Delivery of paclitaxel across cellular barriers using a dendrimer-based nanocarrier

TY - JOUR

T1 - Delivery of paclitaxel across cellular barriers using a dendrimer-based nanocarrier

AU - Teow, Huey Minn

AU - Zhou, Zhengyuan

AU - Najlah, Mohammad

AU - Yusof, Siti R.

AU - Abbott, N. Joan

AU - D'Emanuele, Antony

PY - 2013/1/30

Y1 - 2013/1/30

N2 - The aim of this study was to investigate the ability of a third-generation (G3) polyamidoamine (PAMAM) dendrimer-based carrier to enhance the permeability of paclitaxel (pac) and to overcome cellular barriers. G3 dendrimers were surface modified with lauryl chains (L) and conjugated with paclitaxel (pac) via a glutaric anhydride (glu) linker, followed by labeling with FITC. Biological evaluation of the dendrimer and conjugates was conducted using the human colon adenocarcinoma cell line (Caco-2) and primary cultured porcine brain endothelial cells (PBECs). LDH assay was used to evaluate the cytotoxicity of the dendrimer and conjugates. Cytotoxicity studies showed that the conjugation of lauryl chains and paclitaxel on G3 dendrimer significantly (p <0.05) increased the cytotoxicity against both cell types. Permeability studies of dendrimer-drug conjugates demonstrated an increase in the apparent permeability coefficient (P-app) in both apical to basolateral A -> B and basolateral to apical B -> A directions across both cell monolayers compared to unmodified G3 and free drug. The B -> A P-app of paclitaxel was significantly (p <0.05) higher than the A -> B P-app, indicating active function of P-gp efflux transporter system in both cell models. L6-G3-glu-pac conjugate had approximately 12-fold greater permeability across both cell monolayers than that of paclitaxel alone.

AB - The aim of this study was to investigate the ability of a third-generation (G3) polyamidoamine (PAMAM) dendrimer-based carrier to enhance the permeability of paclitaxel (pac) and to overcome cellular barriers. G3 dendrimers were surface modified with lauryl chains (L) and conjugated with paclitaxel (pac) via a glutaric anhydride (glu) linker, followed by labeling with FITC. Biological evaluation of the dendrimer and conjugates was conducted using the human colon adenocarcinoma cell line (Caco-2) and primary cultured porcine brain endothelial cells (PBECs). LDH assay was used to evaluate the cytotoxicity of the dendrimer and conjugates. Cytotoxicity studies showed that the conjugation of lauryl chains and paclitaxel on G3 dendrimer significantly (p <0.05) increased the cytotoxicity against both cell types. Permeability studies of dendrimer-drug conjugates demonstrated an increase in the apparent permeability coefficient (P-app) in both apical to basolateral A -> B and basolateral to apical B -> A directions across both cell monolayers compared to unmodified G3 and free drug. The B -> A P-app of paclitaxel was significantly (p <0.05) higher than the A -> B P-app, indicating active function of P-gp efflux transporter system in both cell models. L6-G3-glu-pac conjugate had approximately 12-fold greater permeability across both cell monolayers than that of paclitaxel alone.

KW - Paclitaxel, Dendrimer prodrugs

KW - Caco-2 cells

KW - Blood-brain barrier

KW - Nano carrier

KW - Drug delivery

KW - BLOOD-BRAIN-BARRIER

KW - POLY AMIDOAMINE DENDRIMERS

KW - MICROVESSEL ENDOTHELIAL-CELLS

KW - IN-VITRO MODEL

KW - P-GLYCOPROTEIN

KW - TRANSEPITHELIAL TRANSPORT

KW - POLYAMIDOAMINE DENDRIMER

KW - SURFACE MODIFICATION

KW - BIOLOGICAL-ACTIVITY

KW - PAMAM DENDRIMERS

U2 - 10.1016/j.ijpharm.2012.10.024

DO - 10.1016/j.ijpharm.2012.10.024

M3 - Article

SN - 0378-5173

VL - 441

SP - 701

EP - 711

JO - INTERNATIONAL JOURNAL OF PHARMACEUTICS

JF - INTERNATIONAL JOURNAL OF PHARMACEUTICS

IS - 1-2

ER -