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Stimuli-responsive nanocarriers for intracellular delivery

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Abstract

The emergence of different nanoparticles (NPs) has made a significant revolution in the field of medicine. Different NPs in the form of metallic NPs, dendrimers, polymeric NPs, carbon quantum dots and liposomes have been functionalized and used as platforms for intracellular delivery of biomolecules, drugs, imaging agents and nucleic acids. These NPs are designed to improve the pharmacokinetic properties of the drug, improve their bioavailability and successfully surpass physiological or pathological obstacles in the biological system so that therapeutic efficacy is achieved. In this review I present some of the current approaches used in intracellular delivery systems, with a focus on various stimuli-responsive nanocarriers, including cell-penetrating peptides, to highlight their various biomedical applications.

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References

  • Allen TM (2002) Ligand-targeted therapeutics in anticancer therapy. Nat Rev Cancer 2:750–763

    CAS  PubMed  Google Scholar 

  • Babin J, Pelletier M, Lepage M, Allard J-F, Morris D, Zhao Y (2009) A new two-photon sensitive block copolymer nanocarrier. Angew Chem Int Ed 48:3329–3332

    CAS  Google Scholar 

  • Baghbani F, Moztarzadeh F (2017) Bypassing multidrug resistant ovarian cancer using ultrasoundresponsive doxorubicin/curcumin co-deliver alginate nanodroplets. Colloids Surf B Biointerfaces 153:132–140

    CAS  PubMed  Google Scholar 

  • Baghbani F, Chegeni M, Moztarzadeh F, Hadian-Ghazvini S, Raz M (2017a) Novel ultrasound-responsive chitosan/perfluorohexane nanodroplets for image-guided smart delivery of an anticancer agent: curcumin. Mater Sci Eng C 74:186–193

    CAS  Google Scholar 

  • Baghbani F, Chegeni M, Moztarzadeh F, Mohandesi JA, Mokhtari-Dizaji M (2017b) Ultrasonic nanotherapy of breast cancer using novel ultrasound-responsive alginate-shelled perfluorohexane nanodroplets: in vitro and in vivo evaluation. Mater Sci Eng C 77:698–707

    CAS  Google Scholar 

  • Bazban-Shotorbani S, Hasani-Sadrabadi MM, Karkhaneh A, Serpooshan V, Jacob KI, Moshaverinia A, Mahmoudi M (2017) Revisiting structure-property relationship of pH-responsive polymers for drug delivery applications. J Control Release 253:46–63

    CAS  PubMed  Google Scholar 

  • Bouchaala R, Anton N, Anton H, Vandamme T, Vermot J, Smail D, Mély Y, Klymchenko AS (2017) Light-triggered release from dye-loaded fluorescent lipid nanocarriersin vitro and in vivo. Colloids Surf B Biointerfaces 156:414–421

    CAS  PubMed  Google Scholar 

  • Canton I, Battaglia G (2012) Endocytosis at the nanoscale. Chem Soc Rev 41:2718–2739

    CAS  PubMed  Google Scholar 

  • Chan DCF, Kirpotin DB, Bunn PA (1993) Synthesis and evaluation of colloidal magnetic iron-oxides for the site-specific radiofrequency induced hyperthermia of cancer. J Magn Magn Mater 122:374–378

    CAS  Google Scholar 

  • Chang Y, Shih YJ, Ko CY, Jhong JF, Liu YL, Wei TC (2011) Hemocompatibility of poly(vinylidene fluoride) membrane grafted with network-like and brush-like antifouling layer controlled via plasma-induced surface PEGylation. Langmuir 27:5445–5455

    CAS  PubMed  Google Scholar 

  • Cheng C, Wei H, Shi B-X, Cheng H, Li C, Gu Z-W, Cheng S-X, Zhang X-Z, Zhuo R-X (2008) Biotinylated thermoresponsive micelle self-assembled from double-hydrophilic block copolymer for drug delivery and tumor target. Biomaterials 29:497–505

    CAS  PubMed  Google Scholar 

  • Cheng R, Feng F, Meng F, Deng C, Feijen J, Zhong Z (2011) Glutathione-responsive nanovehicles as a promising platform for targeted intracellular drug and gene delivery. J Control Release 152:2–12

    CAS  PubMed  Google Scholar 

  • Chilkoti A, Dreher MR, Meyer DE, Raucher D (2002) Targeted drug delivery by thermally responsive polymers. Adv Drug Deliv Rev 54:613–630

    CAS  PubMed  Google Scholar 

  • Derfus AM, Chen AA, Min D-H, Ruoslahti E, Bhatia SN (2007) Targeted quantum dot conjugates for siRNA delivery. Bioconjug Chem 18:1391–1396

    CAS  PubMed  Google Scholar 

  • Ding C, Li Z (2017) A review of drug release mechanisms from nanocarrier systems. Mater Sci Eng C 76:1440–1453

    CAS  Google Scholar 

  • Doherty GJ, McMahon HT (2009) Mechanisms of endocytosis. Annu Rev Biochem 78:857–859

    CAS  PubMed  Google Scholar 

  • Dowaidara M, Abdelhamid HN, Hällbrink M, Zou X, Langel U (2017) Graphene oxide nanosheets in complex with cell penetrating peptides for oligonucleotides delivery. BBA Gen Subjects 1861:2334–2341

    Google Scholar 

  • Duchardt F, Fotin-Mleczek M, Schwarz H, Fischer R, Brock R (2007) A comprehensive model for the cellular uptake of cationic cell-penetrating peptides. Traffic 8:848–866

    CAS  PubMed  Google Scholar 

  • Dumville JC, O'Meara S, Deshpande S, Speak K (2011) Hydrogel dressings for healing diabetic foot ulcers. Cochrane Database Syst Rev 9:CD009101

    Google Scholar 

  • Elegbede AI, Banerjee J, Hanson AJ, Tobwala S, Ganguli B, Wang R et al (2008) Mechanistic studies of the triggered release of liposomal contents by matrix metalloproteinase-9. J Am Chem Soc 130:10633–10642

    CAS  PubMed  PubMed Central  Google Scholar 

  • Fomina N, Sankaranarayanan J, Almutairi A (2012) Photochemical mechanisms of lighttriggered release from nanocarriers. Adv Drug Deliv Rev 64:1005–1020

    CAS  PubMed  PubMed Central  Google Scholar 

  • Frenkel V (2008) Ultrasound mediated delivery of drugs and genes to solid tumors. Adv Drug Deliv Rev 60:1193–1208

    CAS  PubMed  PubMed Central  Google Scholar 

  • Frimpong RA, Hilt JZ (2010) Magnetic nanoparticles in biomedicine: synthesis, functionalization and applications. Nanomedicine (London) 5:1401–1414

    CAS  Google Scholar 

  • Gao W, Chan JM, Farokhzad OC (2010) pH-responsive nanoparticles for drug delivery. Mol Pharm 7:1913–1920

    CAS  PubMed  PubMed Central  Google Scholar 

  • Gao J, Liu W, Xia Y, Li W, Sun J, Chen H et al (2011) The promotion of siRNA delivery to breast cancer overexpressing epidermal growth factor receptor through anti-EGFR antibody conjugation by immunoliposomes. Biomaterials 32:3459–3470

    CAS  PubMed  Google Scholar 

  • Ginn SL, Alexander IE, Edelstein ML, Abedi MR, Wixon J (2013) Gene therapy clinical trials worldwide to 2012—an update. J Gene Med 15:65–77

    CAS  PubMed  Google Scholar 

  • Han G, Ghosh P, De M, Rotello VM (2007) Drug and gene delivery using gold nanoparticles. NanoBiotechnology 3:40–45

    CAS  Google Scholar 

  • Han L, Zhang XY, Wang YL, Li X, Yang XH, Huang M, Hu K, Li LH, Wei Y (2017) Redox-responsive theranostic nanoplatforms based on inorganic nanomaterials. J Control Release 259:40–52

    CAS  PubMed  Google Scholar 

  • Immordino ML, Dosio F, Cattel L (2006) Stealth liposomes: review of the basic science, rationale, and clinical applications, existing and potential. Int J Nanomedicine 1:297–315

    CAS  PubMed  PubMed Central  Google Scholar 

  • Jeong JH, Kim SW, Park TG (2007) Molecular design of functional polymers for gene therapy. Prog Polym Sci 32:1239–1274

    CAS  Google Scholar 

  • Jewell CM, Lynn DM (2008) Surface-mediated delivery of DNA: cationic polymers take charge. Curr Opin Colloid Interface Sci 13:395–402

    CAS  PubMed  PubMed Central  Google Scholar 

  • Jia L, Xu J-P, Wang H, Ji J (2011) Polyamidoamine dendrimers surface engineered with biomimetic phosphorylcholine as potential drug delivery carriers. Colloids Surf B Biointerfaces 84:49–54

    CAS  PubMed  Google Scholar 

  • Jia YP, Ma BY, Wei XW, Qian ZY (2017) The in vitro and in vivo toxicity of gold nanoparticles. Chin Chem Lett 28:691–702

    CAS  Google Scholar 

  • Jiang SY, Cao ZQ (2010) Ultralow-fouling, functionalizable, and hydrolyzable zwitterionic materials and their derivatives for biological applications. Adv Mater 22:920–932

    CAS  PubMed  Google Scholar 

  • Joshi S, Cooke JRN, Chan DKW, Ellis JA, Hossain SS, Singh-Moon RP, Wang M, Bigio IJ, Bruce JN, Straubinger RM (2017) Liposome size and charge optimization for intraarterial delivery to gliomas. Drug Deliv Transl Res 3:225–233

    Google Scholar 

  • Kamaly N, Xiao Z, Valencia PM, Radovic-Moreno AF, Farokhzad OC (2012) Targeted polymeric therapeutic nanoparticles: design, development and clinical translation. Chem Soc Rev 41:2971–3010

    CAS  PubMed  PubMed Central  Google Scholar 

  • Koo H, Huh MS, Sun I-C, Yuk SH, Choi K, Kim K, Kwon IC (2011) In vivo targeted delivery of nanoparticles for theranosis. Acc Chem Res 44:1018–1028

    CAS  PubMed  Google Scholar 

  • Kooiman K, Vos HJ, Versluis M, de Jong N (2014) Acoustic behavior of microbubbles and implications for drug delivery. Adv Drug Deliv Rev 72C:28–48

    Google Scholar 

  • Kumar B, Jalodia K, Kumar P, Gautam HK (2017) Recent advances in nanoparticle-mediated drug delivery. J Drug Delivery Sci Technol 41:260–268

    CAS  Google Scholar 

  • Kunath K, von Harpe A, Fischer D, Peterson H, Bickel U, Voigt K, Kissel T (2003) Low molecular-weight polyethylenimine as a non-viral vector for DNA delivery: comparison of physicochemical properties, transfection efficiency and in vivo distribution with high molecular weight polyethylenimine. J Control Release 89:113–125

    CAS  PubMed  Google Scholar 

  • Kuppusamy P, Li H, Ilangovan G, Cardounel AJ, Zweier JL, Yamada K, Krishna MC, Mitchell JB (2002) Noninvasive imaging of tumor redox status and its modification by tissue glutathione levels. Cancer Res 62:307–312

    CAS  PubMed  Google Scholar 

  • Lee ES, Gao Z, Kim D, Park K, Kwon IC, Bae YH (2008) Super pH-sensitive multifunctional polymeric micelle for tumor pH(e) specific TAT exposure and multidrug resistance. J Control Release 129:228–236

    CAS  PubMed  PubMed Central  Google Scholar 

  • Lehner R, Wang X, Marsch S, Hunziker P (2013) Intelligent nanomaterials for medicine: carrier platforms and targeting strategies in the context of clinical application. Nanomed Nanotech Biol Med 9:742–757

    CAS  Google Scholar 

  • Li S-D, Huang L (2008) Pharmacokinetics and biodistribution of nanoparticles. Mol Pharm 5:496–504

    CAS  PubMed  Google Scholar 

  • Lin JT, Liuc ZK, Zhuc QL, Rongd XH, Liang CL, Wang J, Mae D, Sund J, Wang GH (2017) Redox-responsive nanocarriers for drug and gene co-delivery basedon chitosan derivatives modified mesoporous silica nanoparticles. Colloids Surf B Biointerfaces 155:41–50

    CAS  PubMed  Google Scholar 

  • Liu YC, Le Ny ALM, Schmidt J, Talmon Y, Chmelka BF, Lee CT Jr (2009) Photo-assisted gene delivery using light-responsive catanionic vesicles. Langmuir 25:5713–5724

    CAS  PubMed  Google Scholar 

  • Liu M, Du H, Zhang W, Zhai G (2017) Internal stimuli-responsive nanocarriers for drug delivery: design strategies and applications. Mater Sci Eng C 71:1267–1280

    CAS  Google Scholar 

  • Luo G, Long J, Zhang B, Liu C, Ji S, Xu J et al (2012) Quantum dots in cancer therapy. Expert Opin Drug Deliv 9:47–58

    CAS  PubMed  Google Scholar 

  • Maeda H, Wu J, Sawa T, Matsumura Y, Hori K (2000) Tumor vascular permeability and the EPR effect in macromolecular therapeutics: a review. J Control Release 65:271–284

    CAS  PubMed  Google Scholar 

  • Maeda H (2010) Tumor-Selective Delivery of Macromolecular Drugs via the EPR Effect: Background and Future Prospects Bioconjugate Chemistry Vol. 21, Issue 5, 19:797–802

    CAS  PubMed  Google Scholar 

  • Manchun S, Dass CR, Sriamornsak P (2012) Targeted therapy for cancer using pH-responsive nanocarrier systems. Life Sci 90:381–387

    CAS  PubMed  Google Scholar 

  • Marturano V, Cerruti P, Carfagna C, Giamberini M, Tylkowski B, Ambrogi V (2015) Photo-responsive polymer nanocapsules. Polymer 70:222–230

    CAS  Google Scholar 

  • Meng F, Hennink WE, Zhong Z (2009) Reduction-sensitive polymers and bioconjugates for biomedical applications. Biomaterials 30:2180–2198

    CAS  PubMed  Google Scholar 

  • Mesken J, Iltzsche A, Mulac D, Langer K (2017) Modifying plasmid-loaded HSA-nanoparticles with cell penetrating peptides—cellular uptake and enhanced gene delivery. Int J Pharm 522:198–209

    CAS  PubMed  Google Scholar 

  • Naeye B, Raemdonck K, Remaut K, Sproat B, Demeester J, De Smedt SC (2010) PEGylation of biodegradable dextran nanogels for siRNA delivery. Eur J Pharm Sci 40:342–351

    CAS  PubMed  Google Scholar 

  • Namdari P, Negahdari B, Eatemadi A (2017) Synthesis, properties and biomedical applications of carbon-based quantum dots: an updated review. Biomed Pharmacother 87:209–222

    CAS  PubMed  Google Scholar 

  • Navarro G, Tros de Ilarduya C (2009) Activated and non-activated PAMAM dendrimers for gene delivery in vitro and in vivo. Nanomedicine 5:287–297

    CAS  PubMed  Google Scholar 

  • Paleos CM, Tsiourvas D, Sideratou Z, Tziveleka L-A (2010) Drug delivery using multifunctional dendrimers and hyperbranched polymers. Expert Opin Drug Deliv 7:1387–1398

    CAS  PubMed  Google Scholar 

  • Pang X, Jiang Y, Xiao Q, Leung AW, Hua H, Xu C (2016) pH-responsive polymer–drug conjugates: design and progress. J Control Release 222:116–129

    CAS  PubMed  Google Scholar 

  • Pärnaste L, Arukuusk P, Langel K, Tenson T, Langel U (2017) The formation of nanoparticles between small interfering RNA and amphipathic cell-penetrating peptides. Mol Ther Nucleic Acids 7:1–10

    PubMed  PubMed Central  Google Scholar 

  • Patra HK, Banerjee S, Chaudhuri U, Lahiri P, Dasgupta AK (2007) Cell selective response to gold nanoparticles. Nanomedicine 3:111–119

    CAS  PubMed  Google Scholar 

  • Pavan GM, Posocco P, Tagliabue A, Maly M, Malek A, Danani A et al (2010) PAMAM dendrimers for siRNA delivery: computational and experimental insights. Chemistry 16:7781–7795

    CAS  PubMed  Google Scholar 

  • Rao NV, Mane S, Kishore A, Das Sarma J, Shunmugam R (2011) Norbornene derived doxorubicin copolymers as drug carriers with pH responsive hydrazone linker. Biomacromolecules 13:221–230

    PubMed  Google Scholar 

  • Saravanakumar G, Kim WJ (2014) Stimuli-responsive polymeric nanocarriers as promising drug and gene delivery systems. In: Prokop A, Iwasaki Y, Harada A (eds) Intracellular delivery II. Springer International Publishing AG, Cham, pp 55–91

    Google Scholar 

  • Schmaljohann D (2006) Thermo- and pH-responsive polymers in drug delivery. Adv Drug Deliv Rev 58:1655–1670

    CAS  PubMed  Google Scholar 

  • Shih Y, Venault A, Tayo LL, Chen SH, Higuchi A, Deratani A, Chinnathambi A, Alharbi SA, Quemener D, Chang Y (2017) A Zwitterionic-shielded carrier with pH-modulated reversible self-assembly for gene transfection. Langmuir 33:1914–1926

    CAS  PubMed  Google Scholar 

  • Shim MS, Kwon YJ (2012) Stimuli-responsive polymers and nanomaterials for gene delivery and imaging applications. Adv Drug Deliv Rev 64:1046–1059

    CAS  PubMed  Google Scholar 

  • Skulason S, Holbrook WP, Thormar H, Gunnarsson GB, Kristmundsdottir T (2012) A study of the clinical activity of a gel combining monocaprin and doxycycline: a novel treatment for herpes labialis. J Oral Pathol Med 41:61–67

    CAS  PubMed  Google Scholar 

  • Son S, Singha K, Kim WJ (2010) Bioreducible BPEI-SS-PEG-cNGR polymer as a tumor targeted nonviral gene carrier. Biomaterials 31:6344–6354

    CAS  PubMed  Google Scholar 

  • Son S, Namgung R, Kim J, Singha K, Kim WJ (2011) Bioreducible polymers for gene silencing and delivery. Acc Chem Res 45:1100–1112

    PubMed  Google Scholar 

  • Sumetpipat K, Baowan D (2014) Three model shapes of doxorubicin for liposome encapsulation. J Mol Model 20:2504

    PubMed  Google Scholar 

  • Suzuki R, Oda Y, Utoguchi N, Maruyama K (2010) Development of ultrasonic cancer therapy using ultrasound sensitive liposome. Yakugaku Zasshi 130:1665–1670

    CAS  PubMed  Google Scholar 

  • Tamura A, Oishi M, Nagasaki Y (2010) Efficient siRNA delivery based on PEGylated and partially quaternized polyamine nanogels: enhanced gene silencing activity by the cooperative effect of tertiary and quaternary amino groups in the core. J Control Release 146:378–387

    CAS  PubMed  Google Scholar 

  • Tashima T (2017) Intelligent substance delivery into cells using cell-penetrating peptides. Bioorg Med Chem Lett 27:121–130

    CAS  PubMed  Google Scholar 

  • Tayo LL, Venault A, Constantino VGR, Caparanga AR, Chinnathambi A, Alharbi SA, Zheng J, Chang Y (2015) Design of hemocompatible poly(DMAEMA-co-PEGMA) hydrogels for controlled release of insulin. J Appl Polym Sci 132(32):1–12. https://doi.org/10.1002/APP.42365

    Google Scholar 

  • Tian H, Li F, Chen J, Huang Y, Chen X (2012) N-isopropylacrylamide-modified polyethylenimines as effective gene carriers. Macromol Biosci 12:1680–1688

    CAS  PubMed  Google Scholar 

  • Tomalia DA, Baker H, Dewald J, Hall M, Kallos G, Martin S et al (1985) A new class of polymers: starburst-dendritic macromolecules. Polym J 17:117–132

    CAS  Google Scholar 

  • Tomatsu I, Peng K, Kros A (2011) Photoresponsive hydrogels for biomedical applications. Adv Drug Deliv Rev 63:1257–1266

    CAS  PubMed  Google Scholar 

  • Waehler R, Russell SJ, Curiel DT (2007) Engineering targeted viral vectors for gene therapy. Nat Rev Genet 8:573–587

    CAS  PubMed  Google Scholar 

  • Wang P, Yin T, Li J, Zheng B, Wang X, Wang Y, Zheng J, Zheng R (2016) Ultrasound-responsive microbubbles for sonography-guided siRNA delivery. Nanomed Nanotech Biol Med 12:1139–1149

    CAS  Google Scholar 

  • Wang X-Q, Zhang Q (2012) pH-sensitive polymeric nanoparticles to improve oral bioavailability of peptide/protein drugs and poorly water-soluble drugs. Eur J Pharm Biopharm 82:219–229

    CAS  PubMed  Google Scholar 

  • Wei H, Zhuo R-X, Zhang X-Z (2013) Design and development of polymeric micelles with cleavable links for intracellular drug delivery. Prog Polym Sci 38:503–535

    CAS  Google Scholar 

  • Xu X, Ray R, Gu Y, Ploehn HJ, Gearheart L, Raker K, Scrivens WA. (2004). "Electrophoretic Analysis and Purification of Fluorescent Single-Walled Carbon Nanotube Fragments". Journal of the American Chemical Society. 126 (40): 12736–7.

    CAS  PubMed  Google Scholar 

  • Yan F, Li L, Deng Z, Jin Q, Chen J, Yang W et al (2013) Paclitaxel–liposome–microbubble complexes as ultrasound-triggered therapeutic drug delivery carriers. J Control Release 166:246–255

    CAS  PubMed  Google Scholar 

  • Yokoyama M (2002) Gene delivery using temperature-responsive polymeric carriers. Drug Discov Today 7:426–432

    CAS  PubMed  Google Scholar 

  • Yokoyama M (2014) Polymeric micelles as drug carriers: Their lights and shadow. Journal of Drug Targeting 22:576–583

    CAS  PubMed  Google Scholar 

  • Zhang W, Shi L, Wu K, An Y (2005) Thermoresponsive micellization of poly(ethylene glycol)-bpoly(N-isopropylacrylamide) in water. Macromolecules 38:5743–5747

    CAS  Google Scholar 

  • Zhang Z, Chao T, Chen S, Jiang S (2006) Superlow fouling sulfobetaine and carboxybetaine polymers on glass slides. Langmuir 22:10072–10077

    CAS  PubMed  Google Scholar 

  • Zhao F, Zhao Y, Liu Y et al (2011) Cellular uptake, intracellular trafficking, and cytotoxicity of nanomaterials. Small 7:1322–1337

    CAS  PubMed  Google Scholar 

  • Zhao Y (2007) Rational design of light-controllable polymer micelles. Chem Rec 7:286–294

    CAS  PubMed  Google Scholar 

  • Zhao Y (2012) Light-responsive block copolymer micelles. Macromolecules 45:3647–3657

    CAS  Google Scholar 

  • Zintchenko A, Susha AS, Concia M, Feldmann J, Wagner E, Rogach AL et al (2009) Drug nanocarriers labeled with near-infrared-emitting quantum dots (quantoplexes): imaging fast dynamics of distribution in living animals. Mol Ther 17:1849–1856

    CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

I would like to congratulate Prof. Fumio Arisaka for his long scientific career and significant contribution to the field of life sciences. I wish him a blissful 70th birthday and more fruitful years to come. I also acknowledge the organizers of this special edition of Biophysical Reviews.

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Correspondence to Lemmuel L. Tayo.

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Tayo, L.L. Stimuli-responsive nanocarriers for intracellular delivery. Biophys Rev 9, 931–940 (2017). https://doi.org/10.1007/s12551-017-0341-z

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