Molecular Engineering and science Institute

Seattle, WA, United States

Molecular Engineering and science Institute

Seattle, WA, United States
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Lane D.D.,Molecular Engineering and science Institute | Chiu D.Y.,Molecular Engineering and science Institute | Su F.Y.,Molecular Engineering and science Institute | Srinivasan S.,Molecular Engineering and science Institute | And 4 more authors.
Polymer Chemistry | Year: 2015

Aqueous reversible addition-fragmentation chain transfer (RAFT) polymerization was employed to prepare a series of linear copolymers of N,N-dimethylacrylamide (DMA) and 2-hydroxyethylacrylamide (HEAm) with narrow values over a molecular weight range spanning three orders of magnitude (103 to 106 Da). Trithiocarbonate-based RAFT chain transfer agents (CTAs) were grafted onto these scaffolds using carbodiimide chemistry catalyzed with DMAP. The resultant graft chain transfer agent (gCTA) was subsequently employed to synthesize polymeric brushes with a number of important vinyl monomer classes including acrylamido, methacrylamido, and methacrylate. Brush polymerization kinetics were evaluated for the aqueous RAFT polymerization of DMA from a 10 arm gCTA. Polymeric brushes containing hydroxyl functionality were further functionalized in order to prepare 2nd generation gCTAs which were subsequently employed to prepare polymers with a brushed-brush architecture with molecular weights in excess of 106 Da. The resultant single particle nanoparticles (SNPs) were employed as drug delivery vehicles for the anthracycline-based drug doxorubicin via copolymerization of DMA with a protected carbazate monomer (bocSMA). Cell-specific targeting functionality was also introduced via copolymerization with a biotin-functional monomer (bioHEMA). Drug release of the hydrazone linked doxorubicin was evaluated as function of pH and serum and chemotherapeutic activity was evaluated in SKOV3 ovarian cancer cells. This journal is © The Royal Society of Chemistry.


Son H.N.,Molecular Engineering and science Institute | Srinivasan S.,Molecular Engineering and science Institute | Yhee J.Y.,University of Seoul | Das D.,Molecular Engineering and science Institute | And 9 more authors.
Polymer Chemistry | Year: 2016

Reversible addition-fragmentation chain transfer (RAFT) polymerization was employed to prepare prodrug polymer carrier systems with the chemotherapeutic agent camptothecin (Cam) and the kinase inhibitor dasatinib (Dt). Copolymers were prepared as dense polyethylene glycol brushes via direct copolymerization of the prodrug macromonomers with polyethylene glycol methacrylate (O950, FW ∼ 950 daltons). The brushes display controlled drug release profiles with little burst or late-phase release aberrations. Hydrolysis studies of the hydrophilic copolymers conducted in human serum showed 33 ± 1.7 and 22 ± 2.4% drug release over the course of 144 h for the ester linked Dt and Cam respectively. Polymer morphology was also shown to play a key role in drug release rates. Copolymers with the drug distributed in the copolymer segment showed faster release rates than diblock copolymers where the hydrophobic drug molecules were localized in discreet hydrophobic blocks. The latter materials were shown to self-assemble into polymeric micelles with the drug block separated from the aqueous phase. Live animal imaging in PC-3 (human prostate cancer cell line) tumor xenographs showed that the fluorescently labeled copolymer brushes were trafficked to the tumor 24 hours post injection. Ex vivo analysis of the harvested tissues showed that polymer accumulated in the tumor with kidney excretion. In vitro cytotoxicity measurements conducted in K562-S and K562-R cells demonstrated ability of the macromolecular conjugates to release active drugs. The direct copolymerization of different drug classes into controlled copolymers via RAFT, together with their favorable release profiles, suggest these carriers merit further study as therapeutic systems. This journal is © The Royal Society of Chemistry 2016.


Das D.,Molecular Engineering and science Institute | Gerboth D.,Molecular Engineering and science Institute | Postma A.,CSIRO | Srinivasan S.,Molecular Engineering and science Institute | And 5 more authors.
Polymer Chemistry | Year: 2016

Polymerization induced self-assembly (PISA) in acetic acid was employed to polymerize the hydrophilic sulfobetaine monomer 2-(N-3-sulfopropyl-N,N-dimethyl ammonium)ethyl methacrylate (DMAPS) and the hydrophobic monomer lauryl methacrylate (LMA). Polymerizations were conducted from a macro chain transfer agent (macro-CTA) consisting of 66% 2-hydroxyethyl methacrylate (HEMA) and 33% poly(ethylene glycol) methyl ether methacrylate FW ∼ 300 Da (O300). A degree of polymerization (DP) of 50 was targeted for the macro-CTA in order to yield diblock copolymers with significantly larger 2nd blocks. From the poly(HEMA-co-O300) macro-CTA, diblock copolymers of poly[(HEMA-co-O300)-b-(DMAPS)] and poly[(HEMA-co-O300)-b-(LMA)] were grown via PISA in acetic acid. In order to maintain colloidal stability, it was necessary to conduct PISA of DMAPS at 10 wt% monomer, while LMA polymerizations maintained stability at 20 wt% monomer. Mnvs. conversion plots for both DMAPS and LMA show linear increases in molecular weight over the course of the polymerizations. Analysis of the molecular weight distributions revealed a progressive narrowing throughout the polymerization from an initial bimodal state. Copolymers of DMAPS and LMA were also synthesized over a large range of comonomer feed ratios. These materials show composition-dependent sizes in buffered solutions between 11 nm for the copolymer containing 80% by mol DMAPS to 75 nm for the copolymer containing 40 mol% DMAPS. PISA in acetic acid was then used to prepare copolymers of DMAPS with a range of hydrophobic polymerizable prodrug monomers as well as a polymerizable peptide macromonomer. The resultant copolymers had narrow molecular weight distributions and were readily soluble in saline solutions. © The Royal Society of Chemistry 2016.


Roy D.,Molecular Engineering and science Institute | Berguig G.Y.,Molecular Engineering and science Institute | Ghosn B.,Molecular Engineering and science Institute | Lane D.D.,Molecular Engineering and science Institute | And 3 more authors.
Polymer Chemistry | Year: 2014

Reversible addition-fragmentation chain transfer (RAFT) polymerization was employed to prepare a nanoparticulate drug delivery system for chemotherapeutics. The nanoparticles contain a PEG "stealth" corona as well as a reactive anhydride functionality designed for conjugating targeting proteins. The multifunctional carrier functionality was achieved by controlling the copolymerization of the hydrophobic monomer lauryl methacrylate (LMA), with a reactive anhydride functional methacrylate (TMA), and a large polyethylene glycol methacrylate monomer (Mn ∼ 950 Da) (O950). RAFT polymerization kinetics of O950 were evaluated as a function of target degrees of polymerization (DPs), initial chain transfer agent to initiator ratio ([CTA]o/[I]o), and solvent concentration. Excellent control over the polymerization was observed for target DPs of 25 and 50 at a [CTA]o/[I]o ratio of 10 as evidenced by narrow and symmetric molecular weight distributions and the ability to prepare block copolymers. The TMA-functional copolymers were conjugated to the tumor targeting protein transferrin (Tf). The targeted copolymer was shown to encapsulate docetaxel at concentrations comparable to the commercial single vial formulation of docetaxel (Taxotere). In vitro cytotoxicity studies conducted in HeLa cells show that the Tf targeting enhances the cancer killing properties relative to the polymer encapsulated docetaxel formulation. © 2014 The Royal Society of Chemistry.


Lane D.D.,Molecular Engineering and science Institute | Su F.Y.,Molecular Engineering and science Institute | Chiu D.Y.,Molecular Engineering and science Institute | Srinivasan S.,Molecular Engineering and science Institute | And 4 more authors.
Polymer Chemistry | Year: 2015

Reversible addition-fragmentation chain transfer (RAFT) polymerization was employed to prepare a series of copolymers consisting of 2-hydroxyethyl methacrylate (HEMA) and poly(ethylene glycol) methyl ether methacrylate (FWavg ∼ 950 Da) (O950) with variable comonomer compositions and molecular weights for use as polymeric scaffolds. Reactivity ratios for the monomer pair were determined to be 1.37 and 0.290 respectively. To these scaffolds trithiocarbonate-based RAFT chain transfer agents (CTAs) were grafted using carbodiimide chemistry. The resultant graft chain transfer agents (gCTA) were subsequently employed to polymerize dimethylaminoethyl methacrylate (DMAEMA) and (HPMA) between degrees of polymerization (DP) of 25 and 200. Kinetic analysis for the polymerization of DMAEMA targeting a DP of 100 from a 34 arm graft gCTA show linear Mn conversion and pseudo first order rate plots with narrow molecular weight distributions that move toward lower elution volumes with monomer conversion. Values for these polymerizations remain low at around 1.20 at monomer conversions as high as 70%. pH-responsive endosomalytic brushes capable of spontaneously self-assembling into polymersomes were synthesized and a combination of dynamic light scattering (DLS), cryoTEM, and red blood cell hemolysis were employed to evaluate the aqueous solution properties of the polymeric brush as a function of pH. Successful encapsulation of ceftazidime and pH-dependent drug release properties were confirmed by HPLC. Intracellular antibiotic activity of the drug-loaded polymersomes was confirmed in a macrophage coculture model of infection with B. thailandensis and RAW 264.7 cells. This journal is © The Royal Society of Chemistry.


PubMed | Molecular Engineering and science Institute
Type: Journal Article | Journal: Polymer chemistry | Year: 2015

Aqueous reversible addition-fragmentation chain transfer (RAFT) polymerization was employed to prepare a series of linear copolymers of N,N-dimethylacrylamide (DMA) and 2-hydroxyethylacrylamide (HEAm) with narrow values over a molecular weight range spanning three orders of magnitude (10

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