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Transbuccal Delivery of CNS Therapeutic Nanoparticles: Synthesis, Characterization, and In Vitro Permeation Studies.

ABSTRACT: This work utilized polyamidoamine (PAMAM) dendrimer G4.5 as the underlying carrier to construct CNS therapeutic nanoparticles and explored the buccal mucosa as an alternative absorption site for administration of the dendritic nanoparticles. Opioid peptide DPDPE was chosen as a model CNS drug. It was coupled to PAMAM dendrimer G4.5 with polyethylene glycol (PEG) or with PEG and transferrin receptor monoclonal antibody OX26 (i.e., PEG-G4.5-DPDPE and OX26-PEG-G4.5-DPDPE). The therapeutic dendritic nanoparticles labeled with 5-(aminoacetamido) fluorescein (AAF) were studied for transbuccal transport using a vertical Franz diffusion cell system mounted with porcine buccal mucosa. For comparison, AAF-labeled PAMAM dendrimers G3.5 and G4.5, and fluorescein isothiocynate (FITC)-labeled G3.0 and G4.0 were also tested for transbuccal delivery. The permeability of PEG-G4.5 (AAF)-DPDPE and OX26-PEG-G4.5(AAF)-DPDPE were on the order of 10(-7) - 10(-6) cm/s. Coadministration of bile salt sodium glycodeoxycholate (NaGDC) enhanced the permeability of dendritic nanoparticles by multiple folds. Similarly, a multifold increase of permeability of dendritic nanoparticles across the porcine buccal mucosal resulted from the application of mucoadhesive gelatin/PEG semi-interpenetrating network (sIPN). These results indicate that transbuccal delivery is a possible route for administration of CNS therapeutic nanoparticles.

SUBMITTER: Yuan Q

PROVIDER: S-EPMC3241219 | biostudies-other | 2011 Nov

REPOSITORIES: biostudies-other

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Project description:This study investigates the development of topically applied non-invasive amino-functionalized silica nanoparticles (AMSN) and O-Carboxymethyl chitosan-coated AMSN (AMSN-CMC) for ocular delivery of 5-Fluorouracil (5-FU). Particle characterization was performed by the DLS technique (Zeta-Sizer), and structural morphology was examined by SEM and TEM. The drug encapsulation and loading were determined by the indirect method using HPLC. Physicochemical characterizations were performed by NMR, TGA, FTIR, and PXRD. In vitro release was conducted through a dialysis membrane in PBS (pH 7.4) using modified Vertical Franz diffusion cells. The mucoadhesion ability of the prepared nanoparticles was tested using the particle method by evaluating the change in zeta potential. The transcorneal permeabilities of 5-FU from AMNS-FU and AMSN-CMC-FU gel formulations were estimated through excised goat cornea and compared to that of 5-FU gel formulation. Eye irritation and ocular pharmacokinetic studies from gel formulations were evaluated in rabbit eyes. The optimum formulation of AMSN-CMC-FU was found to be nanoparticles with a particle size of 249.4 nm with a polydispersity of 0.429, encapsulation efficiency of 25.8 ± 5.8%, and drug loading capacity of 5.2 ± 1.2%. NMR spectra confirmed the coating of AMSN with the CMC layer. In addition, TGA, FTIR, and PXRD confirmed the drug loading inside the AMSN-CMC. Release profiles showed 100% of the drug was released from the 5-FU gel within 4 h, while AMSN-FU gel released 20.8% of the drug and AMSN-CMC-FU gel released around 55.6% after 4 h. AMSN-CMC-FU initially exhibited a 2.45-fold increase in transcorneal flux and apparent permeation of 5-FU compared to 5-FU gel, indicating a better corneal permeation. Higher bioavailability of AMSN-FU and AMSN-CMC-FU gel formulations was found compared to 5-FU gel in the ocular pharmacokinetic study with superior pharmacokinetics parameters of AMSN-CMC-FU gel. AMSN-CMC-FU showed 1.52- and 6.14-fold higher AUC0-inf in comparison to AMSN-FU and 5-FU gel, respectively. AMSN-CMC-FU gel and AMSN-FU gel were "minimally irritating" to rabbit eyes but showed minimal eye irritation potency in comparison to the 5 FU gel. Thus, the 5-FU loaded in AMSN-CMC gel could be used as a topical formulation for the treatment of ocular cancer.

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Transbuccal Delivery of CNS Therapeutic Nanoparticles: Synthesis, Characterization, and In Vitro Permeation Studies.

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