Oral lipid-based nanoformulation of tafenoquine enhanced bioavailability and blood stage antimalarial efficacy and led to a reduction in human red blood cell loss in mice

Abstract

Tafenoquine (TQ), a new synthetic analog of primaquine, has relatively poor bioavailability and associated toxicity in glucose-6-phosphate dehydrogenase (G6PD)-deficient individuals. A microemulsion formulation of TQ (MTQ) with sizes <20 nm improved the solubility of TQ and enhanced the oral bioavailability from 55% to 99% in healthy mice (area under the curve 0 to infinity: 11,368±1,232 and 23,842±872 min·μmol/L) for reference TQ and MTQ, respectively. Average parasitemia in Plasmodium berghei -infected mice was four- to tenfold lower in the MTQ-treated group. In vitro antiplasmodial activities against chloroquine-sensitive and chloroquine-resistant strains of Plasmodium falciparum indicated no change in half maximal inhibitory concentration, suggesting that the microemulsion did not affect the inherent activity of TQ. In a humanized mouse model of G6PD deficiency, we observed reduction in toxicity of TQ as delivered by MTQ at low but efficacious concentrations of TQ. We hereby report an enhancement in the solubility, bioavailibility, and efficacy of TQ against blood stages of Plasmodium parasites without a corresponding increase in toxicity.

Preclinical assessment of 68Ga‐PSMA‐617 entrapped in a microemulsion delivery system for applications in prostate cancer PET/CT imaging

“…The radioactivity subsequently accumulated in the bladder, peaking to a maximum of 12.45%ID/mL after 38 minutes as depicted in Figure . In literature, PSMA‐617 was found in other organs, such as the proximal renal tubules and salivary glands . This means that when [ 68 Ga]Ga‐PSMA‐617 is used as a target for radionuclide therapy, there will be a radiation dose delivered to these organs although at reduced doses as compared with prostate cancer cells .…”

“…In literature, PSMA‐617 was found in other organs, such as the proximal renal tubules and salivary glands . This means that when [ 68 Ga]Ga‐PSMA‐617 is used as a target for radionuclide therapy, there will be a radiation dose delivered to these organs although at reduced doses as compared with prostate cancer cells . This impacts the safe dose and side effect profile of PSMA‐targeted therapy because ultimately significant radiation damage to nontarget organs needs to be avoided.…”

“…There is therefore a medical need to develop drug delivery systems that selectively transport antitumour drugs or radiopharmaceuticals into the tumour cells. Delivery systems, which have demonstrated improved therapeutic index with minimal side effects, are micelles, liposomes, lipid‐based emulsions, and polymeric nanoparticles . The use of delivery systems such as swollen micelles or microemulsions (MEs) can improve the efficacy of a drug, allowing the total dose to be reduced and therefore minimise side effects and toxicity of the formulated compound…”

Stimulation of Suicidal Erythrocyte Death by Tafenoquine

“…The effect of tafenoquine treatment on eryptosis may be enhanced in clinical conditions with accelerated eryptosis, such as iron deficiency [35], dehydration [85], hyperphosphatemia [86], chronic kidney disease (CKD) [87][88][89][90], hemolytic-uremic syndrome [91], diabetes [92], hepatic failure [93], malignancy [35], sepsis [94], malaria [35], sickle-cell disease [35], beta-thalassemia [35], Hb-C-deficiency [35], glucose-6-phosphate dehydrogenase (G6PD) deficiency [35], and Wilsons disease [95]. Notably, tafenoquine toxicity is enhanced in patients with G6PD-deficiency [96].…”

Nanomedicines for Malaria Chemotherapy: Encapsulation vs. Polymer Therapeutics

“…Rochford and colleagues reported a humanized mouse model developed by grafting nonobese diabetic/SCID mice with human G6PD-deficient blood through daily transfusions for two weeks (236). These animal models offer great testing platforms for testing the efficiency of nanomedicine delivery systems to reduce the G6PD deficiency-dependent hemolytic toxicity of the 8-aminoquinolines and other antimalarials (129).…”