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1.
Nanotechnology ; 21(42): 425101, 2010 Oct 22.
Article in English | MEDLINE | ID: mdl-20858931

ABSTRACT

Single-walled carbon nanotubes (SWNTs) due to their unique structural and physicochemical properties, have been proposed as delivery systems for a variety of diagnostic and therapeutic agents. However, SWNTs have proven difficult to solubilize in aqueous solution, limiting their use in biological applications. In an attempt to improve SWNTs' solubility, biocompatibility, and to increase cell penetration we have thoroughly investigated the construction of carbon scaffolds coated with aliphatic carbon chains and phospholipids to obtain micelle-like structures. At first, oxidized SWNTs (2370 ± 30 nmol mg(-1) of SWNTs) were covalently coupled with an alcoholic chain (stearyl alcohol, C(18)H(37)OH; 816 nmol mg(-1) of SWNTs). Subsequently, SWNTs-COOC(18)H(37) derivatives were coated with phosphatidylethanolamine (PE) or -serine (PS) phospholipids obtaining micelle-like structures. We found that cellular uptake of these constructs by phagocytic cells occurs via an endocytotic mechanism for constructs larger than 400 nm while occurs via diffusion through the cell membrane for constructs up to 400 nm. The material that enters the cell by phagocytosis is actively internalized by macrophages and localizes inside endocytotic vesicles. In contrast the material that enters the cells by diffusion is found in the cell cytosol. In conclusion, we have realized new biomimetic constructs based on alkylated SWNTs coated with phospholipids that are efficiently internalized by different cell types only if their size is lower than 400 nm. These constructs are not toxic to the cells and could now be explored as delivery systems for non-permeant cargoes.


Subject(s)
Cell Membrane/metabolism , Fatty Alcohols/chemistry , Nanotubes, Carbon/chemistry , Phospholipids/chemistry , Cell Line , Cell Line, Tumor , Cell Membrane Permeability , Cell Survival , Fatty Alcohols/pharmacokinetics , Humans , Macrophages/cytology , Micelles , Nanotubes, Carbon/ultrastructure , Oxidation-Reduction , Phagocytosis , Phospholipids/pharmacokinetics , Solubility
2.
Antiviral Res ; 81(2): 93-102, 2009 Feb.
Article in English | MEDLINE | ID: mdl-18977391

ABSTRACT

In the attempt to eradicate HIV-1 infection, a strategy to eliminate macrophages, one of the most important cellular reservoirs in sustaining virus replication during HAART, could be of great benefit in the suppression of viral rebound. Aware of the ability of clodronate to cause macrophage depletion, the effect of the administration of clodronate encapsulated in erythrocytes on disease progression and on viral rebound was evaluated in a murine model of AIDS (MAIDS). One group of LP-BM5 retroviral complex-infected C57BL/6 mice received oral administrations of azidothymidine and dideoxyinosine daily for 12 weeks; two other groups received in addition, either clodronate-loaded erythrocytes or free clodronate at 7-10 day intervals. At the end of the treatment, the three groups maintained parameters characterizing disease progression similar to those of uninfected mice and showed a significantly lower level of BM5d DNA than infected mice in all organs and cells tested. To assess the viral rebound, some animals were left for an additional 4 month period without any treatment. After this time, the BM5d DNA content in blood leukocytes increased in all groups, but the group having received clodronate-loaded erythrocytes, in addition to transcriptase inhibitors, showed a significant delay in viral rebound.


Subject(s)
DNA, Viral/blood , Macrophages/immunology , Murine Acquired Immunodeficiency Syndrome/immunology , Viral Load , Animals , Anti-HIV Agents/administration & dosage , Clodronic Acid/administration & dosage , Didanosine/administration & dosage , Female , Immunologic Factors/administration & dosage , Leukocyte Reduction Procedures , Mice , Mice, Inbred C57BL , Murine Acquired Immunodeficiency Syndrome/drug therapy , Zidovudine/administration & dosage
3.
Adv Drug Deliv Rev ; 60(2): 286-95, 2008 Jan 14.
Article in English | MEDLINE | ID: mdl-17997501

ABSTRACT

Drug delivery has been greatly improved over the years by means of chemical and physical agents that increase bioavailability, improve pharmacokinetic and reduce toxicities. At the same time, cell based delivery systems have also been developed. These possesses a number of advantages including prolonged delivery times, targeting of drugs to specialized cell compartments and biocompatibility. Here we'll focus on erythrocyte-based drug delivery. These systems are especially efficient in releasing drugs in circulations for weeks, have a large capacity, can be easily processed and could accommodate traditional and biologic drugs. These carriers have also been used for delivering antigens and/or contrasting agents. Carrier erythrocytes have been evaluated in thousands of drug administration in humans proving safety and efficacy of the treatments. Erythrocyte-based delivery of new and conventional drugs is thus experiencing increasing interests in drug delivery and in managing complex pathologies especially when side effects could become serious issues.


Subject(s)
Cell Transplantation/methods , Drug Delivery Systems/methods , Erythrocytes/cytology , Animals , Drug Carriers , Erythrocytes/chemistry , Erythrocytes/metabolism , Humans , Macrophages/metabolism , Pharmaceutical Preparations/administration & dosage , Pharmaceutical Preparations/metabolism
4.
Article in English | MEDLINE | ID: mdl-18058516

ABSTRACT

Homo- and heterodimers of nucleoside/nucleotide analogues as reverse transcriptase inhibitors are effective on HIV-1-infected human monocyte-derived macrophages (M/M) compared to the single drugs or their combination. Since the combined treatment of lamivudine (3TC) and tenofovir ((R)PMPA) has an antiretroviral efficacy and a synergic effect respect to separate drugs, the heterodinucleotide 3TCpPMPA was synthesized. A single administration of the dimer as free drug or 3TCpPMPA-loaded RBC selectively targeted to M/M was able to almost completely protect macrophages from "de novo" infection.


Subject(s)
Adenine/analogs & derivatives , Anti-HIV Agents/administration & dosage , Lamivudine/analogs & derivatives , Organophosphonates/administration & dosage , Adenine/administration & dosage , Adenine/chemical synthesis , Adenine/chemistry , Anti-HIV Agents/chemical synthesis , Anti-HIV Agents/chemistry , Drug Delivery Systems , Drug Design , Erythrocytes/metabolism , HIV-1/drug effects , HIV-1/physiology , Humans , In Vitro Techniques , Lamivudine/administration & dosage , Lamivudine/chemical synthesis , Lamivudine/chemistry , Macrophages/drug effects , Macrophages/virology , Organophosphonates/chemical synthesis , Organophosphonates/chemistry , Tenofovir , Virus Replication/drug effects
5.
Eur Rev Med Pharmacol Sci ; 10(1): 27-31, 2006.
Article in English | MEDLINE | ID: mdl-16494108

ABSTRACT

BACKGROUND: We have recently demonstrated that low doses of Dexamethasone 21-P (Dex 21-P), loaded in autologous erythrocytes and administered at monthly intervals, have been able to maintain steroid-dependent patients with Crohn's disease (CD) and ulcerative colitis (UC) in clinical remission with a progressive and complete tapering of systemic steroids. AIM: Since multi-drug resistance 1 gene (MDR1) has a potential influence on Dexamethasone (Dex) bioavailability, we designed this study to investigate the correlation between MDR1 genotype and Dex pharmacokinetic after its delivery in patients with inflammatory bowel disease (IBD). MATERIALS AND METHODS: Seventeen steroid-dependent consecutive patients with IBD (10 UC mean age 36 +/- 12, and 7 Crohn's disease mean age 31 +/- 5) were consecutively recruited. The C3435T polymorphism of MDR1 gene was studied by Denaturing High Performance Liquid Chromatography (DHPLC). Serum level of Dex were determined at the end of the infusion and after 15 days by high performance liquid chromatography electrospray mass spectrometry. RESULTS: The mean dose of Dex 21-P administered was 9.9 mg +/- 4 (range 2.7-20.3), while the mean levels of Dex at the end of the infusion and after 15 days were 0.66 +/- 0.23 mM and 0.06 +/- 0.06 mM, respectively. Concerning the C3435T genotype, two patients were wild-type, eleven heterozygotes, and four homozygotes. No correlation between basal or 15-days plasma level of Dex and MDR1 genotype was found (r = 0.19 and r = 0.21, respectively). CONCLUSION: Our findings demonstrated that Dex plasma level, after infusion of autologous erythrocytes loaded with Dex 21-P are completely independent by the MDR 1 gene polymorphism. This could be another potential advantage of this modality of drug delivering.


Subject(s)
Colitis, Ulcerative/genetics , Crohn Disease/genetics , Dexamethasone/analogs & derivatives , Genes, MDR/genetics , Prodrugs/pharmacokinetics , Adult , Colitis, Ulcerative/drug therapy , Colitis, Ulcerative/metabolism , Crohn Disease/drug therapy , Crohn Disease/metabolism , Dexamethasone/administration & dosage , Dexamethasone/blood , Dexamethasone/pharmacokinetics , Drug Carriers , Erythrocytes , Female , Humans , Male , Middle Aged , Polymorphism, Genetic , Prodrugs/administration & dosage
7.
J Antimicrob Chemother ; 53(5): 863-6, 2004 May.
Article in English | MEDLINE | ID: mdl-15056645

ABSTRACT

OBJECTIVE: To evaluate the efficacy of erythrocytes loaded with the haemolytic toxin listeriolysin O against Mycobacterium avium replication within human macrophages. METHODS: Recombinant listeriolysin O was loaded in human erythrocytes by a procedure of hypotonic dialysis and isotonic resealing. Loaded erythrocytes were modified to allow them to be recognized and taken up by human macrophages infected with M. avium. The antimycobacterial activity of the erythrocytes loaded with listeriolysin O was evaluated by supernatant and intracellular cfu counts on days 4 and 7 post-erythrocyte administration. RESULTS: Recombinant listeriolysin O was encapsulated in human erythrocytes to reach final concentrations ranging from 1 to 4 ng/mL of erythrocytes. Erythrocytes loaded with increasing quantities of recombinant protein were able to reduce (at most by 50%) M. avium replication in a dose-dependent fashion when administered to infected macrophages. CONCLUSIONS: Erythrocytes loaded with listeriolysin O are effective against M. avium replication within macrophages. We are confident that the strategy presented could be useful against mycobacteria other than M. avium (such as Mycobacterium tuberculosis and Mycobacterium leprae) by itself or as part of an antimycobacterial treatment.


Subject(s)
Bacterial Toxins/pharmacology , Erythrocytes/chemistry , Heat-Shock Proteins/pharmacology , Hemolysin Proteins/pharmacology , Macrophages/microbiology , Mycobacterium avium/drug effects , Mycobacterium avium/growth & development , Cells, Cultured , Colony Count, Microbial , Hemolysis/drug effects , Humans , Macrophages/drug effects , Macrophages/ultrastructure , Microscopy, Electron , Recombinant Proteins/pharmacology
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