Micelles Based on Acid Degradable Poly(acetal urethane): Preparation, pH-Sensitivity, and Triggered Intracellular Drug Release.

Polyurethanes are a unique class of biomaterials that are widely used in medical devices. In spite of their easy synthesis and excellent biocompatibility, polyurethanes are less explored for controlled drug delivery due to their slow or lack of degradation. In this paper, we report the design and development of novel acid degradable poly(acetal urethane) (PAU) and corresponding triblock copolymer micelles for pH-triggered intracellular delivery of a model lipophilic anticancer drug, doxorubicin (DOX). PAU with Mn ranging from 4.3 to 12.3 kg/mol was conveniently prepared from polycondensation reaction of lysine diisocyanate (LDI) and a novel diacetal-containing diol, terephthalilidene-bis(trimethylolethane) (TPABTME) using dibutyltin dilaurate (DBTDL) as a catalyst in N,N-dimethylformamide (DMF). The thiol-ene click reaction of Allyl-PAU-Allyl with thiolated PEG (Mn = 5.0 kg/mol) afforded PEG-PAU-PEG triblock copolymers that readily formed micelles with average sizes of about 90-120 nm in water. The dynamic light scattering (DLS) measurements revealed fast swelling and disruption of micelles under acidic pH. UV/vis spectroscopy corroborated that acetal degradation was accelerated at pH 4.0 and 5.0. The in vitro release studies showed that doxorubicin (DOX) was released in a controlled and pH-dependent manner, in which ca. 96%, 73%, and 30% of drug was released within 48 h at pH 4.0, 5.0, and 7.4, respectively. Notably, MTT assays displayed that DOX-loaded PEG-PAU-PEG micelles had a high in vitro antitumor activity in both RAW 264.7 and drug-resistant MCF-7/ADR cells. The confocal microscopy and flow cytometry experiments demonstrated that PEG-PAU-PEG micelles mediated efficient cytoplasmic delivery of DOX. Importantly, blank PEG-PAU-PEG micelles were shown to be nontoxic to RAW 264.7 and MCF-7/ADR cells even at a high concentration of 1.5 mg/mL. Hence, micelles based on poly(acetal urethane) have appeared as a new class of biocompatible and acid-degradable nanocarriers for efficient intracellular drug delivery.

[1]  Hae-Won Kim,et al.  Naturally and synthetic smart composite biomaterials for tissue regeneration. , 2013, Advanced drug delivery reviews.

[2]  H. Deng,et al.  Molecular Engineered Super‐Nanodevices: Smart and Safe Delivery of Potent Drugs into Tumors , 2012, Advanced materials.

[3]  Qizhi Chen,et al.  Elastomeric biomaterials for tissue engineering , 2013 .

[4]  X. Jing,et al.  Synthesis of OH-group-containing, biodegradable polyurethane and protein fixation on its surface. , 2011, Biomacromolecules.

[5]  Kyle E Broaders,et al.  Acetal-derivatized dextran: an acid-responsive biodegradable material for therapeutic applications. , 2008, Journal of the American Chemical Society.

[6]  F. Meng,et al.  Biodegradable micelles with sheddable poly(ethylene glycol) shells for triggered intracellular release of doxorubicin. , 2009, Biomaterials.

[7]  Cory E. Leeson,et al.  Biodegradable polyurethane ureas with variable polyester or polycarbonate soft segments: effects of crystallinity, molecular weight, and composition on mechanical properties. , 2011, Biomacromolecules.

[8]  Zhiyuan Zhong,et al.  pH-Sensitive degradable polymersomes for triggered release of anticancer drugs: a comparative study with micelles. , 2010, Journal of controlled release : official journal of the Controlled Release Society.

[9]  C. Duvall,et al.  A porous tissue engineering scaffold selectively degraded by cell-generated reactive oxygen species. , 2014, Biomaterials.

[10]  N. Nishiyama,et al.  Systemic siRNA delivery to a spontaneous pancreatic tumor model in transgenic mice by PEGylated calcium phosphate hybrid micelles. , 2014, Journal of controlled release : official journal of the Controlled Release Society.

[11]  J. Feijen,et al.  Redox and pH-responsive degradable micelles for dually activated intracellular anticancer drug release. , 2013, Journal of controlled release : official journal of the Controlled Release Society.

[12]  Chun Wang,et al.  Block copolymer micelles with acid-labile ortho ester side-chains: Synthesis, characterization, and enhanced drug delivery to human glioma cells. , 2011, Journal of controlled release : official journal of the Controlled Release Society.

[13]  S. Paul,et al.  Pro-angiogenic character of endothelial cells and gingival fibroblasts cocultures in perfused degradable polyurethane scaffolds. , 2015 .

[14]  Jiehua Li,et al.  Self-assembly of biodegradable polyurethanes for controlled delivery applications , 2012 .

[15]  N. Murthy,et al.  A novel strategy for encapsulation and release of proteins: hydrogels and microgels with acid-labile acetal cross-linkers. , 2002, Journal of the American Chemical Society.

[16]  Xuesi Chen,et al.  Self-assemblies of pH-activatable PEGylated multiarm poly(lactic acid-co-glycolic acid)-doxorubicin prodrugs with improved long-term antitumor efficacies. , 2013, Macromolecular bioscience.

[17]  Andrew P Goodwin,et al.  Acetals as pH-sensitive linkages for drug delivery. , 2004, Bioconjugate chemistry.

[18]  Jun Li,et al.  Biodegradable hyperbranched amphiphilic polyurethane multiblock copolymers consisting of poly(propylene glycol), poly(ethylene glycol), and polycaprolactone as in situ thermogels. , 2012, Biomacromolecules.

[19]  Chaoliang He,et al.  pH and reduction dual responsive polyurethane triblock copolymers for efficient intracellular drug delivery , 2013 .

[20]  R. Zhuo,et al.  Synthesis and in vitro drug release behavior of amphiphilic triblock copolymer nanoparticles based on poly (ethylene glycol) and polycaprolactone. , 2005, Biomaterials.

[21]  Z. Wang,et al.  Residue cytotoxicity of a hydrazone-linked polymer–drug conjugate: implication for acid-responsive micellar drug delivery , 2015 .

[22]  Michael Jay,et al.  Polymer Micelles with Hydrazone-Ester Dual Linkers for Tunable Release of Dexamethasone , 2011, Pharmaceutical Research.

[23]  Siling Wang,et al.  pH‐ and NIR Light‐Responsive Micelles with Hyperthermia‐Triggered Tumor Penetration and Cytoplasm Drug Release to Reverse Doxorubicin Resistance in Breast Cancer , 2015 .

[24]  Ling Che,et al.  Cyclodextrin-derived pH-responsive nanoparticles for delivery of paclitaxel. , 2013, Biomaterials.

[25]  Jiehua Li,et al.  Synthesis and Characterization of pH-Sensitive Biodegradable Polyurethane for Potential Drug Delivery Applications , 2011 .

[26]  Rupei Tang,et al.  Diblock copolymers of polyethylene glycol and a polymethacrylamide with side-chains containing twin ortho ester rings: synthesis, characterization, and evaluation as potential pH-responsive micelles. , 2015, Macromolecular bioscience.

[27]  Ru Cheng,et al.  Acetal-linked paclitaxel prodrug micellar nanoparticles as a versatile and potent platform for cancer therapy. , 2013, Biomacromolecules.

[28]  Jiehua Li,et al.  Construction of targeting-clickable and tumor-cleavable polyurethane nanomicelles for multifunctional intracellular drug delivery. , 2013, Biomacromolecules.

[29]  F. Meng,et al.  Core-crosslinked pH-sensitive degradable micelles: A promising approach to resolve the extracellular stability versus intracellular drug release dilemma. , 2012, Journal of controlled release : official journal of the Controlled Release Society.

[30]  Jessica L. Cohen,et al.  Conjugation chemistry through acetals toward a dextran-based delivery system for controlled release of siRNA. , 2012, Journal of the American Chemical Society.

[31]  H. Deng,et al.  Cellular uptake of polyurethane nanocarriers mediated by gemini quaternary ammonium. , 2011, Biomaterials.

[32]  J. Santerre,et al.  Biodegradation and in vivo biocompatibility of a degradable, polar/hydrophobic/ionic polyurethane for tissue engineering applications. , 2011, Biomaterials.

[33]  R. Haag,et al.  pH-responsive micro- and nanocarrier systems. , 2014, Angewandte Chemie.

[34]  Jiehua Li,et al.  Biodegradable multiblock polyurethane micelles with tunable reduction-sensitivity for on-demand intracellular drug delivery , 2014 .

[35]  Qiang Fu,et al.  Toward the next-generation nanomedicines: design of multifunctional multiblock polyurethanes for effective cancer treatment. , 2013, ACS nano.

[36]  Jianhua Zhang,et al.  Comb-like amphiphilic copolymers bearing acetal-functionalized backbones with the ability of acid-triggered hydrophobic-to-hydrophilic transition as effective nanocarriers for intracellular release of curcumin. , 2013, Biomacromolecules.

[37]  Shirui Mao,et al.  Smart pH-sensitive and temporal-controlled polymeric micelles for effective combination therapy of doxorubicin and disulfiram. , 2013, ACS nano.

[38]  M. Qiao,et al.  Enhanced effect of pH-sensitive mixed copolymer micelles for overcoming multidrug resistance of doxorubicin. , 2014, Biomaterials.

[39]  Meng Zheng,et al.  pH-sensitive degradable chimaeric polymersomes for the intracellular release of doxorubicin hydrochloride. , 2012, Biomaterials.

[40]  Joel A. Cohen,et al.  Acetalated dextran is a chemically and biologically tunable material for particulate immunotherapy , 2009, Proceedings of the National Academy of Sciences.

[41]  F. Prósper,et al.  Heart regeneration after myocardial infarction using synthetic biomaterials. , 2015, Journal of controlled release : official journal of the Controlled Release Society.

[42]  Jiehua Li,et al.  The degradation and biocompatibility of pH-sensitive biodegradable polyurethanes for intracellular multifunctional antitumor drug delivery. , 2012, Biomaterials.

[43]  M. Stenzel,et al.  Acid-degradable polymers for drug delivery: a decade of innovation. , 2013, Chemical communications.

[44]  Zhiyuan Zhong,et al.  pH-responsive biodegradable micelles based on acid-labile polycarbonate hydrophobe: synthesis and triggered drug release. , 2009, Biomacromolecules.