Issue 7, 2015

Enhanced transcellular penetration and drug delivery by crosslinked polymeric micelles into pancreatic multicellular tumor spheroids

Abstract

Many attempts have been made in the application of multicellular tumor spheroids (MCTS) as a 3D tumor model to investigate their biological responses upon introduction of polymeric micelles as nanocarriers for therapeutic applications. However, the micelle penetration pathways in MCTS are not yet known. In this study, micelles (uncrosslinked, UCM) were prepared by self-assembly of block copolymer poly(N-(2-hydroxypropyl) methacrylamide-co-methacrylic acid)-block-poly(methyl methacrylate) (P(HPMA-co-MAA)-b-PMMA). Subsequently, the shells were crosslinked to form relatively stable micelles (CKM). Both UCM and CKM penetrated deeper and delivered more doxorubicin (DOX) into MCTS than the diffusion of the free DOX. Additionally, CKM revealed higher delivery efficiency than UCM. The inhibition of caveolae-mediated endocytosis, by Filipin treatment, decreased the uptake and penetration of the micelles into MCTS. Treatment with Exo1, an exocytosis inhibitor, produced the same effect. Furthermore, movement of the micelles through the extracellular matrices (ECM), as modelled using collagen micro-spheroids, appeared to be limited to the peripheral layer of the collagen spheroids. Those results indicate that penetration of P(HPMA-co-MAA)-b-PMMA micelles depended more on transcellular transport than on diffusion through ECM between the cells. DOX-loaded CKM inhibited MCTS growth more than their UCM counterpart, due to possible cessation of endocytosis and exocytosis in the apoptotic peripheral cells, caused by faster release of DOX from UCM.

Graphical abstract: Enhanced transcellular penetration and drug delivery by crosslinked polymeric micelles into pancreatic multicellular tumor spheroids

Supplementary files

Article information

Article type
Paper
Submitted
13 sep 2014
Accepted
25 nov 2014
First published
05 dec 2014

Biomater. Sci., 2015,3, 1085-1095

Author version available

Enhanced transcellular penetration and drug delivery by crosslinked polymeric micelles into pancreatic multicellular tumor spheroids

H. Lu, R. H. Utama, U. Kitiyotsawat, K. Babiuch, Y. Jiang and M. H. Stenzel, Biomater. Sci., 2015, 3, 1085 DOI: 10.1039/C4BM00323C

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