New binary thermoresponsive polymeric system for local chemoradiotherapy

Abstract

Radiolabeled thermoresponsive polymers (TRPs) with cloud-point temperatures between room temperature and body temperature may have an advantage for local radiotherapeutical applications because TRPs may be isotopically labeled in solution at room temperature and injected as a solution, and at the site of application, the polymers form a depo because of phase separation at body temperature. A new polymeric drugdelivery system designed for combined local chemoradiotherapy with an injectable TRP bearing a radionuclide and the hydrophobic moiety doxorubicin (DOX) was synthesized and characterized. In the system, DOX served as an antiproliferative agent with known synergic effects with ionizing radiation and the hydrophobic moiety controlling bioerosion and elimination of the system at the same time. DOX was bound to the polymer carrier by a hydrolytically labile N-glycosylamine bond. Hydrolysis of the N-glycosylamine bond thus controlled the DOX release and dissolution of the system in the model aqueous milieu. DOX was slowly released during incubation in aqueous milieu at 37 C, which caused complete dissolution of the bioerodable polymer within about 2 weeks. The model radionuclide iodine 125, bound to a small amount of poly(N-isopropylacrylamide-co-N-methacryloyl tyrosinamide), was retained in the separated phase and also slowly dissolved during the incubation.

Smart polymers in drug delivery systems on crossroads: Which way deserves following?

“…During hydrolysis of the hydrazone bond a hydrophobic ketone is released and the polymer chain is hydrophilized, which leads to increase in CPT above body temperature and polymer re-dissolution. Alternatively, if the hydrophobic moiety to be hydrolyzed out from the polymer is an anticancer agent such as doxorubicin [34], drug release may be synchronized with re-dissolution.…”

Hydrogels based on N-isopropylmethacrylamide and N-isopropylacrylamide

“…The release of the drug substance from the copolymer based on NIPMAM and MAM comonomer containing hydrophobic alkyle residues through dissolution due to the hydrolythic cleavage of hydrazone bond is graphically presented in Figure 4 [105].…”

Nano‐sized Carrier Systems as New Materials for Nuclear Medicine

“…Brachytherapy currently used in clinical medicine is realized by implantation of macroscopic metal closed seeds into the tumor. However, there exists another approach using nanostructured thermoresponsive materials which is currently studied [8][9][10]38]. Thermoresponsive (sometimes also called thermosensitive) polymers with lower critical solubility temperature (LCST) are soluble in aqueous milieu at low temperature while coil-to-globule transition followed by aggregation into nanoparticles and subsequent macroscopic phase separation occures at higher temperature (above their cloud point temperature, CPT).…”

“…It was proven on a model system that if such polymer [poly(I\Msopropyl acrylamide) (PNIPAA) in this case], soluble at room temperature and precipitated at body temperature, is injected into muscle, it remains in the site of application and is only slowly eliminated from the local depo [39]. It should thus be useful for local injectable brachytherapy without the necessity of surgery and with the possibility to eliminate the polymer after it fulfills its task [8][9][10]38].…”

“…Most currently studied nanosystems designed for medicinal purposes are chemical drug or nucleic acid (gene) delivery systems. Radionuclides however have certain advantages compared to chemical drugs for the nanosized drug delivery systems [6][7][8][9][10], above all:…”