TY - JOUR
T1 - Development of a rapid-onset, acid-labile linkage polyplex-mixed micellar system for anticancer therapy
AU - Hung, Shiou Fen
AU - Wen, Yu Han
AU - Yu, Lu Yi
AU - Chiu, Hsin Cheng
AU - Chiang, Yi Ting
AU - Lo, Chun Liang
N1 - Publisher Copyright:
© 2021 by the authors. Licensee MDPI, Basel, Switzerland.
PY - 2021/6/1
Y1 - 2021/6/1
N2 - In the treatment of cancers, small interfering ribonucleic acids (siRNAs) are delivered into cells to inhibit the oncogenic protein’s expression; however, polyanions, hydrophilicity, and rapid degradations in blood, endosomal or secondary lysosomal degradation hamper clinal applications. In this study, we first synthesized and characterized two copolymers: methoxy poly(ethylene glycol)-b-poly(2-hydroxy methacrylate-ketal-pyridoxal) and methoxy poly(ethylene glycol)-b-poly(methacrylic acid-co-histidine). Afterwards, we assembled two polymers with the focal adhesion kinase (FAK) siRNA, forming polyplex-mixed micelles for the treatment of the human colon cancer cell line HCT116. In terms of the physiological condition, the cationic pyridoxal molecules that were conjugated on the copolymer with ketal bonds could electrostatically attract the siRNA. Additionally, the pyridoxal could form a hydrophobic core together with the hydrophobic deprotonated histidine molecules in the other copolymer and the hydrophilic polyethylene glycol (PEG) shell to protect the siRNA. In an acidic condition, the pyridoxal would be cleaved from the polymers due to the breakage of the ketal bonds and the histidine molecules can simultaneously be protonated, resulting in the endosome/lysosome escape effect. On the basis of our results, the two copolymers were successfully prepared and the pyridoxal derivatives were identified to be able to carry the siRNA and be cleavable by the copolymers in an acidic solution. Polyplex-mixed micelles were prepared, and the micellar structures were identified. The endosome escape behavior was observed using a confocal laser scanning microscopy (CLSM). The FAK expression was therefore reduced, and the cytotoxicity of siRNA toward human colon cancer cells was exhibited, rapidly in 24 h. This exceptional anticancer efficiency suggests the potential of the pH-sensitive polyplex-mixed micellar system in siRNA delivery.
AB - In the treatment of cancers, small interfering ribonucleic acids (siRNAs) are delivered into cells to inhibit the oncogenic protein’s expression; however, polyanions, hydrophilicity, and rapid degradations in blood, endosomal or secondary lysosomal degradation hamper clinal applications. In this study, we first synthesized and characterized two copolymers: methoxy poly(ethylene glycol)-b-poly(2-hydroxy methacrylate-ketal-pyridoxal) and methoxy poly(ethylene glycol)-b-poly(methacrylic acid-co-histidine). Afterwards, we assembled two polymers with the focal adhesion kinase (FAK) siRNA, forming polyplex-mixed micelles for the treatment of the human colon cancer cell line HCT116. In terms of the physiological condition, the cationic pyridoxal molecules that were conjugated on the copolymer with ketal bonds could electrostatically attract the siRNA. Additionally, the pyridoxal could form a hydrophobic core together with the hydrophobic deprotonated histidine molecules in the other copolymer and the hydrophilic polyethylene glycol (PEG) shell to protect the siRNA. In an acidic condition, the pyridoxal would be cleaved from the polymers due to the breakage of the ketal bonds and the histidine molecules can simultaneously be protonated, resulting in the endosome/lysosome escape effect. On the basis of our results, the two copolymers were successfully prepared and the pyridoxal derivatives were identified to be able to carry the siRNA and be cleavable by the copolymers in an acidic solution. Polyplex-mixed micelles were prepared, and the micellar structures were identified. The endosome escape behavior was observed using a confocal laser scanning microscopy (CLSM). The FAK expression was therefore reduced, and the cytotoxicity of siRNA toward human colon cancer cells was exhibited, rapidly in 24 h. This exceptional anticancer efficiency suggests the potential of the pH-sensitive polyplex-mixed micellar system in siRNA delivery.
KW - Acid-labile
KW - Anticancer therapy
KW - Mixed micelle
KW - SiRNA delivery
UR - http://www.scopus.com/inward/record.url?scp=85107978135&partnerID=8YFLogxK
U2 - 10.3390/polym13111823
DO - 10.3390/polym13111823
M3 - Article
AN - SCOPUS:85107978135
SN - 2073-4360
VL - 13
JO - Polymers
JF - Polymers
IS - 11
M1 - 1823
ER -