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Evaluation of interstitial protein delivery in multicellular layers model

Title
Evaluation of interstitial protein delivery in multicellular layers model
Authors
Kim S.-Y.Kim T.H.Choi J.H.Lee K.C.Park K.D.Lee S.-J.Kuh H.-J.
Ewha Authors
이승진
SCOPUS Author ID
이승진scopus
Issue Date
2012
Journal Title
Archives of Pharmacal Research
ISSN
0253-6269JCR Link
Citation
vol. 35, no. 3, pp. 531 - 541
Indexed
SCIE; SCOPUS; KCI WOS scopus
Abstract
The limited efficacy of anticancer protein drugs is related to their poor distribution in tumor tissue. We examined interstitial delivery of four model proteins of different molecular size and bioaffinity in multicellular layers (MCL) of human cancer cells. Model proteins were tumor necrosis factor-related apoptosis-including ligand (TRAIL), cetuximab, RNase A, and IgG. MCLs were cultured in Transwell inserts, exposed to drugs, then cryo-sectioned for image acquisition using fluorescence microscopy (fluorescent dye-labeled TRAIL, RNase A, IgG) or immunohistochemistry (cetuximab). TRAIL and cetuximab showed partial penetration into MCLs, whereas RNase A and IgG showed insignificant penetration. At 10-fold higher dose, a significant increase in penetration was observed for IgG only, while cetuximab showed an intense accumulation limited to the front layers. PEGylated TRAIL and RNase A formulated in a heparin-Pluronic (HP) nanogel showed significantly improved penetration attributable to increased stability and extracellular matrix binding, respectively. IgG penetration was significantly enhanced with paclitaxel pretreatment as a penetration enhancer. The present study suggests that MCL culture may be useful in evaluation of protein delivery in the tumor interstitium. Four model proteins showed limited interstitial penetration in MCL cultures. Bioaffinity, rather than molecular size, seems to have a positive effect on tissue penetration, although high binding affinity may lead to sequestration in the front cell layers. Polymer conjugation and nanoformulation, such as PEGylation and HP nanogel, or use of penetration enhancers are potential strategies to increase interstitial delivery of anticancer protein drugs.
DOI
10.1007/s12272-012-0317-2
Appears in Collections:
약학대학 > 약학과 > Journal papers
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