Injectable Drug-loaded Hydrogels Based On The Supramolecular Polymeric Prodrugs

Recently, environmentally sensitive polymers have been widely studied and applied in the materials for drug controlled release. Antitumor drugs have been covalently bonded onto the environmentally sensitive polymers to form polymeric prodrugs in order to improve the stability of the drugs and achieve the controlled release of the drugs. However, because all polymers have polydispersity, these covalently bonded polymeric prodrugs are not pure chemical compounds, but mixtures, which make it difficult for them to be approved by the drug administration of most countries.Herein, we developed a novel pH-sensitive supramolecular polymeric drug based on host-guest interaction. Adamantane modified small molecular prodrug was firmly connected to the cyclodextrin polymer to form a supramolecular polymeric drug through the strong host-guest interaction between β-cyclodextrin and adamantane moieties, which could combine the advantages of polymeric prodrug and purity of the small molecular prodrug.An acid-sensitive small molecular prodrug, adamantane-modified doxorubicin (AD-DOX), was synthesized via an acid-labile benzoic-imine linkage between adamantine benzaldehyde and doxorubicin. We developed two injectable drug-loaded hydrogels. On one hand, β-cyclodextrin modified polyaldehyde dextran (PAD-CD), was synthesized through the Schiff’s base reaction between amino β-cyclodextrin and polyaldehyde dextran. The pH-sensitive supramolecular polymeric prodrug could be facilely prepared from PAD-CD and AD-DOX through the strong host-guest interaction. Then supramolecular polymeric prodrug was in situ crosslinked by carboxymethyl chitosan, resulting in an injectable DOX-loaded hydrogel based on the Schiff’s base reaction. On the other hand, cyclodextrin dendritic polymer was synthesized through the Michael addition reaction between the aminated β-cyclodextrin and polyethylene glycol diacrylate (PEGDA). The other pH-sensitive supramolecular polymeric prodrug could be facilely prepared from cyclodextrin dendritic polymer and adamantane-modified doxorubicin (AD-DOX) through the strong host-guest interaction. Finally, the polyethylene glycol polymer with multiple thiol groups was synthesized by one-pot polycondensation and used to crosslink the supramolecular polymeric prodrug, resulting in an injectable DOX-loaded hydrogel based on the thiol-ene "click" reaction.These acid-responsive injectable hydrogels could achieve the sustained drug release at the tumor sites. Moreover, the excellent biocompatibility and biodegradability make these drug-loaded hydrogels promising candidates as drug carriers for intratumor drug delivery in clinical applications.