Targeting CD146 using folic acid-conjugated nanoparticles and suppression of tumor growth in a mouse glioma model.
OBJECTIVE
Glioma stem cells (GSCs) are responsible for tumor initiation, therapeutic resistance, and recurrence. CD146 is mainly expressed in dividing GSCs and regulates cell cycle progression. However, the evaluation of the efficacy of targeted therapy against CD146 in vivo remains to be investigated. In this study, the authors aimed to develop gene therapy targeting GSCs using chitosan oligosaccharide lactate (COL) nanoparticles (NPs) conjugated with folic acid-polyethylene glycol (FA-PEG-COL NPs) for in vitro and in vivo delivery of CD146 small-interfering RNA (siCD146) and to determine the effect of CD146 knockdown on tumor growth.


METHODS
To examine the uptake of NPs by tumor cells, immunofluorescence staining, flow cytometry, and in vivo imaging were performed. The knockdown effect of siCD146 was measured by western blot and water-soluble tetrazolium salt-8 assay in mouse glioma cells. The efficacy of siRNA therapy-targeted GSCs was evaluated by monitoring tumor growth through in vivo imaging and histological analysis.


RESULTS
In vivo accumulation of the FA-PEG-COL NPs in subcutaneous and intracranial gliomas following NP administration via a mouse tail vein was observed. Additionally, in vitro delivery of siCD146 ionically cross-linked NPs, reduced CD146 levels, and suppressed growth in the glioma tumor sphere. Evaluation of the in vivo therapeutic effects of siCD146-cross-linked NPs in a mouse glioma model revealed significant suppression of intracranial tumor growth, with complete removal of the tumor observed in some mice on histological examination. Furthermore, delivery of siCD146 significantly reduced the Ki-67 index in residual tumor tissues relative to that in control mice.


CONCLUSIONS
CD146 is a potential therapeutic target, and folic acid-conjugated NPs delivering siRNA may facilitate gene therapy in malignant gliomas.
['Fukui|Naoki|N|', 'Yawata|Toshio|T|', 'Nakajo|Takahito|T|', 'Kawanishi|Yu|Y|', 'Higashi|Youichirou|Y|', 'Yamashita|Tatsuyuki|T|', 'Aratake|Takaaki|T|', 'Honke|Koichi|K|', 'Ueba|Tetsuya|T|']
D000818:Animals D001932:Brain Neoplasms D051929:CD146 Antigen D045744:Cell Line, Tumor D002645:Chickens D005492:Folic Acid D018390:Gene Targeting D015316:Genetic Therapy D005910:Glioma D051379:Mice D008807:Mice, Inbred BALB C D008809:Mice, Inbred C3H D008819:Mice, Nude D053758:Nanoparticles D034741:RNA, Small Interfering
CD146 nanoparticle glioma stem cell gene therapy siRNA glioblastoma oncology