Gene delivery is, arguably, the biggest bottleneck in gene therapy. Adeno-associated virus (AAVs) are the historical mainstay, but they are expensive to manufacture and have payload limits and immunological issues. Lipid nanoparticles, which delivered the mRNA COVID-19 vacines, are mostly limited to targeting the liver. To deleiver gene based therapeutics both cost-effectively and to a wider varity of tissue targets, polypmer nanoparticles may be the answer. Tehre are about 10 to the 60 possible polymers one can synthesis. (Dutton, “Possible polymer delivery systems outnumber the stars” Genetic Engineering and Biotechnology News” (Feb. 2024).
Ferromagnetic particles: In the 1960s, attempts were made to use ferromagnetic particles as constrast agents for X-ray diagnosis and for magnetically controlled drug targeting. The irreversible aggregation of the magnetic particles under the influence of a magentic field proved to be a problem during in vivo application. Ferromagnetic particles have such great magnetic moments that the particles agglomerate to form greater aggregates even when they are provided with a polymer coating. Such ferromagnetic particles would sedimetn in the body during parenteral adminsitration and the toxid side effects would be great. (US5,916,539).
Superparamagnetic particles: The irreversible agglomeration of the magnetic particles in the magnetic field can be avoided by using superparamagnetic particles which have no remanence (i.e., they can be moved and concentrated reversibly in a magnetic gradient field). These superparamagnetic particles include, for example, iron oxides having a particle diameter small than 0.02 um (Pilgrimm, US 5,916,539).
–ultrasmall superparamagentic iron oxide nanoparticles (USPIO or SPIO): see right hand panel
–Gadolinium (Gd) chelate nanoparticles: enhance MRI contrast via a T1 relaxation mechanisms in contrast to superparamagnetic iron oxide nanoparticles which enhance contrast via a T2 relaxation mechanisms. They can be synthesized by a variety of methods such as by reacting a solution of gadolinium citrate with a chelator such as diethylenetriaminepentaacetic acid (“DTPA”), or with DTPA derivatized with a linker containing another active group to facilitate addition of the Gd-chelate to another compound such as a targeting group.