Novel nelfinavir mesylate loaded d -α-tocopheryl polyethylene glycol 1000 succinate micelles for enhanced pediatric anti HIV therapy: In vitro characterization and in vivo evaluation

Morettón, Marcela A.; Taira, Carlos A.; Flor, Sabrina; Bernabeu, Ezequiel; Lucangioli, Silvia; Höcht, Christián; Chiappetta, Diego Andrés

doi:10.1016/j.colsurfb.2014.09.031

Cited by 39 publications

(13 citation statements)

References 36 publications

(44 reference statements)

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“…These findings suggested that after drug encapsulation within the core, DOX altered the aggregation pattern of TPGS:T1107 mixture leading to a slight shift to lower average D h . Similar behavior was observed for nelfinavir-loaded TPGS micelles (Moretton et al, 2014) and rifampicin-loaded poly(epsilon-caprolactone)-b-PEG-b-poly(epsiloncaprolactone) polymeric micelles (Moretton et al, 2010).…”

Section: Accepted Manuscriptsupporting

confidence: 73%

Zebrafish (Danio rerio) model as an early stage screening tool to study the biodistribution and toxicity profile of doxorubicin-loaded mixed micelles

Calienni

Cagel

Montanari

et al. 2018

Toxicology and Applied Pharmacology

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Doxorubicin (DOX) hydrochloride is a powerful anthracycline antibiotic used for the treatment of various types of malignancies, particularly ovarian and metastatic breast cancer. However, DOX presents severe side effects, such as hepatotoxicity, nephrotoxicity, dose-limiting myelosuppression, brain damage and cardiotoxicity. A liposomal formulation, Doxil®, was approved by the FDA, which has managed to reduce the number of cardiac events in patients with metastatic breast cancer. However, in comparison to free DOX, Doxil® has not shown significant improvements regarding survival. We have previously designed DOX-loaded mixed micelles (MMDOX) composed of D-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) and Tetronic® T1107. To assess the potential toxic effects of this novel formulation, in this work the zebrafish (Danio rerio) model was used to evaluate its in vivo toxicity and teratogenicity. This study evaluated and compared the effects of DOX exposure from different formulations (free DOX, MMDOX and Doxil®) on the swimming activity, morphological alterations, cardiac rhythm, lethality rate and DOX biodistribution. MMDOX showed lower lethal effects, morphological alterations and neurotoxic effects than the free drug. This study shows the potential of the MMDOX to be an effective DOX-delivery system because it could reduce the side effects.

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Section: Accepted Manuscriptsupporting

confidence: 73%

Zebrafish (Danio rerio) model as an early stage screening tool to study the biodistribution and toxicity profile of doxorubicin-loaded mixed micelles

Calienni

Cagel

Montanari

et al. 2018

Toxicology and Applied Pharmacology

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“…an intense NOE between the CH3(a) of TPGS and the protons at the primary rim of DIMEB, Me (6), is also detected (circle 3, Figure 8). These CD protons (21 in Me(6)), by averaging both variables calculated for each dataset (SI, Figure S8).…”

Section: Topology Of the Tpgs-dimeb Complexmentioning

confidence: 96%

“…TPGS has been extensively investigated for its solubilizing capacity in drug delivery [2][3][4] and approved by the FDA. Most studies in the literature have used TPGS-1000, which comprises 23 EO units, and a number of drug formulations based on this amphiphile have been developed, including micelles 5,6 , microparticles 7 , nanoparticles 8 and microemulsifying systems 9 , where TPGS is used as a solubilizer, absorption enhancer and a drug-carrier 10,11 , especially for poorly watersoluble drugs. Many of these studies have focused on the delivery of anticancer drugs 12 , since TPGS inhibits the activity of P-glycoproteins transporters (P-gp), which is responsible for the poor permeability of many cancer drugs through physiological barriers 13 .…”

Section: Introductionmentioning

confidence: 99%

Structural and Spectroscopic Characterization of TPGS Micelles: Disruptive Role of Cyclodextrins and Kinetic Pathways

Puig-Rigall¹,

Grillo

Dreiss³

et al. 2017

Langmuir

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The aggregation and structure of d-α-tocopheryl polyethylene glycol succinate micelles, TPGS-1000, an amphiphilic derivative of vitamin E, were characterized using scattering and spectroscopic methods, and the impact of different cyclodextrins (CDs) on the self-assembly was investigated, with the view of combining these two versatile pharmaceutical excipients in drug formulations. Combined small-angle neutron scattering (SANS), dynamic light scattering, and time-resolved and steady-state fluorescence emission experiments revealed a core-shell architecture with a high aggregation number (N ≈ 100) and a highly hydrated poly(ethylene oxide) corona (∼11 molecules of solvent per ethylene oxide unit). Micelles form gradually, with no sharp onset. Structural parameters and hydration of the aggregates were surprisingly stable with both temperature and concentration, which is a critical advantage for their use in pharmaceutical formulations. CDs were shown to affect the self-assembly of TPGS in different ways. Whereas native CDs induced the precipitation of a solid complex (pseudopolyrotaxane), methylated β-CDs led to different outcomes: constructive (micellar expansion), destructive (micellar rupture), or no effect, depending on the number of substituents and whether the substitution pattern was regular or random on the rims of the macrocycle. Time-resolved SANS studies on mixtures of TPGS with regularly dimethylated β-CD (DIMEB), which ruptures the micelles, revealed an almost instantaneous demicellization (<100 ms) and showed that the process involved the formation of large aggregates whose size evolved over time. Micellar rupture is caused by the formation of a TPGS-DIMEB inclusion complex, involving the incorporation of up to three macrocycles on the tocopherol, as shown by proton nuclear magnetic resonance (NMR) and ROESY NMR. Analysis of NMR data using Hill's equation revealed that the binding is rather cooperative, with the threading of the CD favoring the subsequent inclusion of additional CDs on the aliphatic moiety.

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“…In this context, it has been reported that TPGS could serve as a pharmaceutical additive for overcoming multidrug resistance and as an inhibitor of P-glycoprotein for increasing the cytotoxicity and bioavailability of anticancer drugs [5,11,12]. It has also been investigated for the treatment of other pathologies including the drug delivery of antiretrovirals and calcium channel blockers [13,14].…”

Section: Accepted Manuscriptmentioning

confidence: 99%

Radiolabeling and biological characterization of TPGS-based nanomicelles by means of small animal imaging

Tesan

Portillo

Morettón

et al. 2017

Nuclear Medicine and Biology

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Novel nelfinavir mesylate loaded d -α-tocopheryl polyethylene glycol 1000 succinate micelles for enhanced pediatric anti HIV therapy: In vitro characterization and in vivo evaluation

Cited by 39 publications

References 36 publications

Zebrafish (Danio rerio) model as an early stage screening tool to study the biodistribution and toxicity profile of doxorubicin-loaded mixed micelles

Zebrafish (Danio rerio) model as an early stage screening tool to study the biodistribution and toxicity profile of doxorubicin-loaded mixed micelles

Structural and Spectroscopic Characterization of TPGS Micelles: Disruptive Role of Cyclodextrins and Kinetic Pathways

Radiolabeling and biological characterization of TPGS-based nanomicelles by means of small animal imaging

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