Influence of peptide dendrimers and sonophoresis on the transdermal delivery of ketoprofen

The aim of this study was to determine the individual and combined effects of peptide dendrimers and low frequency ultrasound on the transdermal permeation of ketoprofen. Arginine terminated peptide dendrimers of varying charges (4(+), 8(+) and 16(+), named as A4. A8 and A16 respectively) were synthesized and characterized. Ketoprofen was subjected to passive, peptide dendrimer-assisted and sonophoretic permeation studies (with and without dendrimer application) across Swiss albino mouse skin, both in vitro and in vivo. The studies revealed that the synthesized peptide dendrimers considerably increased the transdermal permeation of ketoprofen and displayed enhancement ratios of up to 3.25 (with A16 dendrimer), compared to passive diffusion of drug alone in vitro. Moreover, the combination of peptide dendrimer treatment and ultrasound application worked in synergy and gave enhancement ratios of up to 1369.15 (with ketoprofen-A16 dendrimer complex). In vivo studies demonstrated that dendrimer and ultrasound-assisted permeation of drug achieved much higher plasma concentration of drug, compared to passive diffusion. Comparison of transdermal and oral absorption studies revealed that transdermal administration of ketoprofen with A8 dendrimer showed comparable absorption and plasma drug levels with oral route. The excised mouse skin after in vivo permeation study with dendrimers and ultrasound did not show major toxic reactions. This study demonstrates that arginine terminated peptide dendrimers combined with sonophoresis can effectively improve the transdermal permeation of ketoprofen. (C) 2017 Elsevier B.V. All rights reserved

Peptide dendrimer-conjugates of ketoprofen: synthesis and ex vivo and in vivo evaluations of passive diffusion, sonophoresis and iontophoresis for skin delivery

The aim of this study was to evaluate skin delivery of ketoprofen when covalently tethered to mildly cationic (2or 4) peptide dendrimers prepared wholly by solid phase peptide synthesis. The amino acids glycine, arginine and lysine formed the dendrimer with ketoprofen tethered either to the lysine side-arm (N) or periphery of dendrimeric branches. Passive diffusion, sonophoresis- and iontophoresis-assisted permeation of each peptide dendrimer-drug conjugate (D1–D4) was studied across mouse skin, both in vitro and in vivo. In addition, skin toxicity of dendrimeric conjugates when trialed with iontophoresis or sonophoresis was also evaluated. All dendrimeric conjugates improved aqueous solubility at least 5-fold, compared to ketoprofen alone, while also exhibiting appreciable lipophilicity. In vitro passive diffusion studies revealed that ketoprofen in its native form was delivered to a greater extent, compared with a dendrimer-conjugated form at the end of 24\ua0h (Q(μg/cm): ketoprofen (68.06\ua0±\ua03.62)\ua0>\ua0D2 (49.62\ua0±\ua02.92)\ua0>\ua0D4 (19.20\ua0±\ua00.89)\ua0>\ua0D1 (6.45\ua0±\ua00.40)\ua0>\ua0D3 (2.21\ua0±\ua00.19). However, sonophoresis substantially increased the skin permeation of ketoprofen-dendrimer conjugates in 30\ua0min (Q(μg/cm): D4 (122.19\ua0±\ua07.14)\ua0>\ua0D2 (66.74\ua0±\ua03.86)\ua0>\ua0D1 (52.10\ua0±\ua03.22)\ua0>\ua0D3 (41.66\ua0±\ua03.22)) although ketoprofen alone again proved superior (Q: 167.99\ua0±\ua09.11\ua0μg/cm). Next, application of iontophoresis was trialed and shown to considerably increase permeation of dendrimeric ketoprofen in 6\ua0h (Q(μg/cm): D2 (711.49\ua0±\ua039.14)\ua0>\ua0D4 (341.23\ua0±\ua016.43)\ua0>\ua0D3 (89.50\ua0±\ua04.99)\ua0>\ua0D1 (50.91\ua0±\ua02.98), with a Qvalue of 96.60\ua0±\ua05.12\ua0μg/cmfor ketoprofen alone). In vivo studies indicated that therapeutically relevant concentrations of ketoprofen could be delivered transdermally when iontophoresis was paired with D2 (985.49\ua0±\ua043.25\ua0ng/mL). Further, histopathological analysis showed that the dendrimeric approach was a safe mode as ketoprofen alone. The present study successfully demonstrates that peptide dendrimer conjugates of ketoprofen, when combined with non-invasive modalities, such as iontophoresis can enhance skin permeation with clinically relevant concentrations achieved transdermally

A simple, precise, and sensitive HPLC method for quantification of letrozole in rat plasma: development, validation, and preclinical pharmacokinetics

Abstract A simple bioanalytical liquid chromatographic method was developed and validated to quantify letrozole (LTZ) in rat plasma. Protein precipitation using acidified chilled acetonitrile (containing 0.1% orthophosphoric acid) was used to extract LTZ from the plasma. Chromatographic separation was carried out on Kinetex C18 reverse phase (RP) column (250 mm × 4.6 mm i.d., 5 μm) using a mixture of 20 mM acetate buffer (pH 5.5) and acetonitirile (60:40 %v/v) eluting at 1.0 mL/min flow rate with the method responses measured at 240 nm. The optimized method was selective and established good linearity with recovery ranging between 91.16 and 99.44%. The validation experiments revealed that the method showed acceptable precision (2.61–7.48%) and accuracy (97.44–102.70%) and was found to be stable. The sensitivity of the method was demonstrated by the lowest concentration (LLOQ) detected at 75 ng/mL. Using the developed method, single-dose oral pharmacokinetics in Sprague-Dawley rats was carried out to successfully confirm the applicability of the method for the quantification of LTZ in biological matrix

Recent advancements in nanomaterial-mediated ferroptosis-induced cancer therapy: Importance of molecular dynamics and novel strategies

Ferroptosis is a novel type of controlled cell death resulting from an imbalance between oxidative harm and protective mechanisms, demonstrating significant potential in combating cancer. It differs from other forms of cell death, such as apoptosis and necrosis. Molecular therapeutics have hard time playing the long-acting role of ferroptosis induction due to their limited water solubility, low cell targeting capacity, and quick metabolism in vivo. To this end, small molecule inducers based on biological factors have long been used as strategy to induce cell death. Research into ferroptosis and advancements in nanotechnology have led to the discovery that nanomaterials are superior to biological medications in triggering ferroptosis. Nanomaterials derived from iron can enhance ferroptosis induction by directly releasing large quantities of iron and increasing cell ROS levels. Moreover, utilizing nanomaterials to promote programmed cell death minimizes the probability of unfavorable effects induced by mutations in cancer-associated genes such as RAS and TP53. Taken together, this review summarizes the molecular mechanisms involved in ferroptosis along with the classification of ferroptosis induction. It also emphasized the importance of cell organelles in the control of ferroptosis in cancer therapy. The nanomaterials that trigger ferroptosis are categorized and explained. Iron-based and noniron-based nanomaterials with their characterization at the molecular and cellular levels have been explored, which will be useful for inducing ferroptosis that leads to reduced tumor growth. Within this framework, we offer a synopsis, which traverses the well-established mechanism of ferroptosis and offers practical suggestions for the design and therapeutic use of nanomaterials.</p