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ACS Macro Letters Oct 2021Among zwitterionic structures, the choline phosphate (CP) group is uniquely attractive for its ability to access novel chemical compositions that embed functional groups...
Among zwitterionic structures, the choline phosphate (CP) group is uniquely attractive for its ability to access novel chemical compositions that embed functional groups directly into the zwitterionic moiety. This paper describes the attachment of fluorinated alkyl groups to CP moieties, yielding zwitterionic monomers and that proved amenable to controlled free radical polymerization and the production of a new set of CP-containing fluorinated polymers and copolymers with phosphorylcholine (PC) zwitterions. This combination of fluorinated hydrocarbons and zwitterions affords novel, water-soluble polymeric amphiphiles that we have examined at fluid interfaces, as coatings, in cell culture, and in magnetic resonance imaging.
Topics: Fluorocarbon Polymers; Phosphates; Phosphorylcholine; Polymerization; Polymers
PubMed: 35549047
DOI: 10.1021/acsmacrolett.1c00451 -
Pharmaceutical Research May 2020Hemolysis is a serious side effect of antitumor alkylphospholipids (APLs) that limits dose levels and is a constraint in their use in therapeutic regimen. Nine prodrugs...
PURPOSE
Hemolysis is a serious side effect of antitumor alkylphospholipids (APLs) that limits dose levels and is a constraint in their use in therapeutic regimen. Nine prodrugs of promising APLs (miltefosine, perifosine, and erufosine) were synthesized so as to decrease their membrane activity and improve their toxicity profile while preserving their antineoplastic potency.
METHODS
The synthesis of the pro-APLs was straightforwardly achieved in one step starting from the parent APLs. The critical aggregation concentration of the prodrugs, their hydrolytic stability under various pH conditions, their blood compatibility and cytotoxicity in three different cell lines were determined and compared to those of the parent antitumor lipids.
RESULTS
The APL prodrugs display antitumor activity which is similar to that of the parent alkylphospholipids but without associated hemolytic toxicity.
CONCLUSION
The pro-APL compounds may be considered as intravenously injectable derivatives of APLs. They could thus address one of the major issues met in cancer therapies involving antitumor lipids and restricting their utilization to oral and topical administration because of limited maximum tolerated dose.
Topics: Administration, Intravenous; Antineoplastic Agents; Cell Line, Tumor; Drug Screening Assays, Antitumor; Drug Stability; Hemolysis; Humans; Maximum Tolerated Dose; Neoplasms; Organophosphates; Phosphorylcholine; Prodrugs; Quaternary Ammonium Compounds
PubMed: 32462253
DOI: 10.1007/s11095-020-02830-y -
Macromolecular Bioscience Apr 2023After cardiac surgery, tissue damage to the heart may cause adhesion between heart and its surrounding tissues. Post-operative cardiac adhesion may lead to limited...
After cardiac surgery, tissue damage to the heart may cause adhesion between heart and its surrounding tissues. Post-operative cardiac adhesion may lead to limited normal cardiac function, decreased quality of cardiac surgery, and increased risk of major bleeding during reoperation. Therefore, it is necessary to develop an effective anti-adhesion therapy to overcome cardiac adhesion. An injectable polyzwitterionic lubricant is developed to prevent adhesion between the heart and surrounding tissues and to maintain normal pumping function of the heart. This lubricant is evaluated in a rat heart adhesion model. Poly (2-methacryloyloxyethyl phosphorylcholine) (i.e., PMPC) polymers are successfully prepared via free radical polymerization of monomer MPC, and the optimal lubricating performance, biocompatibility both in vitro and in vivo is demonstrated. Besides, a rat heart adhesion model is conducted to evaluate the bio-functionality of lubricated PMPC. The results prove that PMPC is a promising lubricant for complete adhesion-prevention. The injectable polyzwitterionic lubricant shows excellent lubricating properties and biocompatibility and can effectively prevent cardiac adhesion.
Topics: Lubricants; Methacrylates; Polymers; Phosphorylcholine; Surface Properties
PubMed: 36866621
DOI: 10.1002/mabi.202200554 -
ACS Macro Letters May 2023Proteins have tremendous potential for vaccine development and disease treatment, but multiple extracellular and intracellular biological barriers must be overcome...
Proteins have tremendous potential for vaccine development and disease treatment, but multiple extracellular and intracellular biological barriers must be overcome before they can exert specific biological functions in the target tissue. The use of polymers as carriers would greatly improve their bioavailability and therapeutic efficiency. Nevertheless, effective protein packaging and cell membrane penetration without causing cytotoxicity is particularly challenging, due largely to the simultaneous distribution of positive and negative charges on protein surface. Here, phosphocholine-functionalized zwitterionic poly(β-amino ester)s, HPAE-D-(±), are developed for cytoplasmic protein delivery. The zwitterionic phosphocholine is capable of binding to both proteins and the cell membrane to facilitate protein packaging and nanoparticle cellular uptake. Compared to amine-functionalized HPAE-E-(+) and carboxylic acid-functionalized HPAE-C-(-), HPAE-D-(±) exhibits much higher cytoplasmic protein delivery efficiency and lower cytotoxicity. In addition, HPAE-D-(±) are readily degraded in aqueous solution. This strategy may be extended to other zwitterions and polymers, thus having profound implications for the development of safe and efficient protein delivery systems.
Topics: Phosphorylcholine; Esters; Polymers
PubMed: 37094219
DOI: 10.1021/acsmacrolett.3c00155 -
Advances in Protein Chemistry and... 2022Transporter proteins, P-glycoprotein (P-gp) and P4ATPase-CDC50, are responsible for the transport of Miltefosine drug across cell membrane of a protozoan parasite...
Transporter proteins, P-glycoprotein (P-gp) and P4ATPase-CDC50, are responsible for the transport of Miltefosine drug across cell membrane of a protozoan parasite Leishmania major. Mutations or change in activity of these proteins may lead to emergence of resistance in the parasite. Owing to the structural and functional importance of these transporter proteins, we have tried to decipher the evolutionary divergence of these Miltefosine transporter proteins across different forms of life including Protists, Fungi, Plants and Animals. We retrieved 96, 207, and 189 sequences of P-gp, P4ATPase and CDC50 proteins respectively, across diverse variety of organisms for the conserved analysis. Phylogenetic trees were constructed for these three transporter proteins based on Bayesian posterior probability inference. The evolutionary analysis concluded that these proteins remain highly conserved throughout the species diversity but still substantial differences in the proteins for host (Homo sapiens) and parasite (L. major) were observed which have led in targeting these Miltefosine transporter proteins in a parasite specific manner. The functional and structural components observed in terms of pattern resulting from the variability in the phylogenetic tree are outlined.
Topics: Animals; Bayes Theorem; Leishmania major; Phosphorylcholine; Phylogeny
PubMed: 35534115
DOI: 10.1016/bs.apcsb.2022.01.005 -
Current Vascular Pharmacology 2022Negatively charged nanoliposomes have a strong attraction towards plasma lipoprotein particles and can thereby regulate lipid metabolism. Here, the impact of such...
BACKGROUND AND AIM
Negatively charged nanoliposomes have a strong attraction towards plasma lipoprotein particles and can thereby regulate lipid metabolism. Here, the impact of such nanoliposomes on dyslipidaemia and progression of atherosclerosis was investigated in a rabbit model.
METHODS
Two sets of negatively-charged nanoliposome formulations including [Hydrogenated Soy Phosphatidylcholine (HSPC)/1,2-distearoyl-sn-glycero-3- phosphoglycerol (DSPG)] and [1,2- Dimyristoyl-sn-glycero-3-phosphorylcholine (DMPC)/1,2-Dimyristoyl-sn-glycero-3-phosphorylcholine (DMPG)/Cholesterol] were evaluated. Rabbits fed a high-cholesterol diet were randomly divided into 3 groups (n=5/group) intravenously administrated with HSPC/DSPG formulation (DSPG group; 100 mmol/kg), DMPC/DMPG formulation (DMPG group; 100 mmol/kg), or the normal saline (control group; 0.9% NaCl) over a 4-week period. The atherosclerotic lesions of the aortic arch wall were studied using haematoxylin and eosin staining.
RESULTS
Both DSPG and DMPG nanoliposome formulations showed a nano-sized range in diameter with a negatively-charged surface and a polydispersity index of <0.1. After 4 weeks administration, the nanoliposome formulations decreased triglycerides (-62±3% [DSPG group] and -58±2% [DMPG group]), total cholesterol (-58±9% [DSPG group] and -37±5% [DMPG group]), and lowdensity lipoprotein cholesterol (-64±6% [DSPG group] and -53±10% [DMPG group]) levels, and increased high-density lipoprotein cholesterol (+67±28% [DSPG group] and +35±19% [DMPG group]) levels compared with the controls. The nanoliposomes showed a significant decrease in the severity of atherosclerotic lesions: mean values of the intima to media ratio in DMPG (0.96±0.1 fold) and DSPG (0.54±0.02 fold) groups were found to be significantly lower than that in the control (1.2±0.2 fold) group (p<0.05).
CONCLUSION
Anionic nanoliposomes containing [HSPC/DSPG] and [DMPC/DMPG] correct dyslipidaemia and inhibit the progression of atherosclerosis.
Topics: Animals; Rabbits; Atherosclerosis; Cholesterol; Dimyristoylphosphatidylcholine; Dyslipidemias; Liposomes; Nanoparticles; Phosphorylcholine
PubMed: 34414873
DOI: 10.2174/1570161119666210820115150 -
Journal of Cellular and Molecular... Jan 2023An acidic environment and hypoxia within the tumour are hallmarks of cancer that contribute to cell resistance to therapy. Deregulation of the PI3K/Akt pathway is common...
An acidic environment and hypoxia within the tumour are hallmarks of cancer that contribute to cell resistance to therapy. Deregulation of the PI3K/Akt pathway is common in colon cancer. Numerous Akt-targeted therapies are being developed, the activity of Akt-inhibitors is, however, strongly pH-dependent. Combination therapy thus represents an opportunity to increase their efficacy. In this study, the cytotoxicity of the Akt inhibitor perifosine and the Bcl-2/Bcl-xL inhibitor ABT-737 was tested in colon cancer HT-29 and HCT-116 cells cultured in monolayer or in the form of spheroids. The efficacy of single drugs and their combination was analysed in different tumour-specific environments including acidosis and hypoxia using a series of viability assays. Changes in protein content and distribution were determined by immunoblotting and a "peeling analysis" of immunohistochemical signals. While the cytotoxicity of single agents was influenced by the tumour-specific microenvironment, perifosine and ABT-737 in combination synergistically induced apoptosis in cells cultured in both 2D and 3D independently on pH and oxygen level. Thus, the combined therapy of perifosine and ABT-737 could be considered as a potential treatment strategy for colon cancer.
Topics: Humans; Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Colonic Neoplasms; Drug Synergism; Phosphatidylinositol 3-Kinases; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-akt; Tumor Microenvironment; Phosphorylcholine
PubMed: 36523175
DOI: 10.1111/jcmm.17636 -
Turkiye Parazitolojii Dergisi May 2022Leishmaniasis is the second deadliest parasitic disease in the World Health Organisation's list of neglected diseases, following malaria. Cutaneous leishmaniasis (CL) is...
OBJECTIVE
Leishmaniasis is the second deadliest parasitic disease in the World Health Organisation's list of neglected diseases, following malaria. Cutaneous leishmaniasis (CL) is the most common form of the disease and it is one of the few communicable diseases with increasing incidence rates owing to factors like armed conflicts and climate change. CL can be divided into two major groups: Acute CL (ACL) and chronic CL (CCL). The aim of this study was to compare the efficacy of miltefosine and pentavalent antimony compounds in the CCL patient samples.
METHODS
Five isolates previously isolated from 5 CCL patients were included in this study. Genotyping is performed using internal transcribed spacer 1 (ITS 1) gene region real-time PCR. drug efficacy tests were applied to determine their activity against meglumine antimoniate (MA) and miltefosine. Serial dilutions (512, 256, 128, 64, 32, 16, 8 and 4 µg/mL) prepared from MA and miltefosine were prepared in 96-well flat-bottom cell culture plates and incubated at 24 °C for 48 hours. The efficacy of the drug on spp. promastigotes after 24 and 48 hours was evaluated by hemocytometer slide and XTT cell viability test.
RESULTS
All of the samples were genotyped as . Evaluation of 24 and 48 hours showed, 128 µg/mL and 256 µg/mL and 32 µg/mL and 64 µg/mL concentrations of miltefosine and MA were enough to kill all the promastigotes respectively. The results of the hemocytometer slide and XTT were consistent.
CONCLUSION
There are no studies investigating the efficacy of miltefosine with the CCL patient group. To overcome the treatment challenges experienced in this special patient group, more studies are needed. According to our results, it is concluded that miltefosine is efficient for the treatment of CCL and further clinical studies with miltefosine will reveal valuable data.
Topics: Antiprotozoal Agents; Humans; Leishmaniasis, Cutaneous; Meglumine Antimoniate; Phosphorylcholine
PubMed: 35604185
DOI: 10.4274/tpd.galenos.2022.85856 -
Langmuir : the ACS Journal of Surfaces... Jul 2023As the key component of extracorporeal membrane oxygenation (ECMO), artificial lung membranes have low gas permeability and plasma leakage problems, and the contact...
As the key component of extracorporeal membrane oxygenation (ECMO), artificial lung membranes have low gas permeability and plasma leakage problems, and the contact between membrane materials and blood can cause coagulation, leading to the blockage of medical equipment and seriously threatening the safety of human life. In our work, poly(4-methyl-1-pentene) hollow fiber membranes (PMP HFMs) were prepared by the thermally induced phase separation (TIPS) method, the redox method was adopted for the surface hydroxylation of PMP HFMs, and then, heparin (Hep) and 2-(methacryloyloxy)ethyl(2-(trimethylammonio)ethyl) phosphate (MPC) were grafted to the surface of PMP HFMs to prepare anticoagulant coatings. The gas permeability and hemo-compatibility of the coatings were investigated by various characterization methods, such as gas flow meter, scanning electron microscope, extracorporeal circulation experiment, etc. The results show that PMP HFMs possess a bicontinuous pore structure with a dense surface layer, which could maintain good gas permeability with an oxygen permeance of 0.8 mL/bar·cm·min and stable gas selectivity. Furthermore, the whole blood circulation of rabbit indicated that a composite surface of bioactive Hep and biopassive MPC might be used as artificial lung membranes without the formation of thrombosis within 21 days.
Topics: Animals; Humans; Rabbits; Membranes, Artificial; Phosphorylcholine; Heparin; Lung; Oxygen
PubMed: 37427880
DOI: 10.1021/acs.langmuir.3c00945 -
Frontiers in Cellular and Infection... 2022Drug repurposing and combination therapy have been proposed as cost-effective strategies to improve Chagas disease treatment. Miltefosine (MLT), a synthetic...
Drug repurposing and combination therapy have been proposed as cost-effective strategies to improve Chagas disease treatment. Miltefosine (MLT), a synthetic alkylphospholipid initially developed for breast cancer and repositioned for leishmaniasis, is a promising candidate against infection. This study evaluates the efficacy of MLT as a monodrug and combined with benznidazole (BZ) in both and models of infection with (VD strain, DTU TcVI). MLT exhibited activity on amastigotes and trypomastigotes with values of IC 0.51 µM (0.48 µM; 0,55 µM) and LC 31.17 µM (29.56 µM; 32.87 µM), respectively. Drug interaction was studied with the fixed-ration method. The sum of the fractional inhibitory concentrations (ΣFICs) resulted in ∑FIC= 0.45 for trypomastigotes and ∑FIC= 0.71 for amastigotes, suggesting synergistic and additive effects, respectively. No cytotoxic effects on host cells were observed. MLT efficacy was also evaluated in a murine model of acute infection alone or combined with BZ. Treatment was well tolerated with few adverse effects, and all treated animals displayed significantly lower mean peak parasitemia and mortality than infected non-treated controls (p<0.05). The studies showed that MLT led to a dose-dependent parasitostatic effect as monotherapy which could be improved by combining with BZ, preventing parasitemia rebound after a stringent immunosuppression protocol. These results support MLT activity in clinically relevant stages from , and it is the first report of positive interaction with BZ, providing further support for evaluating combined schemes using MLT and exploring synthetic alkylphospholipids as drug candidates.
Topics: Animals; Chagas Disease; Mice; Nitroimidazoles; Parasitemia; Phosphorylcholine; Trypanocidal Agents; Trypanosoma cruzi
PubMed: 35865815
DOI: 10.3389/fcimb.2022.855119