Create 1 slide for Cyclodextrin-Based Strategies for siRNA Delivery: From Molecular Design to Therapeutic Gene Silencing” Compared to other delivery systems, cyclodextrins (CDs) have an added advantage of having no or low toxicity. Cyclodextrin-based delivery systems have the added advantage of offering nucleic acid delivery without the need for transfection agents. Natural CDs lack the tendency to bind to nucleic acids; therefore, modifications need to be made to the CD structures. The last couple of years have seen intense research in amphiphilic monomers, CD-based polymers, hybrid dendrimers, covalent CD systems, and host-guest systems, especially the β-CD-adamantane systems. In order to improve the transfection efficiency, several strategies have been employed including charge modification and inclusion of active transport systems. Among charge modifications, primary amines are preferred over quaternary ammonium groups, since the former can be protonated and, therefore, facilitate escape from endosomes. A major advantage of the host-guest systems is the ease of modification. This allows the simple incorporation of targeting groups or stealth polyethylene glycol (PEG) groups. First-in-man (Phase-I) clinical trial of CALAA-01 demonstrated good safety and tolerability when used for the treatment of solid tumors. Cancer therapies targeting VEGF and Bcl-2 are also at an advanced stage of development. Brain delivery of CD-based siRNA has been achieved to suppress the expression of mutated huntingtin protein in Huntington’s disease. Cyclodextrin-based delivery systems are at a relatively earlier stage of development compared to other siRNA delivery systems. Off-target effects and endosomal entrapment of the delivery systems remain challenging areas for further development.
Create 1 slide for
Cyclodextrin-Based Strategies for siRNA Delivery: From Molecular Design to
Therapeutic Gene Silencing”
Compared to other delivery systems, cyclodextrins (CDs) have an added advantage of having no
or low toxicity. Cyclodextrin-based delivery systems have the added advantage of offering
nucleic acid delivery without the need for transfection agents. Natural CDs lack the tendency to
bind to nucleic acids; therefore, modifications need to be made to the CD structures. The last
couple of years have seen intense research in amphiphilic monomers, CD-based polymers,
hybrid dendrimers, covalent CD systems, and host-guest systems, especially the
β-CD-adamantane systems.
In order to improve the transfection efficiency, several strategies have been employed including
charge modification and inclusion of active transport systems. Among charge modifications,
primary amines are preferred over quaternary ammonium groups, since the former can be
protonated and, therefore, facilitate escape from endosomes. A major advantage of the host-guest
systems is the ease of modification. This allows the simple incorporation of targeting groups or
stealth polyethylene glycol (PEG) groups.
First-in-man (Phase-I) clinical trial of CALAA-01 demonstrated good safety and tolerability
when used for the treatment of solid tumors. Cancer therapies targeting VEGF and Bcl-2 are also
at an advanced stage of development. Brain delivery of CD-based siRNA has been achieved to
suppress the expression of mutated huntingtin protein in Huntington’s disease.
Cyclodextrin-based delivery systems are at a relatively earlier stage of development compared to
other siRNA delivery systems. Off-target effects and endosomal entrapment of the delivery
systems remain challenging areas for further development.
Created using ChatSlide
This project focuses on the innovative design of cyclodextrins (CDs) for safer delivery of siRNA, eliminating the need for toxic transfection agents. By engineering CDs to effectively bind and protect siRNA, we will compare their efficacy against polymers and dendrimers. Additionally, we aim to translate this delivery design into practical gene silencing applications, enhancing uptake through amines and targeting strategies, with clinical proof from CALAA-01 for brain delivery. Emphasis will...