A degradable brush polymer-drug conjugate for pH-responsive release of doxorubicin

To achieve high precision and efficacy in disease treatment, biodegradability and environmental responsivity are highly desired in drug delivery systems. Having a polylactide (PLA)-based biodegradable scaffold conjugated with doxorubicin (DOX) moieties via pH-responsive linkages, a brush polymer–drug conjugate (BPDC) was synthesized and studied. The biodegradable scaffold, PLA-graft-aldehyde/polyethylene glycol (PLA-g-ALD/PEG), was prepared via a copper-catalyzed alkyne–azide click reaction. Subsequently, the BPDC was obtained by conjugating doxorubicin with the scaffold through an acid-sensitive Schiff base linkage. The well-controlled structures of the resulting BPDC and its precursors were verified by proton nuclear magnetic resonance and gel permeation chromatography characterization. As revealed by dynamic light scattering and transmission electron microscopy, the BPDC had a well-defined nanostructure with the size of 10–30 nm. A drug release study of the BPDC demonstrated a much faster release of DOX at the pH of 5.5 than at the pH of 7.4. Both cell internalization and cytotoxicity studies of the BPDC in MCF-7 breast cancer cells indicated its significant potential for application as a novel anticancer nanomedicine.

[1]  Xiabin Jing,et al.  Biodegradable synthetic polymers: Preparation, functionalization and biomedical application , 2012 .

[2]  Jianjun Cheng,et al.  Facile functionalization of polyesters through thiol-yne chemistry for the design of degradable, cell-penetrating and gene delivery dual-functional agents. , 2012, Biomacromolecules.

[3]  C. Monneret,et al.  Doxorubicin conjugates for selective delivery to tumors. , 2008, Topics in current chemistry.

[4]  Chih-Kuang Chen,et al.  Well‐defined drug‐conjugated biodegradable nanoparticles by azide–alkyne click crosslinking in miniemulsion , 2012 .

[5]  D. Gewirtz,et al.  A critical evaluation of the mechanisms of action proposed for the antitumor effects of the anthracycline antibiotics adriamycin and daunorubicin. , 1999, Biochemical pharmacology.

[6]  Colin Bonduelle,et al.  Functionalized polyesters from organocatalyzed ROP of gluOCA, the O-carboxyanhydride derived from glutamic acid. , 2008, Chemical communications.

[7]  Ming Jiang,et al.  Synthesis of cationic polylactides with tunable charge densities as nanocarriers for effective gene delivery. , 2013, Molecular pharmaceutics.

[8]  Robert Langer,et al.  Engineering of self-assembled nanoparticle platform for precisely controlled combination drug therapy , 2010, Proceedings of the National Academy of Sciences.

[9]  Jianjun Cheng,et al.  Anticancer Polymeric Nanomedicines , 2007 .

[10]  H. Haisma,et al.  A novel doxorubicin-glucuronide prodrug DOX-GA3 for tumour-selective chemotherapy: distribution and efficacy in experimental human ovarian cancer , 2001, British Journal of Cancer.

[11]  Jeremiah A. Johnson,et al.  Synthesis of Acid-Labile PEG and PEG-Doxorubicin-Conjugate Nanoparticles via Brush-First ROMP , 2014, ACS macro letters.

[12]  Todd Emrick,et al.  PEG- and peptide-grafted aliphatic polyesters by click chemistry. , 2005, Journal of the American Chemical Society.

[13]  D. Bolikal,et al.  Highly water soluble taxol derivatives: 2′-polyethyleneglycol esters as potential prodrugs , 1994 .

[14]  T. Park,et al.  Biodegradable polymeric micelles composed of doxorubicin conjugated PLGA-PEG block copolymer. , 2001, Journal of controlled release : official journal of the Controlled Release Society.

[15]  Chong Cheng,et al.  pH-Sensitive brush polymer-drug conjugates by ring-opening metathesis copolymerization. , 2011, Chemical communications.

[16]  Joseph M. DeSimone,et al.  Strategies in the design of nanoparticles for therapeutic applications , 2010, Nature Reviews Drug Discovery.

[17]  Nicolas Bertrand,et al.  The journey of a drug-carrier in the body: an anatomo-physiological perspective. , 2012, Journal of controlled release : official journal of the Controlled Release Society.

[18]  G. Pasut,et al.  Polymer-drug conjugation, recent achievements and general strategies , 2007 .

[19]  Honggang Cui,et al.  Supramolecular nanostructures formed by anticancer drug assembly. , 2013, Journal of the American Chemical Society.

[20]  Huub Schellekens,et al.  The Immunogenicity of Polyethylene Glycol: Facts and Fiction , 2013, Pharmaceutical Research.

[21]  Wim E. Hennink,et al.  Synthesis and characterization of allyl functionalized poly(α-hydroxy)acids and their further dihydroxylation and epoxidation , 2008 .

[22]  A. Lowman,et al.  Biodegradable nanoparticles for drug delivery and targeting , 2002 .

[23]  Yan Xia,et al.  Drug-loaded, bivalent-bottle-brush polymers by graft-through ROMP. , 2010, Macromolecules.

[24]  Marcus Weck,et al.  Functional lactide monomers: methodology and polymerization. , 2006, Biomacromolecules.

[25]  Hua Ai,et al.  Micellar carriers based on block copolymers of poly(ε-caprolactone) and poly(ethylene glycol) for doxorubicin delivery , 2004 .

[26]  Mary Edson,et al.  Adriamycin(hydrazone)-antibody conjugates require internalization and intracellular acid hydrolysis for antitumor activity , 2005, Cancer Immunology, Immunotherapy.

[27]  D. Richardson,et al.  Molecular Pharmacology of the Interaction of Anthracyclines with Iron , 2005, Molecular Pharmacology.

[28]  Paula T. Hammond,et al.  A Convergent Synthetic Platform for Single-Nanoparticle Combination Cancer Therapy: Ratiometric Loading and Controlled Release of Cisplatin, Doxorubicin, and Camptothecin , 2014, Journal of the American Chemical Society.

[29]  Wing-Cheung Law,et al.  Functional Polylactide-g-Paclitaxel―Poly(ethylene glycol) by Azide―Alkyne Click Chemistry , 2011 .

[30]  Andrew P. Dove,et al.  Synthesis and Functionalization of Thiol-Reactive Biodegradable Polymers , 2012 .

[31]  Michel Vert,et al.  Synthesis and Characterization of Novel Degradable Polyesters Derived from d-Gluconic and Glycolic Acids , 1999 .

[32]  Chih-Kuang Chen,et al.  Polylactide-graft-doxorubicin nanoparticles with precisely controlled drug loading for pH-triggered drug delivery. , 2014, Biomacromolecules.

[33]  R B Greenwald,et al.  PEG drugs: an overview. , 2001, Journal of controlled release : official journal of the Controlled Release Society.

[34]  Elizabeth M Topp,et al.  Release from polymeric prodrugs: linkages and their degradation. , 2004, Journal of pharmaceutical sciences.

[35]  Todd Emrick,et al.  Soluble camptothecin derivatives prepared by click cycloaddition chemistry on functional aliphatic polyesters. , 2007, Bioconjugate chemistry.

[36]  K. Ulbrich,et al.  N-(2-Hydroxypropyl)methacrylamide-based polymer conjugates with pH-controlled activation of doxorubicin for cell-specific or passive tumour targeting. Synthesis by RAFT polymerisation and physicochemical characterisation. , 2010, European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences.

[37]  David A Tirrell,et al.  Core-clickable PEG-branch-azide bivalent-bottle-brush polymers by ROMP: grafting-through and clicking-to. , 2011, Journal of the American Chemical Society.

[38]  Z. Lu,et al.  HPMA copolymer-anticancer drug conjugates: design, activity, and mechanism of action. , 2000, European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V.

[39]  Chih-Kuang Chen,et al.  Well-defined degradable brush polymer-drug conjugates for sustained delivery of Paclitaxel. , 2013, Molecular pharmaceutics.

[40]  Hui Liang,et al.  Degradable and biocompatible aldehyde-functionalized glycopolymer conjugated with doxorubicinvia acid-labile Schiff base linkage for pH-triggered drug release , 2011 .

[41]  C. Laurencin,et al.  Biodegradable polymers as biomaterials , 2007 .

[42]  U. Schubert,et al.  Poly(ethylene glycol) in drug delivery: pros and cons as well as potential alternatives. , 2010, Angewandte Chemie.

[43]  K. Ulbrich,et al.  Polymeric anticancer drugs with pH-controlled activation. , 2004, Advanced drug delivery reviews.

[44]  O. Pillai,et al.  Polymers in drug delivery. , 2001, Current opinion in chemical biology.

[45]  David J. Fox,et al.  Ring-opening polymerization of an O-carboxyanhydride monomer derived from L-malic acid , 2011 .

[46]  H. Maeda,et al.  A new concept for macromolecular therapeutics in cancer chemotherapy: mechanism of tumoritropic accumulation of proteins and the antitumor agent smancs. , 1986, Cancer research.

[47]  Chih-Kuang Chen,et al.  Clicking Well‐Defined Biodegradable Nanoparticles and Nanocapsules by UV‐Induced Thiol‐Ene Cross‐Linking in Transparent Miniemulsions , 2011, Advanced materials.

[48]  Christopher J. Cramer,et al.  High Tg aliphatic polyesters by the polymerization of spirolactide derivatives , 2010 .

[49]  Xiabin Jing,et al.  Synthesis and characterization of the paclitaxel/MPEG-PLA block copolymer conjugate. , 2005, Biomaterials.

[50]  Amolkumar Karwa,et al.  Poly(ethylene oxide)-block-polyphosphester-based Paclitaxel Conjugates as a Platform for Ultra-high Paclitaxel-loaded Multifunctional Nanoparticles. , 2013, Chemical science.

[51]  Jean Coudane,et al.  Synthesis and ring-opening polymerisation of a new alkyne-functionalised glycolide towards biocompatible amphiphilic graft copolymers , 2013 .

[52]  Afsaneh Lavasanifar,et al.  Amphiphilic block copolymers for drug delivery. , 2003, Journal of pharmaceutical sciences.

[53]  N R Hunter,et al.  Synthesis and evaluation of water-soluble polyethylene glycol-paclitaxel conjugate as a paclitaxel prodrug , 1996, Anti-cancer drugs.

[54]  Renjie Chen,et al.  A polymer–drug conjugate for doxorubicin: Synthesis and biological evaluation of pluronic F127‐doxorubicin amide conjugates , 2011 .

[55]  Chih-Kuang Chen,et al.  Biodegradable cationic polymeric nanocapsules for overcoming multidrug resistance and enabling drug-gene co-delivery to cancer cells. , 2014, Nanoscale.

[56]  Xiabin Jing,et al.  Biodegradable block copolymer-doxorubicin conjugates via different linkages: preparation, characterization, and in vitro evaluation. , 2010, Biomacromolecules.

[57]  Gregory L. Baker,et al.  “Clickable” Polyglycolides: Tunable Synthons for Thermoresponsive, Degradable Polymers , 2008 .

[58]  Chong Cheng,et al.  Synthesis and biomedical applications of functional poly(α-hydroxyl acid)s , 2014 .

[59]  Robert Langer,et al.  Impact of nanotechnology on drug delivery. , 2009, ACS nano.

[60]  Jianjun Cheng,et al.  Polymeric Nanomedicines Based on Poly(lactide) and Poly(lactide-co-glycolide). , 2012, Current opinion in solid state & materials science.

[61]  S. Siegel,et al.  Effect of adriamycin on DNA, RNA, and protein synthesis in cell-free systems and intact cells. , 1976, Cancer research.

[62]  Ruth Duncan,et al.  Development of HPMA copolymer-anticancer conjugates: clinical experience and lessons learnt. , 2009, Advanced drug delivery reviews.

[63]  Ruth Duncan,et al.  Polymer conjugates as anticancer nanomedicines , 2006, Nature Reviews Cancer.

[64]  Molly S. Shoichet,et al.  Polymer Scaffolds for Biomaterials Applications , 2010 .

[65]  K. Ulbrich,et al.  HPMA copolymer conjugates of paclitaxel and docetaxel with pH-controlled drug release. , 2010, Molecular pharmaceutics.

[66]  Richard B Greenwald,et al.  Effective drug delivery by PEGylated drug conjugates. , 2003, Advanced drug delivery reviews.

[67]  R B Greenwald,et al.  Drug delivery systems: water soluble taxol 2'-poly(ethylene glycol) ester prodrugs-design and in vivo effectiveness. , 1996, Journal of medicinal chemistry.