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Enhanced transcellular penetration and drug delivery by crosslinked polymeric micelles into pancreatic multicellular
Hongxu Lu1, Robert H Utama, Uraiphan Kitiyotsawat
1Centre for Advanced Macromolecular Design, School of Chemistry, University of New South Wales, Kensington, Sydney, New South Wales 2052, Australia. M.Stenzel@unsw.edu.au.
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.
Insights
Polymeric micelles effectively deliver doxorubicin into multicellular tumor spheroids (MCTS) via transcellular transport, with crosslinked micelles showing enhanced delivery. This targeted delivery inhibits tumor growth more effectively than free drug.
Area of Science:
- Biomedical Engineering
- Nanotechnology
- Cancer Research
Background:
- Multicellular tumor spheroids (MCTS) are crucial 3D models for studying tumor biology and drug delivery.
- Understanding nanocarrier penetration pathways within MCTS is essential for optimizing cancer therapeutics.
- Polymeric micelles offer potential as nanocarriers for targeted drug delivery in cancer treatment.
Purpose of the Study:
- To elucidate the penetration pathways of poly(N-(2-hydroxypropyl) methacrylamide-co-methacrylic acid)-block-poly(methyl methacrylate) (P(HPMA-co-MAA)-b-PMMA) micelles in MCTS.
- To compare the delivery efficiency of uncrosslinked (UCM) and crosslinked (CKM) micelles loaded with doxorubicin (DOX).
- To investigate the role of cellular transport mechanisms in micelle penetration within MCTS.
Main Methods:
- Preparation of UCM and CKM from P(HPMA-co-MAA)-b-PMMA block copolymers.
- Assessment of micelle and doxorubicin penetration into MCTS.
- Inhibition studies using Filipin (caveolae-mediated endocytosis inhibitor) and Exo1 (exocytosis inhibitor).
- Evaluation of micelle movement through collagen micro-spheroids to model extracellular matrix (ECM) interaction.
Main Results:
- Both UCM and CKM delivered significantly more doxorubicin into MCTS compared to free DOX.
- CKM exhibited higher delivery efficiency than UCM into MCTS.
- Inhibition of endocytosis and exocytosis reduced micelle uptake and penetration, indicating reliance on transcellular transport.
- Micelle movement within collagen ECM was limited to the periphery, suggesting limited diffusion through the matrix.
Conclusions:
- P(HPMA-co-MAA)-b-PMMA micelle penetration in MCTS is primarily mediated by transcellular transport rather than ECM diffusion.
- Crosslinked micelles (CKM) demonstrate superior doxorubicin delivery efficiency into MCTS.
- DOX-loaded CKM showed enhanced inhibition of MCTS growth, potentially due to sustained drug release and effects on apoptotic cells.
