Formulation, Characterization, and Antitumor Properties of Trans- and Cis-Citral in the 4T1 Breast Cancer Xenograft Mouse Model
Purpose Citral is composed of a random mixture of two geometric stereoisomers geranial ( trans -citral) and neral ( cis -citral) yet few studies have directly compared their in vivo antitumor properties. A micelle formulation was therefore developed. Methods Geranial and neral were synthesized. Comm...
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Published in | Pharmaceutical research Vol. 32; no. 8; pp. 2548 - 2558 |
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Main Authors | , , , |
Format | Journal Article |
Language | English |
Published |
New York
Springer US
01.08.2015
Springer Nature B.V |
Subjects | |
Online Access | Get full text |
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Summary: | Purpose
Citral is composed of a random mixture of two geometric stereoisomers geranial (
trans
-citral) and neral (
cis
-citral) yet few studies have directly compared their
in vivo
antitumor properties. A micelle formulation was therefore developed.
Methods
Geranial and neral were synthesized. Commercially-purchased citral, geranial, and neral were formulated in PEG-b-PCL (block sizes of 5000:10,000, Mw/Mn 1.26) micelles.
In vitro
degradation, drug release, cytotoxicity, flow cytometry, and western blot studies were conducted. The antitumor properties of drug formulations (40 and 80 mg/kg based on MTD studies) were evaluated on the 4T1 xenograft mouse model and tumor tissues were analyzed by western blot.
Results
Micelles encapsulated drugs with >50% LE at 5–40% drug to polymer (
w/w
), displayed sustained release (t
1/2
of 8–9 h), and improved drug stability at pH 5.0. The IC
50
of drug formulations against 4T1 cells ranged from 1.4 to 9.9 μM. Western blot revealed that autophagy was the main cause of cytotoxicity. Geranial at 80 mg/kg was most effective at inhibiting tumor growth.
Conclusions
Geranial is significantly more potent than neral and citral at 80 mg/kg (
p
< 0.001) and western blot of tumor tissues confirms that autophagy and not apoptosis is the major mechanism of tumor growth inhibition in
p53-null
4T1 cells. |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 |
ISSN: | 0724-8741 1573-904X |
DOI: | 10.1007/s11095-015-1643-0 |