title: Degradable ketal-based block copolymer nanoparticles for anticancer drug delivery: a systematic evaluation.
abstract: Low solubility of potent (anticancer) drugs is a major driving force for the development of noncytotoxic, stimuli-responsive nanocarriers, including systems based on amphiphilic block copolymers. In this regard, we investigated the potential of block copolymers based on 2-hydroxyethyl acrylate (HEA) and the acid-sensitive ketal-containing monomer (2,2-dimethyl-1,3-dioxolane-4-yl)methyl acrylate (DMDMA) to form responsive drug nanocarriers. Block copolymers were successfully synthesized by sequential reversible addition-fragmentation chain transfer (RAFT) polymerization, in which we combined a hydrophilic poly(HEA)x block with a (responsive) hydrophobic poly(HEAm-co-DMDMAn)y copolymer block. The DMDMA content of the hydrophobic block was systematically varied to investigate the influence of polymer design on physicochemical properties and in vitro biological performance. We found that a DMDMA content higher than 11 mol % is required for self-assembly behavior in aqueous medium. All particles showed colloidal stability in PBS at 37 °C for at least 4 days, with sizes ranging from 23 to 338 nm, proportional to the block copolymer DMDMA content. Under acidic conditions, the nanoparticles decomposed into soluble unimers, of which the decomposition rate was inversely proportional to the block copolymer DMDMA content. Flow cytometry and confocal microscopy showed dose-dependent, active in vitro cellular uptake of the particles loaded with hydrophobic octadecyl rhodamine B chloride (R18). The block copolymers showed no intrinsic in vitro cytotoxicity, while loaded with paclitaxel (PTX), a significant decrease in cell viability was observed comparable or better than the two commercial PTX nanoformulations Abraxane and Genexol-PM at equal PTX dose. This systematic approach evaluated and showed the potential of these block copolymers as nanocarriers for hydrophobic drugs.
authors.affiliation: Department of Pharmaceutics, Ghent University , Ottergemsesteenweg 460, 9000 Ghent, Belgium.
authors.forename: Benoit
authors.initials: B
authors.lastname: Louage
authors.forename: Qilu
authors.initials: Q
authors.lastname: Zhang
authors.forename: Nane
authors.initials: N
authors.lastname: Vanparijs
authors.forename: Lenny
authors.initials: L
authors.lastname: Voorhaar
authors.forename: Sofie
authors.initials: S
authors.lastname: Vande Casteele
authors.forename: Yang
authors.initials: Y
authors.lastname: Shi
authors.forename: Wim E
authors.initials: WE
authors.lastname: Hennink
authors.forename: Jan
authors.initials: J
authors.lastname: Van Bocxlaer
authors.forename: Richard
authors.initials: R
authors.lastname: Hoogenboom
authors.forename: Bruno G
authors.initials: BG
authors.lastname: De Geest
mesh_terms: D000179:Acrylates / Q000737:chemistry*; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D001673:Biodegradation, Environmental; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D016503:Drug Delivery Systems; D005260:Female; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D058726:Nanoconjugates / Q000008:administration & dosage / Q000737:chemistry*; D017239:Paclitaxel / Q000008:administration & dosage*
chemical_list: D000179:Acrylates; D000970:Antineoplastic Agents; D058726:Nanoconjugates; C035957:2-hydroxyethyl acrylate; D017239:Paclitaxel