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Synthesis, preformulation and liposomal formulation of cholesteryl carborane esters with various fatty chains
Fars Alanazi1, Hengguang Li, David S Halpern
1Department of Pharmaceutical and Biomedical Science, College of Pharmacy, The University of Georgia, Athens, GA 30602, USA.
Abstract:
The elevated expression of LDL receptor on tumor cells provides one attractive approach for targeted drug delivery to tumor cells. Suitable antitumor compounds, however, need to be synthesized and developed which mimic the native cholesteryl esters (as major constituent of LDL) in chemical structure for targeted delivery to tumor cells through the over-expressed LDL receptors. In the present study, new antitumor compounds were designed containing cholesterol, fatty chain and carborane which is used as the antitumor unit. Three new compounds were synthesized with a three-step reaction scheme. Similar to the native cholesteryl esters, these compounds are extremely hydrophobic and, before any further biological studies, suitable liposomal formulations for these new compounds are required. Various liposomal formulations as well as the preformulation characterization of these new compounds were thus examined. The incorporation efficiency of the compounds in liposomes was found to vary significantly depending on the type of fatty chain attached and the ratio of cholesterol:phospholipid used as the excipients of liposomal formulation.
Insights
New cholesterol-based antitumor compounds were synthesized for targeted delivery via LDL receptors. Liposomal formulations were developed, with incorporation efficiency depending on fatty chain and lipid ratios.
Area of Science:
- Medicinal Chemistry
- Nanotechnology
- Oncology
Background:
- Overexpressed low-density lipoprotein (LDL) receptors on tumor cells present a target for drug delivery.
- Developing antitumor agents that mimic native cholesteryl esters is crucial for effective LDL receptor-mediated delivery.
- Existing treatments necessitate novel strategies for enhanced tumor targeting and efficacy.
Purpose of the Study:
- To design and synthesize novel antitumor compounds incorporating cholesterol, a fatty chain, and a carborane moiety.
- To create suitable liposomal formulations for these hydrophobic compounds to enable targeted delivery.
- To investigate the preformulation characteristics and liposomal incorporation efficiency of the synthesized compounds.
Main Methods:
- Three novel cholesterol-carborane compounds were synthesized using a three-step reaction.
- Liposomal formulations were prepared using various cholesterol:phospholipid ratios and fatty acid chains.
- Preformulation studies and incorporation efficiency assessments were conducted for the liposomal drug delivery systems.
Main Results:
- The synthesized compounds exhibit high hydrophobicity, similar to native cholesteryl esters.
- Liposomal formulation incorporation efficiency varied significantly based on the fatty chain and cholesterol:phospholipid ratio.
- Successful development of liposomal formulations is a prerequisite for further biological evaluation.
Conclusions:
- Novel cholesterol-carborane conjugates show potential for targeted cancer therapy via LDL receptors.
- Liposomal formulation optimization is critical for maximizing drug loading and delivery efficiency.
- These findings pave the way for in vivo studies of these targeted antitumor agents.