Polymeric Micelles Employing Platinum(II) Linker for the Delivery of the Kinase Inhibitor Dactolisib

Abstract

Polymeric micelles are attractive nanocarriers for hydrophobic drug molecules such as the kinase inhibitor dactolisib. Two different poly(ethylene glycol)–poly(acrylic acid) (PEG‐b‐PAA) block‐copolymers are synthesized, PEG(5400)‐b‐PAA(2000) and PEG(10000)‐b‐PAA(3700), respectively. Polymeric micelles are formed by self‐assembly once dactolisib is conjugated via the ethylenediamine platinum(II) linker (Lx) to the PAA block of the block copolymers. Dactolisib micelles with dactolisib loading content of 17% w/w show good colloidal stability and display sustained release of Lx‐dactolisib over 96 h in PBS at 37 °C, while media containing reagents that compete for platinum coordination (e.g., glutathione (GSH) or dithiothreitol (DTT)) effectuate release of the parent inhibitor dactolisib at similar release rates. Dactolisib/lissamine‐loaded micelles are internalized by human breast adenocarcinoma cells (MCF‐7) in a dose and time‐dependent manner as demonstrated by confocal microscopy. Dactolisib‐loaded micelles inhibit the PI3K/mTOR signaling pathway at low concentrations (400 × 10−9 m) and exhibit potent cytotoxicity against MCF‐7 cells with IC50 values of 462 ± 46 and 755 ± 75 × 10−9 m for micelles with either short or longer PEG‐b‐PAA block lengths. In conclusion, dactolisib loaded PEG‐b‐PAA micelles are successfully prepared and hold potential for nanomedicine‐based tumor delivery of dactolisib.

Tyrosine Kinase Inhibitors for Glioblastoma Multiforme: Challenges and Opportunities for Drug Delivery

“…Various delivery systems such as polymeric nanoparticles, magnetic nanoparticles, dendrimers, lipid based systems including liposomes, nanostructured lipid carriers, and solid lipid nanoparticles can be utilized for effective delivery of drugs to brain [ 139 ]. Nanocarriers that can adequately retain the drug during circulation and release it on accumulation at tumor site can greatly improve the therapeutic index of the loaded drugs [ 140 ].…”

Double-hydrophilic block copolymer–metal ion associations: Structures, properties and applications

“…Metal complexes have been used, possibly partially hydrolyzed. This has often been the case for platinum (used in the form of the diamino salt [Pt(NH3)2(H2O)2] 2+ issued from the cis-platine, [100,117] 1.2-diaminocyclohexane platinum(II), [123] PtCl6 2- [94] or more elaborated structures [116]), gold (mainly in the form of tetrachloroaurate AuCl4 - [86]), palladium (PdCl4 2-[14]), etc. More complex architectures, such as coordination polymers with europium, gadolinium, iron or manganese [75,[135][136][137][138] or polyoxometallates based on molybdenum [76,93] or aluminum [44], have also been built.…”

“…The kinetics of release often exhibited two regimes: a fast regime in the first few hours and a slow regime in the next few days. Dactolisib (a dual inhibitor of phosphatidylinositol-3-kinase), [116] 5-fluorouracil (used to treat cancer), [54] or the Alexa 680 dye [122] were also trapped inside HPICs to incorporate the final system with biological materials.…”

Folate decorated polymeric micelles for targeted delivery of the kinase inhibitor dactolisib to cancer cells

“…In the present study, we coupled the hydrophobic kinase inhibitor dactolisib (DLB) via the platinum linker Lx to pendant carboxylic groups of poly(ethylene glycol)-b-poly(acrylic acid) (PEG-PAA) block copolymers; the formed polymer-Lx-drug complexes spontaneously selfassemble into polymeric micelles in an aqueous milieu due to hydrophobicity of the drug-modified PAA block (Shi et al, 2019b). DLB is a potent inhibitor of phosphatidylinositol-3-kinase (PI3K) and mammalian Target of Rapamycin (mTOR) and has been investigated as anticancer agent in phase II clinical trials.…”