A PEGylated liposomal formulation of prochlorperazine that limits brain exposure but retains dynamin II activity: A potential adjuvant therapy for cancer patients receiving chemotherapeutic mAbs.
In: Nanomedicine: Nanotechnology, Biology & Medicine, Jg. 56 (2024-02-01), S. N.PAG
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Zugriff:
Anti-cancer monoclonal antibodies often fail to provide therapeutic benefit in receptor-positive patients due to rapid endocytosis of antibody-bound cell surface receptors. High dose co-administration of prochlorperazine (PCZ) inhibits endocytosis and sensitises tumours to mAbs by inhibiting dynamin II but can also introduce neurological side effects. We examined the potential to use PEGylated liposomal formulations of PCZ (LPCZ) to retain the anti-cancer effects of PCZ, but limit brain uptake. Uncharged liposomes showed complete drug encapsulation and pH-dependent drug release, but cationic liposomes showed limited drug encapsulation and lacked pH-dependent drug release. Uncharged LPCZ showed comparable inhibition of EGFR internalisation to free PCZ in KJD cells. After IV administration to rats, LPCZ reduced the plasma clearance and brain uptake of PCZ compared to IV PCZ. The results suggest that LPCZ may offer some benefit over PCZ as an adjunct therapy in cancer patients receiving mAb treatment. Liposomal Prochlorperazine (LPCZ) was formulated to retain the promising anti-tumour effects of the drug when delivered at high IV doses with anti-cancer mAbs, but limit brain uptake which causes central adverse effects including akathisia and agitation. LPCZ retained the anti-tumoural effects of the drug that are mediated by dynamin II inhibition, and reduced brain biodistribution across the blood brain barrier (BBB). LPCZ may provide a useful alternative to PCZ that is being examined in clinical trials in Australia as an adjunct therapy for cancer patients undergoing treatment with mAbs. [Display omitted] [ABSTRACT FROM AUTHOR]
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Titel: |
A PEGylated liposomal formulation of prochlorperazine that limits brain exposure but retains dynamin II activity: A potential adjuvant therapy for cancer patients receiving chemotherapeutic mAbs.
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Autor/in / Beteiligte Person: | Subasic, Christopher N. ; Simpson, Fiona ; Minchin, Rodney F. ; Kaminskas, Lisa M. |
Zeitschrift: | Nanomedicine: Nanotechnology, Biology & Medicine, Jg. 56 (2024-02-01), S. N.PAG |
Veröffentlichung: | 2024 |
Medientyp: | academicJournal |
ISSN: | 1549-9634 (print) |
DOI: | 10.1016/j.nano.2024.102733 |
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