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A targeted and adjuvanted nanocarrier lowers the effective dose of liposomal amphotericin B and enhances adaptive immunity in murine cutaneous leishmaniasis.

ABSTRACT: Amphotericin B (AmB), the most effective drug against leishmaniasis, has serious toxicity. As Leishmania species are obligate intracellular parasites of antigen presenting cells (APC), an immunopotentiating APC-specific AmB nanocarrier would be ideally suited to reduce the drug dosage and regimen requirements in leishmaniasis treatment. Here, we report a nanocarrier that results in effective treatment shortening of cutaneous leishmaniasis in a mouse model, while also enhancing L. major specific T-cell immune responses in the infected host.We used a Pan-DR-binding epitope (PADRE)-derivatized-dendrimer (PDD), complexed with liposomal amphotericin B (LAmB) in an L. major mouse model and analyzed the therapeutic efficacy of low-dose PDD/LAmB vs full dose LAmB.PDD was shown to escort LAmB to APCs in vivo, enhanced the drug efficacy by 83% and drug APC targeting by 10-fold and significantly reduced parasite burden and toxicity. Fortuitously, the PDD immunopotentiating effect significantly enhanced parasite-specific T-cell responses in immunocompetent infected mice.PDD reduced the effective dose and toxicity of LAmB and resulted in elicitation of strong parasite specific T-cell responses. A reduced effective therapeutic dose was achieved by selective LAmB delivery to APC, bypassing bystander cells, reducing toxicity and inducing antiparasite immunity.

SUBMITTER: Daftarian PM

PROVIDER: S-EPMC3814840 | biostudies-other | 2013 Dec

REPOSITORIES: biostudies-other

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A targeted and adjuvanted nanocarrier lowers the effective dose of liposomal amphotericin B and enhances adaptive immunity in murine cutaneous leishmaniasis.

Daftarian Pirouz M PM Stone Geoffrey W GW Kovalski Leticia L Kumar Manoj M Vosoughi Aram A Urbieta Maitee M Blackwelder Pat P Dikici Emre E Serafini Paolo P Duffort Stephanie S Boodoo Richard R Rodríguez-Cortés Alhelí A Lemmon Vance V Deo Sapna S Alberola Jordi J Perez Victor L VL Daunert Sylvia S Ager Arba L AL

The Journal of infectious diseases 20130729 11

<h4>Background</h4>Amphotericin B (AmB), the most effective drug against leishmaniasis, has serious toxicity. As Leishmania species are obligate intracellular parasites of antigen presenting cells (APC), an immunopotentiating APC-specific AmB nanocarrier would be ideally suited to reduce the drug dosage and regimen requirements in leishmaniasis treatment. Here, we report a nanocarrier that results in effective treatment shortening of cutaneous leishmaniasis in a mouse model, while also enhancing ...[more]

PMID: 23901083

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Project description:IntroductionTreatment of cutaneous and mucosal leishmaniasis (CL and ML, respectively) must be individualised as there is no universal therapeutic approach. Intravenous liposomal amphotericin B (L-AmB) is an accessible and relatively safe treatment that has been increasingly used for the treatment of CL and ML. While several descriptive studies have been published on the efficacy and safety of L-AmB, there are no interventional studies. Moreover, the findings from published studies have not yet been integrated and synthesised. Therefore, we aim to evaluate and consolidate the descriptive evidence on the efficacy and the safety of Intravenous L-AmB treatment for CL and ML in both the New and Old World.Methods and analysesA systematic review of all relevant study types with no restriction on date or language of publication will be conducted. Online databases including MEDLINE, The Cochrane Library, EMBASE, EBSCO, Scopus, Ovid and WHO databases were searched on 3 April 2020. The search included all study types that assess Intravenous L-AmB treatment for CL and ML in humans. The Population, Intervention, Comparison, Outcome and Study Design strategy and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines will be used to determine which studies will be selected for final inclusion. The quality of included case series and case reports will be assessed using modified quality assessment tools. A narrative synthesis of the findings will be provided and the primary outcome and secondary outcome of interest, response rate and adverse events rate, respectively, and the 95% CI will be ascertained. Estimates from individual studies will be pooled using random-effects model.Ethics and disseminationThis systematic review does not require formal ethical approval since no primary data will be collected. Findings will be disseminated through a peer-reviewed publication and relevant conferences.Prospero registration numberCRD42020173440.

Project description:BackgroundThere is a continued need to develop effective and safe treatments for visceral leishmaniasis (VL). Preclinical studies on pharmacokinetics and pharmacodynamics of anti-infective agents, such as anti-bacterials and anti-fungals, have provided valuable information in the development and dosing of these agents. The aim of this study was to characterise the pharmacokinetic and pharmacodynamic properties of the anti-leishmanial drugs AmBisome and miltefosine in a preclinical disease model of VL.Methodology / principal findingsBALB/c mice were infected with L. donovani (MHOM/ET/67/HU3) amastigotes. Groups of mice were treated with miltefosine (orally, multi-dose regimen) or AmBisome (intravenously, single dose regimen) or left untreated as control groups. At set time points groups of mice were killed and plasma, livers and spleens harvested. For pharmacodynamics the hepatic parasite burden was determined microscopically from tissue impression smears. For pharmacokinetics drug concentrations were measured in plasma and whole tissue homogenates by LC-MS. Unbound drug concentrations were determined by rapid equilibrium dialysis. Doses exerting maximum anti-leishmanial effects were 40 mg/kg for AmBisome and 150 mg/kg (cumulatively) for miltefosine. AmBisome displayed a wider therapeutic range than miltefosine. Dose fractionation at a total dose of 2.5 mg/kg pointed towards concentration-dependent anti-leishmanial activity of AmBisome, favouring the administration of large doses infrequently. Protein binding was >99% for miltefosine and amphotericin B in plasma and tissue homogenates.Conclusion / significanceUsing a PK/PD approach we propose optimal dosing strategies for AmBisome. Additionally, we describe pharmacokinetic and pharmacodynamic properties of miltefosine and compare our findings in a preclinical disease model to available knowledge from studies in humans. This approach also presents a strategy for improved use of animal models in the drug development process for VL.

Dataset Information

A targeted and adjuvanted nanocarrier lowers the effective dose of liposomal amphotericin B and enhances adaptive immunity in murine cutaneous leishmaniasis.

Publications

A targeted and adjuvanted nanocarrier lowers the effective dose of liposomal amphotericin B and enhances adaptive immunity in murine cutaneous leishmaniasis.

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