Table 5.
Drug Delivery and Nanomedicine-Based Strategies Evaluated Against Trypanosoma cruzi in Experimental Pre-Clinical Studies
| Formulation | Drug/Active Molecule | Route | Outcome | Ref. |
|---|---|---|---|---|
| Classical formulations | ||||
| Solid dispersion in poloxamer 407 | BNZ | oral | 15–60 mg/kg/day solid dispersion compared with classical 50 mg mg/kg/day. Same efficacy in infected mice with lower side effects in acute and chronic phases, and reduced hepatotoxicity in mice. | [203] |
| Solutions with co-solvents: PEG400/water and CMC/water |
BNZ | oral | 20–60 mg/kg/day solutions compared with classical BNZ doses produced the same efficacy in infected mice (Tulahuen strain) | [204] |
| Nanostructured lipid-based formulations | ||||
| Nanostructured Lipid formulations |
Amphotericin B | i.v. oral |
Fungizone® deoxycholate, AmBisome® liposome, Amphocil® colloidal dispersion, Abelcet® lipid complex. AmBisome® was the most effective formulation with the lowest host toxicity, but less than BNZ and NFX. Different protocols: BALB/c mice infected T. cruzi Y/Tulahuen strains BNZ or NFX (controls) cleared blood trypomastigote more rapidly than amphotericin B (1 week × 3 weeks). AmBisome was the most effective formulation with the lowest host toxicity. | [205] |
| Liposome (Ambisome®) | Amphotericin B | i.p. | Efficacy in acute and chronic phases of mice infected with T. cruzi Tulahuen strain. The formulation showed efficacy in acute and chronic phases of mice infected with T. cruzi Tulahuen strain. | [206] |
| Liposome (Ambisome®) |
Amphotericin B | i.v. | AmBisome® prolonged survival, without cure. Amastigote nests found in tissues of all mice treated, heart and brain in histopathological analysis in acute and chronic mice models (Y and CL strains). AmBisome® prolonged survival without cure of infection in repeated dose regimen. | [207] |
| pH-sensitive liposomes (DOPE:CHEMS) |
Etanidazole | i.v. | Reduced parasitemia in infected mice with liposome formulation at lower doses versus no effect of free drug. Liposome showed in vitro activity against amastigote and reduced parasitemia of infected mice. | [209] |
| Nanoarchaeosomes | Imiquimod | Infected mice (RA strain) treated with the formulation in acute phase had improved survival and showed parasitemia reduction. However, efficacy was lower than BNZ classical treatment with 100mg/kg/day. | [218] | |
| Self-emulsifying drug delivery system (SEDDS) | BNZ | oral | Toxicity and efficacy similar to free-BNZ. Practical and personalized orally administered liquid dosage form. | [212] |
| Self-emulsifying drug delivery system (SEDDS) | BNZ | oral | Formulation was safe for mice. No additional drug toxicity in infected mice (Y strain) in 20 days at doses of 100 mg/kg/day was observed. Oral BNZ-SEDDS increased BNZ AUC. |
[210] |
| Self-emulsifying drug delivery system (SEDDS) | Ravuconazole | oral | SEDDS demonstrated low in vitro and in vivo toxicity and improved ravuconazole activity in vitro and reduced toxicity in vivo. No formulation and drug toxicity was observed in mice. | [211] |
| Polymeric-based nanomedicines | ||||
| Poly-aggregated Amphotericin B in albumin microspheres | Amphotericin B | oral | T. cruzi-infected mice (Y strain) treated for 10 days (10–15 mg/kg/day) reduced 75% parasitemia and prolonged survival. Unable to cure mice. | [217] |
| Nanospheres of polyethylene glycol-polylactide | Bis-triazole D0870 | i.v. | T. cruzi-infected mice treated for 30 days (3 mg/kg/day) had cure rate of 90% for CL strain and 60% for Y strain in the acute phase of infection | [216] |
| Nanocapsules of polyethylene glycol-polylactide | Lychnopholide (LYC) (sesquiterpene lactone) |
i.v. oral |
Formulation induced high cure levels in acute or chronic mice infection, including drug resistant strains and displayed minimal cardiotoxicity. Potent in vivo anti-T. cruzi activity. LYC-NC reduced cardiotoxicity compared with free-LYC. In vivo LYC-NC effects include: cure rates of 100% by PCR analysis in tissue; it induced cure in mice infected with Colombian strain and in mice in chronic phase of infection; nanocapsules increased AUC of LYC in 12-fold; high cure rates and reduced inflammation in heart of mice infected by Y, CL, VL10 and Colombian strains. |
[138–140],[144] |
| Micelles of polyoxyethylene-polyoxypropylene block copolymer (poloxamer 188) | Benznidazole | oral | Acute treatment of infected mice decreased heart inflammation and anti-T. cruzi specific antibodies levels. Intermittent treatments of mice with chronic infection were as effective as daily treatment. Nicaragua strain-infected mice (C57BL/6) treated (25–75mg/kg/day) during the chronic phase: low doses of BNZ-nanoparticles treatment (25 mg/kg/day) resulted in 40% negative PCR in the immunosuppressed mice. Continuous 30 consecutive days and intermittent regime once time week during 13 weeks for 7 days showed similar reduction of parasitemia compared to classical regime. | [197,213] |
| Nanoparticles of poly-epsilon-caprolactone | Ursolic acid | i.v. | In vivo anti-T. cruzi activity led to reduction of parasitemia levels inT. cruzi-infected mice (C57BL/6), Y strain. Mice treated during the acute phase during 7 days with ursolic acid-nanoparticles showed similar reduction of parasitemia compared to BNZ. Reduced hepatotoxicity for nanoparticles. | [214] |
| Microparticles of poly(D,L-lactide-co-glycolide) | (-)-Hinokinin | s.c. | T. cruzi infected mice (clone CLB5) treated 20 days at 40mg/kg with Hinokinin-nanoparticles and 20 mg/kg/day with free-Hinokinin. Blood parasitemia was slightly reduced with Hinokinin-nanoparticles by fresh blood examination. No mice cure was reported. | [215] |
Abbreviations: i.v, intravenous; i.p., intraperitoneal; s.c., subcutaneous; BNZ, benznidazole; NFX, nifurtimox.