Synthesis and Properties of Some 13-cis- and All-trans-retinamides

Shealy, Y. Fulmer; Frye, Jerry L.; O’Dell, C. Allen; Thorpe, Martha C.; Kirk, Marion; Coburn, W. C.; Sporn, Michael B.

doi:10.1002/jps.2600730610

Cited by 27 publications

(9 citation statements)

References 19 publications

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“…PVP had a broad endotherm starting at113.93°C corresponding to its dehydration. Fenretinide has been reported to be present in at least two different polymorphic forms with melting peaks of 173-175°C [35] and178-181°C [1]. The physical mixture of fenretinide with lactose and PVP showed the characteristic endotherms for lactose and fenretinide (peak onsets at 172.12°C, 139.40°C, and 209.46°C), indicating no interaction between them.…”

Section: Resultsmentioning

confidence: 99%

Preparation and in vitro evaluation of hydrophilic fenretinide nanoparticles

Ledet

Graves

Glotser

et al. 2015

International Journal of Pharmaceutics

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Fenretinide is an effective anti-cancer drug with high in vitro cytotoxicity and low in vivo systemic toxicity. In clinical trials, fenretinide has shown poor therapeutic efficacy following oral administration – attributed to its low bioavailability and solubility. The long term goal of this project is to develop a formulation for the oral delivery of fenretinide. The purpose of this part of the study wasto prepare and characterize hydrophilic nanoparticle formulations of fenretinide. Three different ratios of polyvinyl pyrrolidone (PVP) to fenretinide were used, namely, 3:1, 4:1, and 5:1. Both drug and polymer were dissolved in a mixture of methanol and dichloromethane (2:23 v/v). Rotary evaporation was used to remove the solvents, and, following reconstitution with water, a high pressure homogenizer was used to form nanoparticles. The particle size and polydispersity index were measured before and after lyophilization. The formulations were studied by scanning electron microscopy (SEM), differential scanning calorimetry (DSC), and x-ray powder diffraction (XRPD). The effectiveness of the formulations was assessed by releasestudies and Caco-2 cell permeability assays. As the PVP content increased, the recovered particle size following lyophilization became more consistent with the pre-lyophilization particle size, especially for those formulations with less lactose. The DSC scans of the formulations did not show any fenretinide melting endotherms, indicating that the drug was either present in an amorphous form in the formulation or that a solid solution of the drug in PVP had formed. For the release studies, the highest drug release among the formulations was 249.2 ± 35.5 ng/mL for the formulation with 4:1 polymer-to-drug. When the permeability of the formulations was evaluated in a Caco-2 cell model, the mean normalized flux for each treatment group was significantly higher (p<0.05) from the fenretinide control. The formulation containing 4:1 polymer-to-drug ratio and 6:5 lactose-to-formulation ratio emerged as the optimal choice for further evaluation as a potential oral delivery formulation for fenretinide.

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Section: Resultsmentioning

confidence: 99%

Preparation and in vitro evaluation of hydrophilic fenretinide nanoparticles

Ledet

Graves

Glotser

et al. 2015

International Journal of Pharmaceutics

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“…The peak with an onset temperature of 173.3°C represents the melting endotherm reported by Shealy et al , and the peak with an onset temperature of 180°C is similar to the melting endotherm of the polymorph reported by Moon et al . [19,33]. The two peaks represent the melting of two polymorphic modifications of fenretinide.…”

Section: Resultsmentioning

confidence: 99%

Formulation and evaluation of biodegradable nanoparticles for the oral delivery of fenretinide

Graves

Ledet

Glotser

et al. 2015

European Journal of Pharmaceutical Sciences

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Fenretinide is an anticancer drug with low water solubility and poor bioavailability. The goal of this study was to develop biodegradable polymeric nanoparticles of fenretinide with the intent of increasing its apparent aqueous solubility and intestinal permeability. Three biodegradable polymers were investigated for this purpose: two different poly lactide-co-glycolide (PLGA) polymers, one acid terminated and one ester terminated, and one poly lactide-co-glycolide/polyethylene glycol (PLGA/PEG) diblock copolymer. Nanoparticles were obtained by using an emulsification solvent evaporation technique. The formulations were characterized by differential scanning calorimetry (DSC), scanning electron microscopy (SEM), and particle size analysis. Dissolution studies and Caco-2 cell permeation studies were also carried out for all formulations. Ultra high performance liquid chromatography coupled with mass spectrometry (UPLC/MS) and ultraviolet detection was used for the quantitative determination of fenretinide. Drug loading and the type of polymer affected the nanoparticles’ physical properties, drug release rate, and cell permeability. While the acid terminated PLGA nanoparticles performed the best in drug release, the ester terminated PLGA nanoparticles performed the best in the Caco-2 cell permeability assays. The PLGA/PEG copolymer nanoparticles performed better than the formulations with ester terminated PLGA in terms of drug release but had the poorest performance in terms of cell permeation. All three categories of formulations performed better than the drug alone in both drug release and cell permeation studies.

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“…Ester and amide derivatives of retinoic acid have been previously prepared in low to moderate yields by the reaction of alcohols or amines with activated retinoic acids, for instance, as acid chlorides, retinoyl fluorides, or retinoyl imidazolides, and DCC as the coupling reagent (29,30,(42)(43)(44). In our new synthesis of porphyrin-retinamides 2-5 (Scheme 1), the retinoic acids were activated as the hydroxybenzotriazole esters and subsequently coupled to monoaminoporphyrin 1 or to a pegylated porphyrin using TBTU as the coupling agent, in reproducibly high yields (49-78%).…”

Section: Discussionmentioning

confidence: 99%

Porphyrin−Retinamides: Synthesis and Cellular Studies

Sibrian‐Vazquez

2007

Bioconjugate Chem.

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A series of four porphyrin-retinamides containing either all-trans- or 13-cis-retinoid acid residues, directly linked to the para-phenyl position of meso-tetraphenylporphyrin or via a low-molecular-weight PEG spacer, have been synthesized. The biological properties of these conjugates were evaluated in a model cell line, human HEp2, and in neuroblastoma SK-N-DZ cells, which exhibit moderate expression of retinoic acid receptors and retinoic acid-induced differentiation. The directly linked porphyrin-retinamides were taken up by a greater extent (20-50% more) in SK-N-DZ than in HEp2 cells. However, the PEG-containing conjugates accumulated maximally within both cell lines and approximately by the same amount, probably due to their increased amphiphilicity. Among all conjugates, the porphyrin-PEG-13-cis-retinamide accumulated the most in both cell lines (about 5 times more than the non-pegylated conjugates). None of the porphyrin-retinamide conjugates were toxic toward HEp2 cells at concentrations up to 100 microM, and only the hydrophobic non-pegylated conjugates were moderately toxic to SK-N-DZ cells [IC50 (dark) = 56-92 microM, and IC50 (at 1 J/cm2) = 6-8 microM]. All conjugates preferentially localized within cellular vesicles that correlated well to the lysosomes and, in addition, the PEG-containing porphyrin-retinamides were also found in the ER.

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Synthesis and Properties of Some 13-cis- and All-trans-retinamides

Cited by 27 publications

References 19 publications

Preparation and in vitro evaluation of hydrophilic fenretinide nanoparticles

Preparation and in vitro evaluation of hydrophilic fenretinide nanoparticles

Formulation and evaluation of biodegradable nanoparticles for the oral delivery of fenretinide

Porphyrin−Retinamides: Synthesis and Cellular Studies

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