demonstrated with mixtures of 3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonate with n-dodecylphosphocholine, n-tetradecylphosphocholine, n-decyl-β-D-maltoside, or n-dodecyl-β-D-maltoside. These results indicate that observed differences in membrane protein stability in these detergents could be due to fluidity in addition to the already determined structural differences.
Topics: Cholic Acids; Maltose; Membrane Fluidity; Micelles; Oxygen; Phosphorylcholine
PubMed: 31023535
DOI: 10.1016/j.bpj.2019.03.019 -
Drug Delivery and Translational Research Jan 2022Cutaneous leishmaniasis (CL) is a neglected tropical disease endemic in ~ 90 countries, with an increasing incidence. Presently available pharmacotherapy implies the...
Cutaneous leishmaniasis (CL) is a neglected tropical disease endemic in ~ 90 countries, with an increasing incidence. Presently available pharmacotherapy implies the systemic administration of moderately/very toxic drugs. Miltefosine (Milt) is the only FDA-approved drug to treat CL via the oral route (Impavido®). It produces side effects; in particular, teratogenic effects are of concern. A topical treatment would have the great advantage of minimising the systemic circulation of the drug, preventing side effects. We prepared dispersions containing Milt and liposomes of different compositions to enhance/modulate trans-epidermal penetration and evaluated in vitro and in vivo efficacy and toxicity, in vitro release rate of the drug and particles size stability with time. Treatments were topically administered to BALB/c mice infected with Leishmania (Leishmania) amazonensis. The dispersions containing 0.5% Milt eliminated 99% of the parasites and cured the lesions with a complete re-epithelisation, no visible scar and re-growth of hair. Fluid liposomes decreased the time to heal the lesion and the time needed to eliminate viable amastigotes from the lesion site. Relapse of the infection was not found 1 month after treatment in any case. Ultraflexible liposomes on the other hand had no significant in vitro effect but decreased in vivo efficacy. A topical Milt formulation including fluid liposomes seems a promising treatment against CL.
Topics: Animals; Leishmania; Leishmaniasis, Cutaneous; Mice; Mice, Inbred BALB C; Models, Theoretical; Phosphorylcholine
PubMed: 33502733
DOI: 10.1007/s13346-021-00896-8 -
Antimicrobial Agents and Chemotherapy Mar 2017An open-label pharmacokinetics (PK) clinical trial was conducted to comparatively assess the PK and explore the pharmacodynamics (PD) of miltefosine in children and... (Clinical Trial)
Clinical Trial
An open-label pharmacokinetics (PK) clinical trial was conducted to comparatively assess the PK and explore the pharmacodynamics (PD) of miltefosine in children and adults with cutaneous leishmaniasis (CL) in Colombia. Sixty patients, 30 children aged 2 to 12 years and 30 adults aged 18 to 60 years, were enrolled. Participants received miltefosine (Impavido) at a nominal dose of 2.5 mg/kg/day for 28 days. Miltefosine concentrations were measured in plasma and peripheral blood mononuclear cells by liquid chromatography-tandem mass spectrometry of samples obtained during treatment and up to 6 months following completion of treatment, when therapeutic outcome was determined. Fifty-two patients were cured, 5 pediatric patients failed treatment, and 3 participants were lost to follow-up. () predominated among the strains isolated (42/46; 91%). Noncompartmental analysis demonstrated that plasma and intracellular miltefosine concentrations were, overall, lower in children than in adults. Exposure to miltefosine, estimated by area under the concentration-time curve and maximum concentration, was significantly lower in children in both the central and intracellular compartments ( < 0.01). persistence was detected in 43% of study participants at the end of treatment and in 27% at 90 days after initiation of treatment. Clinical response was not dependent on parasite elimination. miltefosine susceptibility was similar for strains from adults and children. Our results document PK differences for miltefosine in children and adults with cutaneous leishmaniasis that affect drug exposure and could influence the outcome of treatment, and they provide bases for optimizing therapeutic regimens for CL in pediatric populations. (This study has been registered at ClinicalTrials.gov under identifier NCT01462500.).
Topics: Adolescent; Adult; Antiprotozoal Agents; Area Under Curve; Child; Child, Preschool; Drug Administration Schedule; Female; Humans; Leishmania braziliensis; Leishmania guyanensis; Leishmaniasis, Cutaneous; Leukocytes, Mononuclear; Male; Middle Aged; Parasitic Sensitivity Tests; Phosphorylcholine; Treatment Outcome
PubMed: 27956421
DOI: 10.1128/AAC.02198-16 -
Naunyn-Schmiedeberg's Archives of... Nov 2021The molecular chaperone HSP90 facilitates the maturation of newly synthesized and unfolded proteins. The client proteins of HSP90 are involved in many processes of...
The molecular chaperone HSP90 facilitates the maturation of newly synthesized and unfolded proteins. The client proteins of HSP90 are involved in many processes of cancer occurrence and development, and therefore, HSP90 is considered as a promising target for the development of anticancer drugs. In contrast to N-terminal inhibitor, C-terminal inhibitor does not induce the pro-survival heat shock response. In order to get novel HSP90 C-terminal inhibitors and more evidences that HSP90 inhibitors could be applied in the therapy of cancer, we conducted a virtual screening toward HSP90 C-terminus from FDA-approved drugs. In this study, miltefosine and octenidine were identified as new HSP90 inhibitors. Miltefosine and octenidine exhibited strong and broad-spectrum anticancer activity and inhibited the proliferation of cancer cell by promoting apoptosis. Western blotting analysis revealed that miltefosine and octenidine significantly down-regulated the expression levels of HSP90 client proteins including p-AKT, CDK6, and ERK, and did not induce overexpression of heat shock proteins including HSP70 and HSP90 in MCF-7 cells. These results were in accordance with the characteristics of HSP90 C-terminal inhibitor. In conclusion, miltefosine and octenidine could disrupt the molecular chaperone function of HSP90, and thus, their strong and broad-spectrum anticancer activity is at least in part attributed to the inhibition activity against HSP90.
Topics: A549 Cells; Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Cell Proliferation; Down-Regulation; Gene Expression Regulation, Neoplastic; HSP70 Heat-Shock Proteins; HSP90 Heat-Shock Proteins; Humans; Imines; MCF-7 Cells; Neoplasms; Phosphorylcholine; Pyridines
PubMed: 34406420
DOI: 10.1007/s00210-021-02133-y -
Biomaterials Science Aug 2016In this study, cisplatin (cis-diaminedichloroplatinum, CDDP) nanocarriers with phosphorylcholine surface tailoring were developed to enhance the anti-tumor potential of...
In this study, cisplatin (cis-diaminedichloroplatinum, CDDP) nanocarriers with phosphorylcholine surface tailoring were developed to enhance the anti-tumor potential of CDDP for the treatment of osteosarcoma. Poly(2-methacryloyloxyethyl phosphorylcholine)-b-poly(methacrylic acid) (PMPC-b-PMAA) was synthesized for the preparation of CDDP/PMPC-b-PMAA micelles. The synthesis, self-assembly, and in vitro drug release were well characterized. In vitro cytotoxicity showed that CDDP/PMPC-b-PMAA micelles can strongly inhibit the proliferation of Saos-2 cells. In vivo experiments indicated that CDDP/PMPC-b-PMAA micelles showed prolonged circulation time, reduced renal accumulation, and enhanced tumor accumulation compared to free CDDP. Overall, the CDDP/PMPC-b-PMAA micelles exhibited optimal anti-tumor activity with minimal side effects in the treatment of osteosarcoma.
Topics: Animals; Antineoplastic Agents; Cell Line, Tumor; Cisplatin; Drug Carriers; Drug Liberation; Female; Human Umbilical Vein Endothelial Cells; Humans; Male; Mice; Mice, Inbred BALB C; Micelles; Nanomedicine; Osteosarcoma; Particle Size; Phosphorylcholine; Polymethacrylic Acids; Xenograft Model Antitumor Assays
PubMed: 27315174
DOI: 10.1039/c6bm00331a -
Tropical Medicine & International... Apr 2019Meglumine antimoniate (MA; Glucantime®), the 80-year-old first-line systemic treatment for all forms of American tegumentary leishmaniasis (ATL) caused by Leishmania... (Review)
Review
American tegumentary leishmaniasis in Brazil: a critical review of the current therapeutic approach with systemic meglumine antimoniate and short-term possibilities for an alternative treatment.
OBJECTIVES
Meglumine antimoniate (MA; Glucantime®), the 80-year-old first-line systemic treatment for all forms of American tegumentary leishmaniasis (ATL) caused by Leishmania (Viannia) braziliensis, Leishmania (Viannia) guyanensis and Leishmania (Leishmania) amazonensis, is highly toxic, presents adverse side-effects and may not attain clinical and parasitological cure. This critical review examines the necessity for intramuscular/intravenous administration of MA, the alternatives to this approach, and the possibilities of developing affordable, accessible and non-toxic drugs or new delivery methods.
METHOD
PubMed searches were performed using the terms 'cutaneous leishmaniasis' or 'American tegumentary leishmaniasis' in combination with 'meglumine antimoniate' or 'N-methyl glucamine' or 'drug repositioning' or 'nanotechnology'. Searches covered a period of 20 years of peer reviewed journals and technical bulletins. We explored the mode of action, pharmacokinetics, toxicity and efficacy of MA, evaluated the progress of ATL therapy in Brazil, and examined the potential of drug repositioning and nanotechnology in accelerating the introduction and/or optimisation of an alternative treatment.
RESULTS
The evidence suggests that ATL therapy will continue to rely on systemic MA in the foreseeable future even though an intralesional subcutaneous route has evolved over the last 10 years. The chances of developing a novel drug for ATL or a new mode of delivery of MA are low. While MA nanocarriers afford a promising approach, this technology is still in its infancy. A more immediate solution would be the production of a bioequivalent of miltefosine, an efficacious oral agent no longer protected by patent.
CONCLUSION
Development of a contemporary treatment requires governmental commitment in bringing together private and public sectors.
Topics: Antiprotozoal Agents; Brazil; Humans; Leishmania braziliensis; Leishmania guyanensis; Leishmaniasis, Cutaneous; Meglumine Antimoniate; Patents as Topic; Phosphorylcholine
PubMed: 30681239
DOI: 10.1111/tmi.13210