Selective intracellular drug delivery from pH-responsive polyion complex micelle for enhanced malignancy suppression in vivo.
The pH-triggered intracellular drug delivery platforms have attracted great interest in malignancy therapy. Herein, a pH-responsive polyion complex (PIC) micelle from anionic acid-sensitive methoxy poly(ethylene glycol)-block-poly(N(ϵ)-((1-carboxy-cis-cyclohexene)-2-carbonyl)-L-lysine) (mPEG-b-PCLL) and cationic doxorubicin (DOX), a model anthracycline antitumor drug, was constructed by electrostatic interaction for directional intracellular drug delivery in malignancy chemotherapy. The PIC micelle kept constant diameter at physiological condition (i.e., pH 7.4), while gradually swelled and finally disassembled at mimicking intratumoral pH (i.e., 6.8) and especially intracellular endo/lysosomal pH (i.e., 5.5). The DOX release from the PIC micelle at pH 7.4 was slow, whereas obviously accelerated at the intracellular acidic condition of pH 5.5. These results should be related to the rapid cleavage of the side amide bond of mPEG-b-PCLL in an acidic environment. The PIC micelle exhibited satisfactory tumor suppression toward the H22 hepatoma-bearing BALB/c mouse model compared with free DOX, which was demonstrated by the upregulated tumor inhibition rate, and the increased necrotic and apoptosis areas in tumor tissue. Furthermore, the enhanced security was also observed in the PIC micelle group in relation to that of free DOX. The above results strongly supported that the acid-sensitive PIC micelle was promising for selective intracellular drug delivery along with upregulated malignancy inhibition.
Department of Urology, the First Hospital of Jilin University, Changchun 130021, PR China; Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun 130022, PR China.
Jixue
J
Wang
Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun 130022, PR China.
Weiguo
W
Xu
Department of Urology, the First Hospital of Jilin University, Changchun 130021, PR China.
Hui
H
Guo
Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun 130022, PR China. Electronic address: jxding@ciac.ac.cn.
Jianxun
J
Ding
Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun 130022, PR China.
Jinjin
J
Chen
Department of Urology, the First Hospital of Jilin University, Changchun 130021, PR China. Electronic address: guanjingjing99@126.com.
Jingjing
J
Guan
Department of Urology, the First Hospital of Jilin University, Changchun 130021, PR China.
Chunxi
C
Wang
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage* / Q000737:chemistry; D017209:Apoptosis / Q000187:drug effects; D004317:Doxorubicin / Q000008:administration & dosage* / Q000737:chemistry; D004337:Drug Carriers / Q000737:chemistry; D016503:Drug Delivery Systems; D006863:Hydrogen-Ion Concentration; D008114:Liver Neoplasms, Experimental / Q000188:drug therapy / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008823:Micelles; D009336:Necrosis; D011092:Polyethylene Glycols / Q000737:chemistry
D000903:Antibiotics, Antineoplastic; D004337:Drug Carriers; D008823:Micelles; D011092:Polyethylene Glycols; D004317:Doxorubicin; C028210:monomethoxypolyethylene glycol
Chemotherapy; In vivo; Intracellular drug delivery; Polyion complex micelle; pH-responsiveness