Thiol–yne and Thiol–ene “Click” Chemistry as a Tool for a Variety of Platinum Drug Delivery Carriers, from Statistical Copolymers to Crosslinked Micelles

Abstract

Statistical and block copolymers based on poly-(2-hydroxyethyl methacrylate) (PHEMA) and poly [oligo-(ethylene glycol) methylether methacrylate] (POEGMEMA) were modified with 4-pentenoic anhydride or 4-oxo-4-(prop-2ynyloxy)butanoic anhydride to generate polymers with pendant vinyl or acetylene, respectively. Subsequent thiolÀene or thiolÀyne reaction with thioglycolic acid or 2-mercaptosuccinic acid leads to polymers with carboxylate functionalities, which were conjugated with cisplatin (cis-diamminedichloroplatinum-(II) (CDDP)) to generate a drug carrier for Pt-drugs. Only the polymers modified with 2-mercaptosuccinic acid resulted in the formation of soluble well-defined polymers with gel formation being prevented. Due to the hydrophobicity of the drug, the block copolymers took on amphiphilic character leading to micelle formation. The micelles were in addition crosslinked to further stabilize their structure. Pt-containing statistical copolymer, micelles, and crosslinked micelles were then tested regarding their cellular uptake by the A549 lung cancer cell line to show a superior uptake of crosslinked micelles. However, due to the better Pt release of the statistical copolymer, the highest cytotoxicity was observed with this type of polymer architecture.

Cisplatin-Induced Formation of Biocompatible and Biodegradable Polypeptide-Based Vesicles for Targeted Anticancer Drug Delivery

“…7,76 The release of cisplatin is initiated in the presence of chloride ions, which results in a ligand exchange from the metal-polymer back to its original metal-chloride complex ( Figure 6A). 7,15 To CDDP release data in Figure 6B shows that in pH 7.4 PBS a slow and sustained release profile is observed with no burst release of drug.…”

“…7,76 The release of cisplatin is initiated in the presence of chloride ions, which results in a ligand exchange from the metal-polymer back to its original metal-chloride complex ( Figure 6A). 7,15 To CDDP release data in Figure 6B shows that in pH 7.4 PBS a slow and sustained release profile is observed with no burst release of drug. This controlled release of CDDP from the vesicles in pH 7.4 PBS is considerably slower than other cisplatin drug delivery systems in the literature 16,47,76 and presents an opportunity for alleviating the systemic drug release/acute toxicity issues that have hampered the use of high cisplatin dosages in cancer therapy.…”

“…3,4 Its incorporation into polymer nanoparticles has been studied for many years as a means to improve its poor water solubility, alleviate the systemic cytotoxicity associated with the free drug and improve drug loading at the tumour site. 5 Nanoscale assemblies for CDDP delivery has for many years largely involved matrix (micelle) systems, demonstrating effective delivery profiles and reduced CDDP associated toxicity, [6][7][8] with a focus on the use of biodegradable and biocompatible polymer systems in recent times. [9][10][11][12][13][14] Most notable has been the widespread use of self-assembling poly(ethylene glycol)-b-poly( Lglutamic acid) (PEG-b-PLG) block copolymers into micellar delivery systems upon conjugation with platinum drugs.…”

Functionalization of polyurethanes by incorporation of alkyne side-groups to oligodiols and subsequent thiol–yne post-modification

“…The absence of a monothiol adduct and thus the absence of double bonds in the final products after the coupling reaction is in accordance with earlier observations on thiol-yne reactions. [17][18][19][20][21] It was found earlier that the addition of the first thiol to the alkyne is the rate-limiting step, which is followed by the fast second thiol addition to the intermediate thiol-alkene. 15,16 The conditions and corresponding degree of functionalization by thiol-yne reactions are summarized in Table 4.…”

“…Therefore, highly efficient reactive systems that do not contain any metal catalyst are often desired. In this respect, light-mediated thiol-ene 13,14 and thiol-yne [15][16][17][18][19][20][21] radical reactions have become widely used as they effectively combine some classical benefits of coupling reactions with the advantages of a photoinitiated process resulting in a powerful method for chemical synthesis and tailorable material fabrication.…”