Biodistribution study and identification of inflammatory sites using nanocapsules labeled with 99mTc–HMPAO

Pereira, Maira Alves; Mosqueira, Vanessa Carla Furtado; Carmo, Vildete A.S.; Ferrari, Cristiano S.; Reis, Eduardo C. O.; Ramaldes, Gilson Andrade; Cardoso, Valbert Nascimento

doi:10.1097/mnm.0b013e32832f2b59

Cited by 21 publications

(19 citation statements)

References 24 publications

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“…The smaller size of LYC-PLA-PEG-NC could be attributed to a difference in the arrangement of the hydrophilic block of the PEG polymer on the NC surface, which influences interfacial tension between solvents during their mixing, generating particles of smaller size. Moreover, NC of small size are more prone to have access to infectious and inflammatory foci due to their ability to diffuse through the leaky endothelium (41). This aspect may be particularly interesting for CD treatment.…”

Section: Discussionmentioning

confidence: 99%

Efficacy of Lychnopholide Polymeric Nanocapsules after Oral and Intravenous Administration in Murine Experimental Chagas Disease

Mello

Branquinho

Oliveira

et al. 2016

Antimicrob Agents Chemother

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The etiological treatment of Chagas disease remains neglected. The compounds available show several limitations, mainly during the chronic phase. Lychnopholide encapsulated in polymeric nanocapsules (LYC-NC) was efficacious in mice infected with Trypanosoma cruzi and treated by intravenous administration during the acute phase (AP). As the oral route is preferred for treatment of chronic infections, such as Chagas disease, this study evaluated the use of oral LYC-NC in the AP and also compared it with LYC-NC administered to mice by the oral and intravenous routes during the chronic phase (CP). The therapeutic efficacy was evaluated by fresh blood examination, hemoculture, PCR, and enzyme-linked immunosorbent assay (ELISA). The cure rates in the AP and CP were 62.5% and 55.6%, respectively, upon oral administration of LYC-poly(D,L-lactide)-polyethylene glycol nanocapsules (LYC-PLA-PEG-NC) and 57.0% and 30.0%, respectively, with LYC-poly--caprolactone nanocapsules (LYC-PCL-NC). These cure rates were significantly higher than that of free LYC, which did not cure any animals. LYC-NC formulations administered orally during the AP showed cure rates similar to that of benznidazole, but only LYC-NC cured mice in the CP. Similar results were achieved with intravenous treatment during the CP. The higher cure rates obtained with LYC loaded in PLA-PEG-NC may be due to the smaller particle size of these NC and the presence of PEG, which influence tissue diffusion and the controlled release of LYC. Furthermore, PLA-PEG-NC may improve the stability of the drug in the gastrointestinal tract. This work is the first report of cure of experimental Chagas disease via oral administration during the CP. These findings represent a new and important perspective for oral treatment of Chagas disease.

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Section: Discussionmentioning

confidence: 99%

Efficacy of Lychnopholide Polymeric Nanocapsules after Oral and Intravenous Administration in Murine Experimental Chagas Disease

Mello

Branquinho

Oliveira

et al. 2016

Antimicrob Agents Chemother

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“…PEG chains retard the rapid removal of NC from the bloodstream by macrophages, consequently prolonging the drug-associated plasma half-life (24,25,37). Thus, these nanoparticles have the chance to extravasate to tissues infected by T. cruzi, particularly at inflammatory sites (26). LYC pharmacokinetics are under investigation by our group.…”

Section: Discussionmentioning

confidence: 99%

“…The unloaded NC were prepared by the same methods described above, but without LYC in the formulation. The mean size and the polydispersity index of the NC were determined as previously described (25,26).…”

Section: Methodsmentioning

confidence: 99%

“…Two types of polymeric NC were used: one conventional form that is rapidly cleared from blood circulation by phagocytes of the mononuclear phagocyte system (PCL NC) and the other (PLA-PEG NC) that circulates longer in blood due to its polymeric steric stabilization which reduces uptake by phagocytes (25). Thus, the probability of LYC to target sites of inflammation induced by the presence of the parasite, particularly during the acute phase of infection, is expected to be increased due to increased plasma circulation time of PEG sterically stabilized NC (20,24,25,26).…”

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confidence: 99%

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Sesquiterpene Lactone in Nanostructured Parenteral Dosage Form Is Efficacious in Experimental Chagas Disease

Branquinho

Mosqueira

Oliveira-Silva

et al. 2014

Antimicrob Agents Chemother

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dThe drugs available for Chagas disease treatment are toxic and ineffective. We studied the in vivo activity of a new drug, lychnopholide (LYC). LYC was loaded in nanocapsules (NC), and its effects were compared to free LYC and benznidazole against Trypanosoma cruzi. Infected mice were treated in the acute phase at 2.0 mg/kg/day with free LYC, LYC-poly--caprolactone NC (LYC-PCL), and LYC-poly(lactic acid)-co-polyethylene glycol NC (LYC-PLA-PEG) or at 50 mg/kg/day with benznidazole solution by the intravenous route. Animals infected with the CL strain, treated 24 h after infection for 10 days, evaluated by hemoculture, PCR, and enzyme-linked immunosorbent assay exhibited a 50% parasitological cure when treated with LYC-PCL NC and 100% cure when treated with benznidazole, but 100% of the animals treated during the prepatent period for 20 days with these formulations or LYC-PLA-PEG NC were cured. In animals with the Y strain treated 24 h after infection for 10 days, only mice treated by LYC-PCL NC were cured, but animals treated in the prepatent period for 20 days exhibited 100, 75, and 62.5% cure when treated with LYC-PLA-PEG NC, benznidazole, and LYC-PCL NC, respectively. Free LYC reduced the parasitemia and improved mice survival, but no mice were cured. LYC-loaded NC showed higher cure rates, reduced parasitemia, and increased survival when used in doses 2five times lower than those used for benznidazole. This study confirms that LYC is a potential new treatment for Chagas disease. Furthermore, the long-circulating property of PLA-PEG NC and its ability to improve LYC efficacy showed that this formulation is more effective in reaching the parasite in vivo.

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“…As a significant part of LYC circulates in plasma inside NC, free drug toxic effects may be diminished by reducing interactions with the heart. Oppositely, the LYC-NC with their reduced sizes (<200 nm) can extravasate and accumulate more in tissues Scientific RepoRts | 7:44998 | DOI: 10.1038/srep44998 compromised by inflammation process, which have leaky endothelium 51 . Thus, differences in the efficacy can be explained by the differences in LYC biodistribution, accumulation in the infectious/inflammatory sites and also by controlled release of LYC inside blood compartment.…”

Section: Discussionmentioning

confidence: 99%

Biodegradable polymeric nanocapsules prevent cardiotoxicity of antitrypanosomal lychnopholide

Farah¹,

Branquinho²,

Roy³

et al. 2017

Archives of Cardiovascular Diseases Supplements

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Chagas disease is a neglected parasitic disease caused by the protozoan Trypanosoma cruzi. New antitrypanosomal options are desirable to prevent complications, including a high rate of cardiomyopathy. Recently, a natural substance, lychnopholide, has shown therapeutic potential, especially when encapsulated in biodegradable polymeric nanocapsules. However, little is known regarding possible adverse effects of lychnopholide. Here we show that repeated-dose intravenous administration of free lychnopholide (2.0 mg/kg/day) for 20 days caused cardiopathy and mortality in healthy C57BL/6 mice. Echocardiography revealed concentric left ventricular hypertrophy with preserved ejection fraction, diastolic dysfunction and chamber dilatation at end-stage. Single cardiomyocytes presented altered contractility and Ca 2+ handling, with spontaneous Ca 2+ waves in diastole. Acute in vitro lychnopholide application on cardiomyocytes from healthy mice also induced Ca 2+ handling alterations with abnormal RyR2-mediated diastolic Ca 2+ release. Strikingly, the encapsulation of lychnopholide prevented the cardiac alterations induced in vivo by the free form repeated doses. Nanocapsules alone had no adverse cardiac effects. Altogether, our data establish lychnopholide presented in nanocapsule form more firmly as a promising new drug candidate to cure Chagas disease with minimal cardiotoxicity. Our study also highlights the potential of nanotechnology not only to improve the efficacy of a drug but also to protect against its adverse effects. Chagas disease (CD) is an important neglected disease caused by an intracellular hemoflagellate protozoan parasite, Trypanosoma cruzi (T. cruzi).There are an estimated 6-7 million infected people worldwide, and the disease causes 12 500 deaths per year, mostly in Latin America (World Health Organization, Switzerland 2015). While CD is principally transmitted to humans by triatomine insects, other routes include blood transfusion or transplantation of contaminated organs, ingestion of contaminated food and congenital transmission from infected mothers to newborns. International migrations contribute to spread the disease in non-endemic areas such as North America, Europe and Western Pacific countries (World Health Organization, Switzerland 2015). CD evolves in different consecutive phases with a short acute period, characterized by patent parasitemia, followed by a chronic phase in which most infected individuals remain asymptomatic (indeterminate form). CD is also a common determinant of non-ischemic cardiomyopathy in addition to digestive complications and neurological disorders. Approximately 30% of patients infected with T. cruzi manifest cardiomyopathy characterized by severe myocarditis and multiple arrhythmias, and/or dilatation and physiological dysfunctions of hollow organs, mainly of the digestive tract, which develop progressively over the years or decades after infection [1][2][3][4] . The clinical course of CD shows great variability, and the mechanisms or determinants responsible for t...

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Biodistribution study and identification of inflammatory sites using nanocapsules labeled with 99mTc–HMPAO

Cited by 21 publications

References 24 publications

Efficacy of Lychnopholide Polymeric Nanocapsules after Oral and Intravenous Administration in Murine Experimental Chagas Disease

Efficacy of Lychnopholide Polymeric Nanocapsules after Oral and Intravenous Administration in Murine Experimental Chagas Disease

Sesquiterpene Lactone in Nanostructured Parenteral Dosage Form Is Efficacious in Experimental Chagas Disease

Biodegradable polymeric nanocapsules prevent cardiotoxicity of antitrypanosomal lychnopholide

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