Simple Synthesis of Cladribine-Based Anticancer Polymer Prodrug Nanoparticles with Tunable Drug Delivery Properties

Abstract

Polymer prodrugs based on cladribine (CdA) as an anticancer drug have been prepared by growing short, well-defined polyisoprene (PI) chains (with number-average molar mass = 1420–4980 g mol–1 and dispersity = 1.09–1.20) from CdA-bearing alkoxyamine by nitroxide-mediated polymerization. Nanoparticles were formed by nanoprecipitation into water of the resulting CdA-PI conjugates and exhibited long-term colloidal stability in different media, tunable colloidal characteristics, drug release profiles, and anticancer activities in vitro, simply by modulating the drug/polymer linker, the polymer chain length and the formulation parameters. No obvious in vivo toxicity to mice was observed following repeated intravenous injections.

Drug-Initiated Synthesis of Heterotelechelic Polymer Prodrug Nanoparticles for in Vivo Imaging and Cancer Cell Targeting

“…Such variations may be explained by the increase of the HLB when Gem-PI-Biot is used (Table S1) and strongly negative zeta potentials, suggesting high colloidal stabilization, as already seen for PIbased prodrug nanoparticles. 17,21,23 N0 and N90 nanoparticles, that exhibit extreme amounts of Gem-PI-Biot, were also characterized by cryo-TEM and displayed spherical morphologies and sizes in agreement with those determined by DLS (Figure 2a and 2b). All nanoparticles were stable with no formation of visible precipitate over time.…”

“…The "druginitiated method" has been performed by reversible-deactivation radical polymerization (RDRP), especially reversible addition-fragmentation chain transfer (RAFT) polymerization 15 and nitroxidemediated polymerization (NMP), 16 leading to well-defined polymer prodrugs from different drug/polymer pairs. [17][18][19][20][21][22][23][24][25] The resulting polymer prodrug nanoparticles exhibited high DL, high colloidal stability without any additional surfactant, significant in vitro cytotoxicity against various cancer cell lines and ability to drastically reduce tumor growth in vivo.…”

Self-stabilized, hydrophobic or PEGylated paclitaxel polymer prodrug nanoparticles for cancer therapy

“…AMA-SG1 and CDP were previously reacted with diglycolic anhydride, giving digly-AMA-SG1 and digly-CDP (Figure 1), to position a diglycolate linker in between the drug and the RDRP moiety to promote drug release. 36 When compared to a single ester bond, the diglycolate group has indeed been shown to endow the drug-polymer conjugates with greater drug release kinetics, resulting in an enhanced therapeutic effect. The resulting Ptx-digly-AMA-SG1 and Ptx-digly-CDP ( Figure 1) were obtained with 82% and 43% coupling yields, respectively (see experimental part, Figures S1 and S2).…”

“…The robustness of the drug-initiated method has been illustrated by its application to a variety of different polymer prodrugs constructed by either ring-opening polymerization (ROP) [29][30][31][32] or reversible-deactivation radical polymerization (RDRP), including nitroxide-mediated radical polymerization (NMP) or reversible addition-fragmentation chain transfer (RAFT) polymerization. [33][34][35][36][37][38][39][40] Promising in vitro and in vivo results in the field of cancer therapy have been reported over the past few years. However, two major concerns currently restricting the wide applicability of this approach still remain:…”

Redox-responsive core cross-linked prodrug micelles prepared by click chemistry for pH-triggered doxorubicin delivery

“…In aqueous media, amphiphilic block copolymers can self-assemble into micelles which consist of hydrophilic corona and hydrophobic core. Drugs can be loaded into these micelles which not only avoid the metabolization and rapid clearance from the body but also reduce toxicity of drug towards healthy tissues [5][6][7][8]. The drug of interest is either dissolved, entrapped, attached or encapsulated into the polymeric micelles depending on the method of preparation [9][10][11].…”