Basic concepts and recent advances in nanogels as carriers for medical applications

Abstract Nanogels in biomedical field are promising and innovative materials as dispersions of hydrogel nanoparticles based on crosslinked polymeric networks that have been called as next generation drug delivery systems due to their relatively high drug encapsulation capacity, uniformity, tunable size, ease of preparation, minimal toxicity, stability in the presence of serum, and stimuli responsiveness. Nanogels show a great potential in chemotherapy, diagnosis, organ targeting and delivery of bioactive substances. The main subjects reviewed in this article concentrates on: (i) Nanogel assimilation in the nanomedicine domain; (ii) Features and advantages of nanogels, the main characteristics, such as: swelling capacity, stimuli sensitivity, the great surface area, functionalization, bioconjugation and encapsulation of bioactive substances, which are taken into account in designing the structures according to the application; some data on the advantages and limitations of the preparation techniques; (iii) Recent progress in nanogels as a carrier of genetic material, protein and vaccine. The majority of the scientific literature presents the multivalency potential of bioconjugated nanogels in various conditions. Today’s research focuses over the overcoming of the restrictions imposed by cost, some medical requirements and technological issues, for nanogels’ commercial scale production and their integration as a new platform in biomedicine.

[1]  Su Seong Lee,et al.  Targeted intracellular protein delivery based on hyaluronic acid-green tea catechin nanogels. , 2016, Acta biomaterialia.

[2]  R. Mukthavaram,et al.  Targeted Nanogels: A Versatile Platform for Drug Delivery to Tumors , 2011, Molecular Cancer Therapeutics.

[3]  K. Landfester,et al.  Hydrogels in Miniemulsions , 2010 .

[4]  M. Calderón,et al.  Stimuli-responsive nanogel composites and their application in nanomedicine. , 2015, Chemical Society reviews.

[5]  Reuben T Chacko,et al.  Synthesis of Nanogel-Protein Conjugates. , 2013, Polymer chemistry.

[6]  Ming Yang,et al.  Well-defined reducible cationic nanogels based on functionalized low-molecular-weight PGMA for effective pDNA and siRNA delivery. , 2016, Acta biomaterialia.

[7]  K. Mills,et al.  Modulation of T Cell and Innate Immune Responses by Retinoic Acid , 2014, The Journal of Immunology.

[8]  K. Akiyoshi,et al.  Nanogel engineering for new nanobiomaterials: from chaperoning engineering to biomedical applications. , 2010, Chemical record.

[9]  Gaurav Kumar Jain,et al.  A review on the strategies for oral delivery of proteins and peptides and their clinical perspectives , 2014, Saudi pharmaceutical journal : SPJ : the official publication of the Saudi Pharmaceutical Society.

[10]  K. Kono,et al.  Cytoplasmic delivery of calcein mediated by liposomes modified with a pH-sensitive poly(ethylene glycol) derivative. , 1997, Biochimica et biophysica acta.

[11]  Krzysztof Matyjaszewski,et al.  ATRP in the design of functional materials for biomedical applications. , 2012, Progress in polymer science.

[12]  A. Concheiro,et al.  Cyclodextrin-based nanogels for pharmaceutical and biomedical applications. , 2012, International journal of pharmaceutics.

[13]  Robert Langer,et al.  Formulation of functionalized PLGA-PEG nanoparticles for in vivo targeted drug delivery. , 2007, Biomaterials.

[14]  L. Pérez-Álvarez,et al.  pH-sensitive chitosan-folate nanogels crosslinked with biocompatible dicarboxylic acids , 2014 .

[15]  Nisha,et al.  Nanogel Based Artificial Chaperone Technology: an Overview , 2013 .

[16]  L. Lyon,et al.  Microgel translocation through pores under confinement. , 2010, Angewandte Chemie.

[17]  S. Khoee,et al.  Dual responsive nanogels for intracellular doxorubicin delivery. , 2016, International journal of pharmaceutics.

[18]  J. S. Park,et al.  Differentiation of endothelial progenitor cells into endothelial cells by heparin-modified supramolecular pluronic nanogels encapsulating bFGF and complexed with VEGF165 genes. , 2014, Biomaterials.

[19]  Enas M. Ahmed,et al.  Hydrogel: Preparation, characterization, and applications: A review , 2013, Journal of advanced research.

[20]  Shigeru Deguchi,et al.  Self-aggregates of hydrophobized polysaccharides in water. Formation and characteristics of nanoparticles , 1993 .

[21]  Probal Banerjee,et al.  In-situ immobilization of quantum dots in polysaccharide-based nanogels for integration of optical pH-sensing, tumor cell imaging, and drug delivery. , 2010, Biomaterials.

[22]  Qiang Zhao,et al.  An Enzyme-Responsive Nanogel Carrier Based on PAMAM Dendrimers for Drug Delivery. , 2016, ACS applied materials & interfaces.

[23]  J. Leroux,et al.  Steric stabilization of liposomes by pH-responsive N-isopropylacrylamide copolymer. , 2002, Journal of pharmaceutical sciences.

[24]  D. Liang,et al.  Multi-responsive nanogels containing motifs of ortho ester, oligo(ethylene glycol) and disulfide linkage as carriers of hydrophobic anti-cancer drugs. , 2011, Journal of controlled release : official journal of the Controlled Release Society.

[25]  Patrick Couvreur,et al.  Stimuli-responsive nanocarriers for drug delivery. , 2013, Nature materials.

[26]  Sílvia A. Ferreira,et al.  Potential of mannan or dextrin nanogels as vaccine carrier/adjuvant systems , 2016 .

[27]  Eugene Lih,et al.  Polymers for cell/tissue anti-adhesion , 2015 .

[28]  Arthur G Erdman,et al.  The big picture on nanomedicine: the state of investigational and approved nanomedicine products. , 2013, Nanomedicine : nanotechnology, biology, and medicine.

[29]  Jingwei Shao,et al.  Nanotechnology-based intelligent drug design for cancer metastasis treatment. , 2014, Biotechnology advances.

[30]  Zesheng An,et al.  Synthesis of architecturally well-defined nanogels via RAFT polymerization for potential bioapplications. , 2011, Chemical communications.

[31]  Zhibing Hu,et al.  Fabrication of monodisperse gel shells and functional microgels in microfluidic devices. , 2007, Angewandte Chemie.

[32]  Minseok Seo,et al.  Polymer particles with various shapes and morphologies produced in continuous microfluidic reactors. , 2005, Journal of the American Chemical Society.

[33]  T. Hirano,et al.  Nanogel-quantum dot hybrid nanoparticles for live cell imaging. , 2005, Biochemical and biophysical research communications.

[34]  A. Kabanov,et al.  Block and Graft Copolymers and Nanogel™ Copolymer Networks for DNA Delivery into Cell , 2000, Journal of drug targeting.

[35]  S. W. Kim,et al.  Self-assembled hydrogel nanoparticle of cholesterol-bearing pullulan as a carrier of protein drugs: complexation and stabilization of insulin. , 1998, Journal of controlled release : official journal of the Controlled Release Society.

[36]  Nouri Nayerossadat,et al.  Viral and nonviral delivery systems for gene delivery , 2012, Advanced biomedical research.

[37]  A. Pich,et al.  Synthesis and Characterization of Poly(vinylcaprolactam)-Based Microgels Exhibiting Temperature and pH-Sensitive Properties , 2006 .

[38]  V. Pillay,et al.  A review of polymeric colloidal nanogels in transdermal drug delivery. , 2015, Current pharmaceutical design.

[39]  Manish K Jaiswal,et al.  Dual pH and temperature stimuli-responsive magnetic nanohydrogels for thermo-chemotherapy. , 2014, Journal of Nanoscience and Nanotechnology.

[40]  Shuguang Zhang,et al.  Emerging biological materials through molecular self-assembly. , 2002, Biotechnology advances.

[41]  Maurizio Prato,et al.  Nanocomposite Hydrogels: 3D Polymer-Nanoparticle Synergies for On-Demand Drug Delivery. , 2015, ACS nano.

[42]  Carol S. Lim,et al.  Basics and recent advances in peptide and protein drug delivery. , 2013, Therapeutic delivery.

[43]  Kazunari Akiyoshi,et al.  Self-assembled cationic nanogels for intracellular protein delivery. , 2008, Bioconjugate chemistry.

[44]  Katharina Landfester,et al.  From Polymeric Particles to Multifunctional Nanocapsules for Biomedical Applications Using the Miniemulsion Process , 2010 .

[45]  S. Ganta,et al.  A review of stimuli-responsive nanocarriers for drug and gene delivery. , 2008, Journal of controlled release : official journal of the Controlled Release Society.

[46]  K. Matyjaszewski,et al.  Synthesis and biodegradation of nanogels as delivery carriers for carbohydrate drugs. , 2007, Biomacromolecules.

[47]  J. S. Park,et al.  Receptor-mediated gene delivery into human mesenchymal stem cells using hyaluronic acid-shielded polyethylenimine/pDNA nanogels. , 2016, Carbohydrate polymers.

[48]  Koen Raemdonck,et al.  Advanced nanogel engineering for drug delivery , 2009 .

[49]  Joseph M DeSimone,et al.  Direct fabrication and harvesting of monodisperse, shape-specific nanobiomaterials. , 2005, Journal of the American Chemical Society.

[50]  O. Ornatsky,et al.  Biocompatible hybrid nanogels. , 2008, Small.

[51]  K. Landfester Miniemulsions for nanoparticle synthesis , 2003 .

[52]  C. Gaillard,et al.  Core Cross-Linking of Dynamic Diblock Copolymer Micelles: Quantitative Study of Photopolymerization Efficiency and Micelle Structure. , 2011 .

[53]  Mary E Napier,et al.  Effect of aspect ratio and deformability on nanoparticle extravasation through nanopores. , 2012, Langmuir : the ACS journal of surfaces and colloids.

[54]  A. Kabanov,et al.  Nanogels as pharmaceutical carriers: finite networks of infinite capabilities. , 2009, Angewandte Chemie.

[55]  J. Z. Hilt,et al.  Magnetic hydrogel nanocomposites for remote controlled pulsatile drug release. , 2008, Journal of controlled release : official journal of the Controlled Release Society.

[56]  Mahdi Karimi,et al.  Temperature-Responsive Smart Nanocarriers for Delivery Of Therapeutic Agents: Applications and Recent Advances. , 2016, ACS applied materials & interfaces.

[57]  Yang Song,et al.  Recent progress in nanomaterials for gene delivery applications. , 2016, Biomaterials science.

[58]  E. Otsuji,et al.  Raspberry-like assembly of cross-linked nanogels for protein delivery. , 2009, Journal of controlled release : official journal of the Controlled Release Society.

[59]  A. Laschewsky Structures and Synthesis of Zwitterionic Polymers , 2014 .

[60]  K. Matyjaszewski,et al.  Atom transfer radical polymerization in inverse miniemulsion: A versatile route toward preparation and functionalization of microgels/nanogels for targeted drug delivery applications , 2009 .

[61]  L. Costantino,et al.  Is there a clinical future for polymeric nanoparticles as brain-targeting drug delivery agents? , 2012, Drug discovery today.

[62]  N. Yamaguchi,et al.  Protein refolding assisted by self‐assembled nanogels as novel artificial molecular chaperone , 2003, FEBS letters.

[63]  S. Bertholet,et al.  Unleashing the potential of NOD- and Toll-like agonists as vaccine adjuvants , 2014, Proceedings of the National Academy of Sciences.

[64]  Krzysztof Matyjaszewski,et al.  Step-Growth “Click” Coupling of Telechelic Polymers Prepared by Atom Transfer Radical Polymerization , 2005 .

[65]  V. Labhasetwar,et al.  Nanogels: Chemistry to Drug Delivery , 2007 .

[66]  A. Valente,et al.  Stimuli-responsive polyamine-DNA blend nanogels for co-delivery in cancer therapy. , 2015, Colloids and surfaces. B, Biointerfaces.

[67]  M. Noda,et al.  Nanogel‐based delivery system enhances PGE2 effects on bone formation , 2007, Journal of cellular biochemistry.

[68]  K. Matyjaszewski,et al.  The development of microgels/nanogels for drug delivery applications , 2008 .

[69]  Murali M. Yallapu,et al.  Design and engineering of nanogels for cancer treatment. , 2011, Drug discovery today.

[70]  H. Börner Strategies exploiting functions and self-assembly properties of bioconjugates for polymer and materials sciences , 2009 .

[71]  Dongmei Xu,et al.  Novel core–shell magnetic nanogels synthesized in an emulsion-free aqueous system under UV irradiation for targeted radiopharmaceutical applications , 2005 .

[72]  Hui Zhang,et al.  New progress and prospects: The application of nanogel in drug delivery. , 2016, Materials science & engineering. C, Materials for biological applications.

[73]  V R Muzykantov,et al.  Nanogel Carrier Design for Targeted Drug Delivery. , 2014, Journal of materials chemistry. B.

[74]  Hongchang Li,et al.  Self-adjuvanted nanovaccine for cancer immunotherapy: Role of lysosomal rupture-induced ROS in MHC class I antigen presentation. , 2016, Biomaterials.

[75]  Carina I C Crucho Stimuli‐Responsive Polymeric Nanoparticles for Nanomedicine , 2015, ChemMedChem.

[76]  Joseph M. DeSimone,et al.  Nanoparticle Drug Delivery Platform , 2007 .

[77]  Michael J. Whitcombe,et al.  Smart polymers for the food industry , 1997 .

[78]  K. Akiyoshi,et al.  Current advances in self-assembled nanogel delivery systems for immunotherapy. , 2015, Advanced drug delivery reviews.

[79]  A. Kabanov,et al.  Interaction of Nanosized Copolymer Networks with Oppositely Charged Amphiphilic Molecules , 2001 .

[80]  C. Dispenza,et al.  Oligonucleotides-decorated-poly(N-vinyl pyrrolidone) nanogels for gene delivery , 2014 .

[81]  M. Tomai,et al.  The use of Toll-like receptor 7/8 agonists as vaccine adjuvants , 2013, Expert review of vaccines.

[82]  G. Demirel,et al.  Poly(N-isopropylacrylamide) layers on silicon wafers as smart DNA-sensor platforms. , 2009, Journal of nanoscience and nanotechnology.

[83]  A. Yarin Stimuli-responsive polymers in nanotechnology: Deposition and possible effect on drug release , 2008 .

[84]  K. Kataoka,et al.  Environment-Sensitive Stabilization of Core−Shell Structured Polyion Complex Micelle by Reversible Cross-Linking of the Core through Disulfide Bond , 1999 .

[85]  F. Gao,et al.  Preparation and characterization of amino-functionalized magnetic nanogels via photopolymerization for MRI applications. , 2009, Colloids and surfaces. B, Biointerfaces.

[86]  Matthew J Dalby,et al.  Hydrogel nanoparticles for drug delivery. , 2013, Nanomedicine.

[87]  D. Fulton,et al.  Triggering Polymeric Nanoparticle Disassembly Through the Simultaneous Application of Two Different Stimuli , 2012 .

[88]  Diannan Lu,et al.  Fabrication of single carbonic anhydrase nanogel against denaturation and aggregation at high temperature. , 2007, Biomacromolecules.

[89]  Dhawal Dorwal NANOGELS AS NOVEL AND VERSATILE PHARMACEUTICALS , 2012 .

[90]  C. Gonçalves,et al.  Self-Assembled Hydrogel Nanoparticles for Drug Delivery Applications , 2010, Materials.

[91]  K. Akiyoshi,et al.  Controlled association of amphiphilic polymers in water : Thermosensitive nanoparticles formed by self-assembly of hydrophobically modified pullulans and poly(N-isopropylacrylamides) , 2000 .

[92]  S. Armes,et al.  Efficient synthesis of sterically stabilized pH-responsive microgels of controllable particle diameter by emulsion polymerization. , 2006, Langmuir : the ACS journal of surfaces and colloids.

[93]  R. Narain,et al.  Biodegradable and nontoxic nanogels as nonviral gene delivery systems. , 2012, Bioconjugate chemistry.

[94]  Kazushi Fujimoto,et al.  Hierarchical Self-Assembly of Hydrophobically Modified Pullulan in Water: Gelation by Networks of Nanoparticles , 2002 .

[95]  J. Engbersen,et al.  Surfactant-free preparation of highly stable zwitterionic poly(amido amine) nanogels with minimal cytotoxicity. , 2016, Acta biomaterialia.

[96]  Hans G. Börner,et al.  Making "Smart Polymers" Smarter: Modern Concepts to Regulate Functions in Polymer Science , 2010 .

[97]  Francisco M Gama,et al.  Polymeric nanogels as vaccine delivery systems. , 2013, Nanomedicine : nanotechnology, biology, and medicine.

[98]  Chulhee Choi,et al.  Hyaluronic acid promotes angiogenesis by inducing RHAMM-TGFβ receptor interaction via CD44-PKCδ , 2012, Molecules and cells.

[99]  Yoon Sung Nam,et al.  Reductively Dissociable siRNA‐Polymer Hybrid Nanogels for Efficient Targeted Gene Silencing , 2013 .

[100]  J. Hubbell,et al.  Amphiphilic hydrogel nanoparticles. Preparation, characterization, and preliminary assessment as new colloidal drug carriers. , 2005, Langmuir : the ACS journal of surfaces and colloids.

[101]  H. Kiyono,et al.  Nanogel antigenic protein-delivery system for adjuvant-free intranasal vaccines. , 2010, Nature materials.

[102]  L. Lyon,et al.  Multifunctional nanogels for siRNA delivery. , 2012, Accounts of chemical research.

[103]  F. Horkay,et al.  Nanostructured Hybrid Hydrogels Prepared by a Combination of Atom Transfer Radical Polymerization and Free Radical Polymerization , 2022 .

[104]  A. Hoffman,et al.  Design of “Smart” polymers that can ­direct intracellular drug delivery , 2002 .

[105]  C. Hawker,et al.  Shell click-crosslinked (SCC) nanoparticles: a new methodology for synthesis and orthogonal functionalization. , 2005, Journal of the American Chemical Society.

[106]  N. Kihara,et al.  Reaction of methyl thioglycolate with chloromethylstyrene microgel: Preparation of core–shell‐type microgel by chemical modification , 1998 .

[107]  K. Tam,et al.  Release kinetics of procaine hydrochloride (PrHy) from pH-responsive nanogels: theory and experiments. , 2008, International journal of pharmaceutics.

[108]  K. Landfester,et al.  Polymer micro- and nanocapsules as biological carriers with multifunctional properties. , 2014, Macromolecular bioscience.

[109]  Y. She,et al.  Enzyme-mediated in situ formation of pH-sensitive nanogels for proteins delivery , 2016 .

[110]  Allan S Hoffman,et al.  Hydrogels for biomedical applications. , 2002, Advanced drug delivery reviews.

[111]  Rakesh K. Sharma,et al.  Delivery of hydrophobised 5-fluorouracil derivative to brain tissue through intravenous route using surface modified nanogels , 2006, Journal of drug targeting.

[112]  H. Kiyono,et al.  Nanogel-based pneumococcal surface protein A nasal vaccine induces microRNA-associated Th17 cell responses with neutralizing antibodies against Streptococcus pneumoniae in macaques , 2015, Mucosal Immunology.

[113]  H. Karasulu Microemulsions as novel drug carriers: the formation, stability, applications and toxicity , 2008, Expert opinion on drug delivery.

[114]  Sergiy Minko,et al.  Stimuli-responsive nanoparticles, nanogels and capsules for integrated multifunctional intelligent systems , 2010 .

[115]  P. Maharjan,et al.  Novel chromatographic separation — The potential of smart polymers , 2008 .

[116]  P. Enkhbaatar,et al.  The Immunobiology of Toll-Like Receptor 4 Agonists: From Endotoxin Tolerance to Immunoadjuvants , 2013, Shock.

[117]  Zhishen Ge,et al.  Polyion Complex Micelles Possessing Thermoresponsive Coronas and Their Covalent Core Stabilization via “Click” Chemistry , 2008 .

[118]  Chaoliang He,et al.  One-step preparation of reduction-responsive poly(ethylene glycol)-poly (amino acid)s nanogels as efficient intracellular drug delivery platforms , 2011 .

[119]  A. Mikos,et al.  Review: Hydrogels for cell immobilization , 2000, Biotechnology and bioengineering.

[120]  K. Akiyoshi,et al.  Single molecular mechanics of a cholesterol-bearing pullulan nanogel at the hydrophobic interfaces. , 2004, Biomaterials.

[121]  F. Alexis,et al.  Stimulus responsive nanogels for drug delivery , 2011 .

[122]  M Asadian-Birjand,et al.  Functional nanogels for biomedical applications. , 2012, Current medicinal chemistry.

[123]  K. Kataoka,et al.  Biodegradable nanogels prepared by atom transfer radical polymerization as potential drug delivery carriers: synthesis, biodegradation, in vitro release, and bioconjugation. , 2007, Journal of the American Chemical Society.

[124]  Samuel M. Cohen,et al.  Cisplatin-loaded core cross-linked micelles: comparative pharmacokinetics, antitumor activity, and toxicity in mice , 2012, International journal of nanomedicine.

[125]  W. Tao,et al.  One-step synthesis of pegylated cationic nanogels of poly(N,N′-dimethylaminoethyl methacrylate) in aqueous solution via self-stabilizing micelles using an amphiphilic macroRAFT agent , 2010 .

[126]  M. Calderón,et al.  Positively Charged Thermoresponsive Nanogels for Anticancer Drug Delivery , 2014 .

[127]  Katharina Landfester,et al.  SYNTHESIS OF COLLOIDAL PARTICLES IN MINIEMULSIONS , 2006 .

[128]  E. Kohli,et al.  Comparison of Nanogel Drug Carriers and their Formulations with Nucleoside 5′-Triphosphates , 2006, Pharmaceutical Research.

[129]  K. Landfester,et al.  Miniemulsion Polymerization as a Means to Encapsulate Organic and Inorganic Materials , 2010 .

[130]  Yoshifumi Amamoto,et al.  Synthesis and Characterization of Polymeric Nanogels , 2012 .

[131]  Abhinav Mehta,et al.  Stimuli-responsive hydrogels in drug delivery and tissue engineering , 2016, Drug delivery.

[132]  Ru Cheng,et al.  Reversibly stabilized multifunctional dextran nanoparticles efficiently deliver doxorubicin into the nuclei of cancer cells. , 2009, Angewandte Chemie.

[133]  H. Tobita,et al.  Network Formation in Emulsion Crosslinking Copolymerization , 1994 .

[134]  Li Tang,et al.  Smart chemistry in polymeric nanomedicine. , 2014, Chemical Society reviews.

[135]  S. Seiffert,et al.  A microgel construction kit for bioorthogonal encapsulation and pH-controlled release of living cells. , 2013, Angewandte Chemie.

[136]  L. Elviri,et al.  Advances in oral controlled drug delivery: the role of drug–polymer and interpolymer non-covalent interactions , 2015, Expert opinion on drug delivery.

[137]  K. Martínek,et al.  Catalysis by alpha-chymotrypsin entrapped into surface-modified polymeric nanogranules in organic solvent. , 1992, European journal of biochemistry.

[138]  K. Akiyoshi,et al.  Cell specific peptide-conjugated polysaccharide nanogels for protein delivery. , 2011, Macromolecular bioscience.

[139]  Y. M. Lee,et al.  Taxol-loaded block copolymer nanospheres composed of methoxy poly(ethylene glycol) and poly(epsilon-caprolactone) as novel anticancer drug carriers. , 2001, Biomaterials.

[140]  William B. Liechty,et al.  Polymers for drug delivery systems. , 2010, Annual review of chemical and biomolecular engineering.

[141]  D. Kohane,et al.  HYDROGELS IN DRUG DELIVERY: PROGRESS AND CHALLENGES , 2008 .

[142]  S. Sahoo,et al.  Nanotech approaches to drug delivery and imaging. , 2003, Drug discovery today.

[143]  R. Jayakumar,et al.  Nanogels for delivery, imaging and therapy. , 2015, Wiley interdisciplinary reviews. Nanomedicine and nanobiotechnology.

[144]  M. Calderón,et al.  Fabrication of thermoresponsive nanogels by thermo-nanoprecipitation and in situ encapsulation of bioactives , 2014 .

[145]  V. Torchilin Multifunctional, stimuli-sensitive nanoparticulate systems for drug delivery , 2014, Nature Reviews Drug Discovery.

[146]  Hui Li,et al.  Glucose‐sensitive and blood‐compatible nanogels for insulin controlled release , 2016 .

[147]  Krzysztof Matyjaszewski,et al.  Inverse miniemulsion ATRP: a new method for synthesis and functionalization of well-defined water-soluble/cross-linked polymeric particles. , 2006, Journal of the American Chemical Society.

[148]  Stephanie D. Steichen,et al.  Stimulus-responsive hydrogels: Theory, modern advances, and applications. , 2015, Materials science & engineering. R, Reports : a review journal.

[149]  K. Landfester,et al.  Miniemulsion polymerization as a versatile tool for the synthesis of functionalized polymers , 2010, Beilstein journal of organic chemistry.

[150]  Yali Li,et al.  pH-Responsive Shell Cross-Linked Nanoparticles with Hydrolytically Labile Cross-Links , 2008 .

[151]  Taizo Shiraishi,et al.  Humoral immune responses in patients vaccinated with 1–146 HER2 protein complexed with cholesteryl pullulan nanogel , 2008, Cancer science.

[152]  Kruti S Soni,et al.  Nanogels: An overview of properties, biomedical applications and obstacles to clinical translation. , 2016, Journal of controlled release : official journal of the Controlled Release Society.

[153]  K. Akiyoshi,et al.  Self-assembled nanogels of cholesteryl-modified polysaccharides: effect of the polysaccharide structure on their association characteristics in the dilute and semidilute regimes. , 2007, Biomacromolecules.

[154]  M. Morbidelli,et al.  Microgel Formation in Emulsion Polymerization , 2007 .

[155]  H. Klok,et al.  Advanced drug delivery devices via self-assembly of amphiphilic block copolymers. , 2001, Advanced drug delivery reviews.

[156]  Huajian Gao,et al.  Advance and Prospect of Bionanomaterials , 2003, Biotechnology progress.

[157]  H. Börner,et al.  Modern trends in polymer bioconjugates design , 2008 .

[158]  M. Vamvakaki Organic Nanoparticle Bioconjugate: Micelles, Cross‐Linked Micelles, and Nanogels , 2014 .

[159]  S. Feng,et al.  A novel controlled release formulation for the anticancer drug paclitaxel (Taxol): PLGA nanoparticles containing vitamin E TPGS. , 2003, Journal of controlled release : official journal of the Controlled Release Society.

[160]  K. Wooley,et al.  Amphiphilic core–shell nanospheres obtained by intramicellar shell crosslinking of polymer micelles with poly(ethylene oxide) linkers , 1998 .

[161]  Hongjian Xu,et al.  Recent advances of thermally responsive nanogels for cancer therapy. , 2015, Therapeutic delivery.

[162]  Seeram Ramakrishna,et al.  Smart functional polymers – a new route towards creating a sustainable environment , 2014 .

[163]  Lei Zhang,et al.  Softer zwitterionic nanogels for longer circulation and lower splenic accumulation. , 2012, ACS nano.

[164]  B. Baird,et al.  Antigen-decorated shell cross-linked nanoparticles: synthesis, characterization, and antibody interactions. , 2005, Bioconjugate chemistry.

[165]  M. G. Finn,et al.  Click Chemistry: Diverse Chemical Function from a Few Good Reactions. , 2001, Angewandte Chemie.

[166]  N. Peppas,et al.  Surface-modified P(HEMA-co-MAA) nanogel carriers for oral vaccine delivery: design, characterization, and in vitro targeting evaluation. , 2014, Biomacromolecules.

[167]  E. Kumacheva,et al.  Biofunctionalized pH‐Responsive Microgels for Cancer Cell Targeting: Rational Design , 2006 .

[168]  S. Vinogradov Nanogels in the race for drug delivery. , 2010, Nanomedicine.

[169]  R. Haag,et al.  Micro- and nanogels with labile crosslinks - from synthesis to biomedical applications. , 2015, Chemical Society reviews.

[170]  D. Fulton,et al.  The formation of core cross-linked star polymer and nanogel assemblies facilitated by the formation of dynamic covalent imine bonds , 2011 .

[171]  F. Chiellini,et al.  Targeted Delivery of Protein Drugs by Nanocarriers , 2010, Materials.

[172]  Diannan Lu,et al.  Lipase nanogel catalyzed transesterification in anhydrous dimethyl sulfoxide. , 2009, Biomacromolecules.

[173]  I. Sjöholm,et al.  Immobilization of proteins in microspheres of biodegradable polyacryldextran. , 1980, Journal of pharmaceutical sciences.

[174]  Y. Joung,et al.  Disulfide-crosslinked heparin-pluronic nanogels as a redox-sensitive nanocarrier for intracellular protein delivery , 2011 .

[175]  Florian D Jochum,et al.  Temperature- and light-responsive smart polymer materials. , 2013, Chemical Society reviews.

[176]  Changping Wang,et al.  Biodegradable Smart Nanogels: A New Platform for Targeting Drug Delivery and Biomedical Diagnostics. , 2016, Langmuir : the ACS journal of surfaces and colloids.

[177]  Jiaming Zhuang,et al.  Polymer nanogels: a versatile nanoscopic drug delivery platform. , 2012, Advanced drug delivery reviews.

[178]  L. Jorgensen,et al.  Design and processing of nanogels as delivery systems for peptides and proteins. , 2014, Therapeutic delivery.

[179]  Alexander V Kabanov,et al.  Nanosized cationic hydrogels for drug delivery: preparation, properties and interactions with cells. , 2002, Advanced drug delivery reviews.

[180]  M. Antonietti,et al.  Intermolecular structure of spherical polyelectrolyte microgels in salt-free solution. 1. Quantification of the attraction between equally charged polyelectrolytes. , 2000 .

[181]  Y. Takei,et al.  Antibody responses against NY-ESO-1 and HER2 antigens in patients vaccinated with combinations of cholesteryl pullulan (CHP)-NY-ESO-1 and CHP-HER2 with OK-432. , 2009, Vaccine.

[182]  B. Lambrecht,et al.  pH-degradable imidazoquinoline-ligated nanogels for lymph node-focused immune activation , 2016, Proceedings of the National Academy of Sciences.

[183]  Michael R Hamblin,et al.  Smart micro/nanoparticles in stimulus-responsive drug/gene delivery systems. , 2016, Chemical Society reviews.

[184]  A. Concheiro,et al.  Cross-linked hydroxypropyl-β-cyclodextrin and γ-cyclodextrin nanogels for drug delivery: Physicochemical and loading/release properties , 2012 .

[185]  Jean-Marie Lehn,et al.  From supramolecular chemistry towards constitutional dynamic chemistry and adaptive chemistry. , 2007, Chemical Society reviews.

[186]  S. Nair,et al.  Smart stimuli sensitive nanogels in cancer drug delivery and imaging: a review. , 2013, Current pharmaceutical design.

[187]  M. C. Stuart,et al.  Emerging applications of stimuli-responsive polymer materials. , 2010, Nature materials.

[188]  C. Hawker,et al.  Functionalization of Micelles and Shell Cross-linked Nanoparticles Using Click Chemistry , 2005 .

[189]  Wuli Yang,et al.  A redox-labile poly(oligo(ethylene glycol)methacrylate)-based nanogel with tunable thermosensitivity for drug delivery , 2016 .

[190]  M. Calderón,et al.  Thermosensitive nanogels based on dendritic polyglycerol and N-isopropylacrylamide for biomedical applications , 2011 .

[191]  Eun Seong Lee,et al.  A self-organized 3-diethylaminopropyl-bearing glycol chitosan nanogel for tumor acidic pH targeting: in vitro evaluation. , 2010, Colloids and surfaces. B, Biointerfaces.

[192]  S. Vinogradov Polymeric nanogel formulations of nucleoside analogs , 2007, Expert opinion on drug delivery.

[193]  Pei Li,et al.  Polyethyleneimine-based core-shell nanogels: a promising siRNA carrier for argininosuccinate synthetase mRNA knockdown in HeLa cells. , 2012, Journal of controlled release : official journal of the Controlled Release Society.

[194]  Christine Vauthier,et al.  Methods for the Preparation and Manufacture of Polymeric Nanoparticles , 2009, Pharmaceutical Research.

[195]  R. Arote,et al.  Degradable polyethylenimines as DNA and small interfering RNA carriers , 2009, Expert opinion on drug delivery.

[196]  A. Kabanov,et al.  Poly(ethylene glycol)–polyethyleneimine NanoGel™ particles: novel drug delivery systems for antisense oligonucleotides , 1999 .

[197]  J. Guan,et al.  Thermosensitive hydrogels for drug delivery , 2011, Expert opinion on drug delivery.

[198]  Yifan Ma,et al.  Bioreducible alginate-poly(ethylenimine) nanogels as an antigen-delivery system robustly enhance vaccine-elicited humoral and cellular immune responses. , 2013, Journal of controlled release : official journal of the Controlled Release Society.

[199]  Reuben T Chacko,et al.  Surface-functionalizable polymer nanogels with facile hydrophobic guest encapsulation capabilities. , 2010, Journal of the American Chemical Society.

[200]  Q. Shi,et al.  Green tea epigallocatechin gallate binds to and inhibits respiratory complexes in swelling but not normal rat hepatic mitochondria. , 2014, Biochemical and biophysical research communications.

[201]  J. Mora,et al.  Vitamin A and immune regulation: role of retinoic acid in gut-associated dendritic cell education, immune protection and tolerance. , 2012, Molecular aspects of medicine.

[202]  D. Shangguan,et al.  PEG-urokinase nanogels with enhanced stability and controllable bioactivity , 2012 .

[203]  S. Khoee,et al.  Nanogels: Chemical Approaches to Preparation , 2015 .

[204]  K. Yadav,et al.  Nanogels as potential nanomedicine carrier for treatment of cancer: A mini review of the state of the art , 2014, Saudi pharmaceutical journal : SPJ : the official publication of the Saudi Pharmaceutical Society.

[205]  Yu-Kyoung Oh,et al.  Target-specific intracellular delivery of siRNA using degradable hyaluronic acid nanogels. , 2007, Journal of controlled release : official journal of the Controlled Release Society.