Eph A10-modified pH-sensitive liposomes loaded with novel triphenylphosphine–docetaxel conjugate possess hierarchical targetability and sufficient antitumor effect both in vitro and in vivo

Abstract

Mitochondrial-targeting therapy was considered to be a promising approach for the efficient treatment of cancer while positive charge induced nonspecific cytotoxicity severely limits its application. To overcome this drawback, a novel mitochondria targeted conjugate triphenylphosphine-docetaxel (TD) has been synthesized successfully and incorporated it into liposomes (EPSLP/TD), which possessed excellent pH-sensitive characteristic, EphA 10 mediated active targetability as well as mitochondria-targeting capability. EPSLP/TD was characterized to have a small particle size, high-encapsulation efficiency and excellent pH-sensitive characteristic. Compared with DTX-loaded liposomes (EPSLP/DTX), EPSLP/TD possessed higher cytotoxicity against MCF-7 cell line. Mitochondrial-targeting assay demonstrated mitochondria-targeting moiety triphenylphosphine (TPP) could efficiently deliver DTX to mitochondria. Western immunoblotting assay indicated that EPSLP/TD could efficiently deliver antitumor drug to mitochondria and induce cell apoptosis via mitochondria-mediated apoptosis pathway. In vivo antitumor study demonstrated EPSLP/TD owed excellent in vivo antitumor activity. Histological assay demonstrated EPSLP/TD showed strongly apoptosis inducing effect, anti-proliferation effect and anti-angiogenesis effect. This work investigated the potential of hierarchical targeting pH-sensitive liposomes is a suitable carrier to activate mitochondria-mediated apoptosis pathway for cancer therapy.

The catalytically defective receptor protein tyrosine kinase EphA10 promotes tumorigenesis in pancreatic cancer cells

“…To our knowledge, this is the first report to demonstrate that levels of EphA10 positively correlate with the tumorigenic potential of pancreatic cancer cells both in vitro and in vivo. EphA10 has been identified as a therapeutic target in breast and prostate cancers, and neutralizing monoclonal antibodies to EphA10 as well as EphA10 antibody‐drug conjugates have been developed 10,11,14,38,39 . Our results suggested that EphA10 may be a valuable therapeutic target to treat refractory pancreatic cancer and other cancers that are positive for EphA10 expression.…”

Nanomedicine for Gene Delivery for the Treatment of Cardiovascular Diseases

“…When micelles are incorporated with hydrophobic therapeutic agents, the solubility problems are solved [84]. Liposomes are compatible with the cell membrane and thus the most popular carriers for cell endocytosis [85, 86]. Polymers could incorporate both hydrophilic and hydrophobic agents to increase solubility [87, 88].…”

Smart Stimuli-Responsive and Mitochondria Targeting Delivery in Cancer Therapy

“… pH Polymer-drug conjugates DOX 4T1 Endocytosis pathway Lysosome & mitochondria 1.9-fold higher 2.5-fold lower Yes (Cas-3 activation) [ 81 ] Eph A10/TPP-DTX liposomes Docetaxel MCF-7 EphA 10 receptor mediated cell endocytosis Mitochondria 0.14-fold lower Lower IC 50 value Yes (highest Cas-3 and Cas-9 expression) [ 42 ] CTPP-CSOSA/celastrol micelles Celastrol MCF-7 Endocytosis pathway Mitochondria Dropped dramatically Lower IC 50 value Yes (obvious increase in Cas-3 and Cas-9 activity) [ 43 ] HER-2/DOX DQAsomes DOX MCF-7 and MCF-7/ADR HER-2 peptide-mediated endocytosis Mitochondria A 6.9% decrease 2.6-fold lower Yes (activated Cas-3 and Cas-9) [ 36 ] PEG-AIE-TPP micelle AIE-TPP MCF-7 Endocytosis pathway Mitochondria – – Yes [ 44 ] HPMA-MSN/DTX nanoparticles Docetaxel HeLa Endocytosis pathway Mitochondria Collapse A lower IC 50 compared to pH7.4 …”