1. T7 Peptide-Conjugated Lipid Nanoparticles for Dual Modulation of Bcl-2 and Akt-1 in Lung and Cervical Carcinomas
- Author
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Robert J. Lee, Chen Kang, Yu Daorui, Yang Liu, Shuhong Tian, Bryant C. Yung, Xiaoju Zhou, Fang Xingyue, Guang Cheng, Qibing Liu, Hewen Li, and Xinwei Cheng
- Subjects
Lung Neoplasms ,Uterine Cervical Neoplasms ,Pharmaceutical Science ,Nanoparticle ,02 engineering and technology ,Conjugated system ,Mice ,03 medical and health sciences ,chemistry.chemical_compound ,Drug Delivery Systems ,0302 clinical medicine ,Drug Discovery ,medicine ,Animals ,Humans ,Nucleotide ,Protein kinase B ,chemistry.chemical_classification ,Lung ,Cholesterol ,Cancer ,Oligonucleotides, Antisense ,021001 nanoscience & nanotechnology ,medicine.disease ,Lipids ,Xenograft Model Antitumor Assays ,medicine.anatomical_structure ,Proto-Oncogene Proteins c-bcl-2 ,chemistry ,A549 Cells ,030220 oncology & carcinogenesis ,Cancer cell ,Cancer research ,Nanoparticles ,Molecular Medicine ,Female ,0210 nano-technology ,Proto-Oncogene Proteins c-akt - Abstract
Expression of Bcl-2 and Akt-1 has been associated with human cancer. G3139 and RX-0201, targeting Bcl-2 and Akt-1, respectively, are antisense oligonucleotides (ASOs) that have shown limited efficacy in clinical trials. Herein, we report a combination of newly designed ASOs based on these agents and was delivered by tumor cell-targeting lipid nanoparticles (LNPs). A "Gapmer" design strategy was applied to these ASOs with the addition of 2'-O-methyl modifications on the nucleotides at 5' and 3' ends. A dual-channel syringe pump-based system was developed for the synthesis of the LNPs. ASO-LNPs composed of DODMA, egg PC, cholesterol, T7-PEG-DSPE, and PEG-DMG at a molar ratio of 35:39.5:20:0.5:5 and carrying either individual ASOs or co-loaded ASO combinations (Co-ASOs) were synthesized and evaluated in both KB and A549 cancer cells and in an A549 murine xenograft model to determine their antitumor effects and biological activities. The ASO-LNPs exhibited excellent colloidal stability and high ASO encapsulation efficiency with relatively small mean particle sizes and moderately positive zeta potentials. Transferrin receptor-targeting T7-conjugated LNPs showed enhanced cellular uptake compared to nontargeted LNPs. In addition, both T7-conjugated Co-ASOs-LNPs and non-T7-conjugated Co-ASOs-LNPs at a molar ratio of (G3139-GAP to RX-0201-GAP at 1:2) showed efficient downregulation of both Bcl-2 and Akt-1 in both A549 and KB cells. Furthermore, T7-conjugated Co-ASOs-LNPs (Co-ASOs-LNPs) produced superior antitumor activity, prolonged the overall survival time, and demonstrated tumor targeting activity in an A549 xenograft model.
- Published
- 2018
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