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Efficient anti-tumor nano-lipoplexes with unsaturated or saturated lipid induce differential genotoxic effects in
Hari Krishnareddy Rachamalla1,2, Sujan Kumar Mondal1,2, Shruti S Deshpande1,2
1Applied Biology Division, CSIR-Indian Institute of Chemical Technology , Hyderabad , India.
Abstract:
Cationic lipids are well-known excipients for nanometric liposomal gene delivery systems. However, because of the suspected, collateral toxicity in normal cells, the use of cationic lipids for the treatment of human tumor is largely limited. Recently, we developed a glucocorticoid receptor (GR)-targeted liposomal, anticancer delivery system (DXE nano-lipoplex), which carried cationic lipid of saturated twin aliphatic chains. It exhibited efficient anti-tumor effect in aggressive and drug-resistant tumor models. Toward exploring lipoplex's human clinical use, we incorporated another nano-lipoplex (D1XE) group that carried cationic lipid with one of its aliphatic chain carrying unsaturation and compared in vivo genotoxicological profiling-based safety assessment and the respective anti-tumor efficacy of the lipoplexes. Thus, both the lipoplexes differ only by the chemical identity of one of their constituent cationic lipid. Unsaturated aliphatic chains in lipid generally impart efficient cell surface fusogenic property in lipid formulations. Herein, we report that nanoplex with unsaturated cationic lipid (D1XE) exhibited better physical appearance with less flocculent behavior than nanoplex with saturated lipid (DXE). Upon multiple injections, D1XE nanoplex imparted better tumor regression but most importantly, exhibited much lower overall toxicity (e.g. genotoxicity, weight loss, etc.) than DXE nanoplex. With a higher antitumor effect but a lower genotoxic effect, D1XE is proved to be a better nanoplex than DXE for the potential clinical trial. Thus, this study clearly delineates the importance of incorporating a constituent lipid that carries a single unsaturated aliphatic chain toward developing efficient anti-tumor nano-lipoplexes with reduced genotoxicity.
Insights
Developing novel nano-lipoplexes for cancer treatment, researchers found that incorporating unsaturated lipids significantly enhanced anti-tumor effects while reducing genotoxicity compared to saturated lipids.
Area of Science:
- Biomedical Engineering
- Nanotechnology
- Oncology
Background:
- Cationic lipids are crucial for liposomal gene delivery but face limitations due to toxicity.
- Existing cationic lipid formulations for cancer treatment are restricted by potential collateral damage to healthy cells.
Purpose of the Study:
- To compare the in vivo safety and anti-tumor efficacy of two nano-lipoplexes, DXE (saturated cationic lipid) and D1XE (unsaturated cationic lipid).
- To evaluate the impact of lipid unsaturation on the genotoxicity and therapeutic performance of glucocorticoid receptor (GR)-targeted liposomal anticancer delivery systems.
Main Methods:
- Development of two nano-lipoplexes (DXE and D1XE) differing only in the saturation of one cationic lipid aliphatic chain.
- In vivo assessment of anti-tumor efficacy and genotoxicological profiling following multiple injections in tumor models.
- Comparative analysis of physical characteristics, tumor regression, and systemic toxicity (e.g., weight loss).
Main Results:
- The D1XE nano-lipoplex, featuring unsaturated cationic lipids, demonstrated improved physical stability and reduced flocculent behavior compared to DXE.
- D1XE exhibited superior tumor regression and significantly lower overall toxicity, including reduced genotoxicity and weight loss, than DXE.
- The presence of a single unsaturated aliphatic chain in the cationic lipid enhanced fusogenic properties and therapeutic outcomes.
Conclusions:
- Incorporating a cationic lipid with a single unsaturated aliphatic chain is critical for developing efficient anti-tumor nano-lipoplexes.
- The D1XE nano-lipoplex shows greater potential for clinical application in cancer therapy due to its enhanced efficacy and improved safety profile.
- This study highlights the importance of lipid chemical structure in optimizing nano-lipoplex design for reduced genotoxicity and improved anti-cancer activity.
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