Title

SYNTHESIS AND EVALUATION OF NOVEL GLYCOSYLATED RGD AMPHIPHILES WITH IMPROVED HYDROPHILICITY FOR αvβ3 INTEGRIN TARGETED DELIVERY OF PACLITAXEL

Lead Author Affiliation

Department of Pharmaceutics and Medicinal Chemistry

Second Author Affiliation

Department of Pharmaceutics and Medicinal Chemistry

Third Author Affiliation

Department of Pharmaceutics and Medicinal Chemistry

Fourth Author Affiliation

Department of Pharmaceutics and Medicinal Chemistry

Fifth Author Affiliation

Department of Pharmaceutics and Medicinal Chemistry

Purpose

To synthesize amphiphiles of glycosylated palmitic acid or stearic acid RGD conjugates and determine critical micellar concentration (CMC) and solubility enhancement of anticancer drug paclitaxel in the micellar solution.

Method

Fmoc-(N-1-Glu(Ac)4-Asn)-OtBu was prepared and deprotected using TFA/DCM. Peptide RGN (N-1-Glu(Ac)4)-D was synthesized on Wang resin using Fmoc chemistry and coupling of amino acids was performed with 2-(7-Aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate, N-Hydroxybenzotriazole and N,N-Diisopropylethylamine. Conjugation of fatty acids to amino group of arginine was carried out by using Benzotriazole-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate and N,N-Diisopropylethylamine. Assembled amphiphiles were cleaved from resin, purified, lyophilized and deacetylation was achieved by treating amphiphiles with 0.14M solution of sodium methoxide in methanol. CMC was determined using the pyrene method. A 2mg/mL stock solution of the amphiphilies were prepared in methanol; following evaporation of organic solvent, 15 mL of distilled water was added, yielding a final pyrene concentration of 6.0 x 10-7 M. Samples were equilibrated at 37°C for 24 hours and CMC was determined by spectrofluorimetry. Paclitaxel loading into micelles was achieved using thin film hydration method. The film formation was achieved by codissolving paclitaxel and amphiphile in a ratio of 1:10 in methanol, followed by evaporation of methanol by passage of nitrogen gas. The film was hydrated and any precipitates of excess drug and amphiphile were removed by centrifugation at 12000g. The solubility of paclitaxel in the micellar solution was determined by HPLC analysis at λmax of 227 nm.

Results

The Mass spectrum showed (M+H)+ ion peak of both amphiphiles- C16-RGN(Glu)D and C18-RGN(Glu)D and reverse HPLC analysis indicated their purity ~90%. The CMC significantly reduced from 60 μM for C16-RGD to 18.50± 3.04 for the C16-RGN(Glu)D and from 40 μM for C18-RGD to 10.57±0.4 for the C18-RGN(Glu)D amphiphiles. Solubility of paclitaxel in the micellar solution increased from 1.13±0.057 μg/ml and 1.95±0.02 μg/ml to 4.43±1.18 μg/ml and 15.21±3.92 μg/ml for the respective glycosylated amphiphiles.

Significance

Incorporation of glycosylated RGD showed considerable reduction in CMC and improvement in the paclitaxel solubility within the micellar solution. Taxol solubility in C18-RGN(Glu)D micelles was enhanced by almost 35 fold compared to its aqueous solubility.

Location

DeRosa University Center, Stockton campus, University of the Pacific

Format

Poster Presentation

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SYNTHESIS AND EVALUATION OF NOVEL GLYCOSYLATED RGD AMPHIPHILES WITH IMPROVED HYDROPHILICITY FOR αvβ3 INTEGRIN TARGETED DELIVERY OF PACLITAXEL

DeRosa University Center, Stockton campus, University of the Pacific