Highly specific in vivo gene delivery for p53-mediated apoptosis and genetic photodynamic therapies of tumour.
Anticancer therapies are often compromised by nonspecific effects and challenged by tumour environments' inherent physicochemical and biological characteristics. Often, therapeutic effect can be increased by addressing multiple parameters simultaneously. Here we report on exploiting extravasation due to inherent vascular leakiness for the delivery of a pH-sensitive polymer carrier. Tumours' acidic microenvironment instigates a charge reversal that promotes cellular internalization where endosomes destabilize and gene delivery is achieved. We assess our carrier with an aggressive non-small cell lung carcinoma (NSCLC) in vivo model and achieve >30% transfection efficiency via systemic delivery. Rejuvenation of the p53 apoptotic pathway as well as expression of KillerRed protein for sensitization in photodynamic therapy (PDT) is accomplished. A single administration greatly suppresses tumour growth and extends median animal survival from 28 days in control subjects to 68 days. The carrier has capacity for multiple payloads for greater therapeutic response where inter-individual variability can compromise efficacy.
Department of Internal Medicine, National Taiwan University College of Medicine, Taipei 10051, Taiwan.
S-Ja
SJ
Tseng
Institute of Medical Science and Technology, National Sun Yat-sen University, Kaohsiung 80424, Taiwan.
Zi-Xian
ZX
Liao
Research Center for Tumor Medical Science, China Medical University, Taichung 40402, Taiwan.
Shih-Han
SH
Kao
Institute of Biotechnology, National Taiwan University, Taipei 10617, Taiwan.
Yi-Fang
YF
Zeng
Graduate Institute of Life Sciences, National Defense Medical Center, Taipei 11490, Taiwan.
Kuo-Yen
KY
Huang
Graduate Institute of Life Sciences, National Defense Medical Center, Taipei 11490, Taiwan.
Hsin-Jung
HJ
Li
Departments of Neurosurgery, Chang Gung Memorial Hospital, Taoyuan 33305, Taiwan.
Chung-Lin
CL
Yang
Department of Industrial and System Engineering, Chung Yuan Christian University, Taoyuan 32023, Taiwan.
Yu-Fan
YF
Deng
Institute of Physics, Academia Sinica, Taipei 11529, Taiwan.
Chi-Feng
CF
Huang
Institute of Biomedical Sciences, Academia Sinica, Taipei 11529, Taiwan.
Shuenn-Chen
SC
Yang
1] Department of Internal Medicine, National Taiwan University College of Medicine, Taipei 10051, Taiwan [2] Institute of Biomedical Sciences, Academia Sinica, Taipei 11529, Taiwan [3] NTU Center for Genomic Medicine, National Taiwan University, Taipei 10051, Taiwan.
Pan-Chyr
PC
Yang
Ian Wark Research Institute, University of South Australia, Mawson Lakes, South Australia 5095, Australia.
Ivan M
IM
Kempson
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D002289:Carcinoma, Non-Small-Cell Lung / Q000628:therapy*; D045744:Cell Line, Tumor; D004121:Dimethyl Sulfoxide; D011992:Endosomes / Q000378:metabolism; D018014:Gene Transfer Techniques; D005971:Glutamates; D049452:Green Fluorescent Proteins / Q000378:metabolism*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D020287:In Situ Nick-End Labeling; D007211:Indoles; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D008807:Mice, Inbred BALB C; D010778:Photochemotherapy / Q000379:methods*; D059016:Tumor Microenvironment / Q000502:physiology*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
D005971:Glutamates; D007211:Indoles; D016159:Tumor Suppressor Protein p53; C508771:killer red protein, Anthomedusae; D049452:Green Fluorescent Proteins; C035260:3-aminoglutaric acid; C007293:DAPI; D004121:Dimethyl Sulfoxide