Research Article

Imaging modalities delivery of RNAi therapeutics in cancer therapy and clinical applications

Loutfy H Madkour*

Published: 03/04/2021 | Volume 5 - Issue 1 | Pages: 005-034


The RNA interference (RNAi) technique is a new modality for cancer therapy, and several candidates are being tested clinically. Nanotheranostics is a rapidly growing field combining disease diagnosis and therapy, which ultimately may add in the development of ‘personalized medicine’.

Technologies on theranostic nanomedicines has been discussed. We designed and developed bioresponsive and fluorescent hyaluronic acid-iodixanol nanogels (HAI-NGs) for targeted X-ray computed tomography (CT) imaging and chemotherapy of MCF-7 human breast tumors. HAI-NGs were obtained with a small size of ca. 90 nm, bright green fluorescence and high serum stability from hyaluronic acid-cystamine-tetrazole and reductively degradable polyiodixanol-methacrylate via nanoprecipitation and a photo-click crosslinking reaction. This chapter presents an over view of the current status of translating the RNAi cancer therapeutics in the clinic, a brief description of the biological barriers in drug delivery, and the roles of imaging in aspects of administration route, systemic circulation, and cellular barriers for the clinical translation of RNAi cancer therapeutics, and with partial content for discussing the safety concerns. Finally, we focus on imaging-guided delivery of RNAi therapeutics in preclinical development, including the basic principles of different imaging modalities, and their advantages and limitations for biological imaging. With growing number of RNAi therapeutics entering the clinic, various imaging methods will play an important role in facilitating the translation of RNAi cancer therapeutics from bench to bedside.

Read Full Article HTML DOI: 10.29328/journal.jro.1001035 Cite this Article


  1. Fire A, Xu S, Montgomery MK, Kostas SA, Driver SE, et al, Potent and specific genetic interference by double-stranded RNA in Caenorhabditis elegans. Nature. 1998; 391: 806–811. PubMed:
  2. Elbashir SM, Harborth J, Lendeckel W, Yalcin A, Weber K, et al. Duplexes of 21-nucleotide RNAs mediate RNA interference in cultured mammalian cells, Nature. 2001; 411: 494–498. PubMed:
  3. Ginn SL, Alexander IE, Edelstein ML, Abedi MR, Wixon J. Gene therapy clinical trials worldwide to 2012—an update. J Gene Med. 2013; 15: 65–77. PubMed:
  4. Thi EP, Mire CE, Ursic-Bedoya R, Geisbert JB, Lee ACH, et al. Marburg virus infection in nonhuman primates: therapeutic treatment by lipid-encapsulated siRNA. Sci Transl Med. 2014; 6: 250ra116. PubMed:
  5. Kaiser PK, Symons RC, Shah SM, Quinlan EJ, Tabandeh H, et al. RNAi-based treatment for neovascular age-related macular degeneration by Sirna-027. Am J Ophthalmol. 2010; 150: 33–39. PubMed:
  6. O’Connell RM, Rao DS, Chaudhuri AA, Baltimore D. Physiological and pathological roles for microRNAs in the immune system. Nat Rev Immunol. 2010; 10: 111–122. PubMed:
  7. van Rooij E, Olson EN. MicroRNA therapeutics for cardiovascular disease: opportunities and obstacles. Nat Rev Drug Discov. 2012; 11: 860–872. PubMed:
  8. Coelho T, Adams D, Silva A, Lozeron P, Hawkins PN, et al. Safety and efficacy of RNAi therapy for transthyretin amyloidosis. N Engl J Med. 2013; 369: 819–829. PubMed:
  9. Davis ME, Zuckerman JE, Choi CH, Seligson D, Tolcher A, et al. Evidence of RNAi in humans from systemically administered siRNA via targeted nanoparticles. Nature. 2010; 464: 1067–1070. PubMed:
  10. Shen H, Sun T, Ferrari M. Nanovector delivery of siRNA for cancer therapy. Cancer Gene Ther. 2012; 19: 367–373. PubMed:
  11. Tabernero J, Shapiro GI, LoRusso PM, Cervantes A, Schwartz GK, et al. First-in-humans trial of an RNA interference therapeutic targeting VEGF and KSP in cancer patients with liver involvement. Cancer Discov. 2013; 3: 406–417. PubMed:
  12. Alexis F, Pridgen E, Molnar LK, Farokhzad OC. Factors affecting the clearance and biodistribution of polymeric nanoparticles. Mol Pharm. 2008; 5: 505–515. PubMed:
  13. Whitehead KA, Langer R, Anderson DG. Knocking down barriers: advances in siRNA delivery. Nat Rev Drug Discov. 2010; 8: 129–138. PubMed:
  14. Li W, Szoka FC, Jr. Lipid-based nanoparticles for nucleic acid delivery. Pharm Res. 2007; 24: 438–449. PubMed:
  15. Mintzer MA, Simanek EE. Nonviral vectors for gene delivery. Chem Rev. 2009; 109: 259–302. PubMed:
  16. Zumbuehl AA, Goldberg M, Leshchiner ES, Busini V, Hossain N, et al. A combinatorial library of lipid-like materials for delivery of RNAi therapeutics. Nat Biotechnol. 2008; 26: 561–569. PubMed:
  17. Semple SC, Akinc A, Chen J, Sandhu AP, Mui BL, et al. Rational design of cationic lipids for siRNA delivery. Nat Biotechnol. 2010; 28: 172–176. PubMed:
  18. Lee CC, MacKay JA, Frechet JM, Szoka FC. Designing dendrimers for biological applications. Nat Biotechnol. 2005; 23: 1517–1526. PubMed:
  19. Pack DW, Hoffman AS, Pun S, Stayton PS. Design and development of polymers for gene delivery. Nat Rev Drug Discov. 2005; 4: 581–593. PubMed:
  20. Thomas M, Klibanov AM. Non-viral gene therapy: polycation-mediated DNA delivery. Appl Microbiol Biotechnol. 2003; 62: 27–34. PubMed:
  21. Mo RH, Zaro JL, Shen WC. Comparison of cationic and amphipathic cell penetrating peptides for siRNA delivery and efficacy. Mol Pharm. 2012; 9: 299–309. PubMed:
  22. Martin ME, Rice KG. Peptide-guided gene delivery. AAPS J. 2007; 9: E18–E29. PubMed:
  23. Dassie JP, Liu XY, Thomas GS, Whitaker RM, Thiel KW, et al, Systemic administration of optimized aptamer-siRNA chimeras promotes regression of PSMAexpressing tumors. Nat Biotechnol. 2009; 27: 839–849. PubMed:
  24. Yao YD, Sun TM, Huang SY, Dou S, Lin L, et al. Targeted delivery of PLK1-siRNA by ScFv suppresses Her2+ breast cancer growth and metastasis. Sci Transl Med. 2012; 4: 130ra148. PubMed:
  25. Choi KY, Silvestre OF, Huang X, Hida N, Liu G, et al. A nanoparticle formula for delivering siRNA or miRNAs to tumor cells in cell culture and in vivo. Nat Protoc. 2014; 9: 1900–1915. PubMed:
  26. Choi KY, Silvestre OF, Huang X, Min KH, Howard GP, et al. Versatile RNA interference nanoplatform for systemic delivery of RNAs. ACS Nano. 2014; 8: 4559–4570. PubMed:
  27. Liu G, Choi KY, Bhirde A, Swierczewska M, Yin J, et al. Sticky nanoparticles: a platform for siRNA delivery by a bis(zinc(II) dipicoly-lamine)-functionalized, self-assembled nanoconjugate. Angew Chem Int. 2012; 51: 445–449. PubMed:
  28. Sokolova V, Epple M. Inorganic nanoparticles as carriers of nucleic acids into cells. Angew Chem Int. Ed Engl. 2008; 47: 1382–1395. PubMed:
  29. Afonin KA, Viard M, Koyfman AY, Martins AN, Kasprzak WK, et al. Multifunctional RNA nanoparticles. Nano Lett. 2014; 14: 5662–5671. PubMed:
  30. Cui DX, Zhang CL, Liu B, Shu Y, Du T, et al. Regression of gastric cancer by systemic injection of RNA nanoparticles carrying both ligand and siRNA. Sci Rep. 2015; 5: e10726. PubMed:
  31. Lee H, Lytton-Jean AKR, Chen Y, Love KT, Park AI, et al. Molecularly self-assembled nucleic acid nanoparticles for targeted in vivo siRNA delivery. Nat Nanotechnol. 2012; 7: 389–393. PubMed:
  32. Rychahou P, Haque F, Shu Y, Zaytseva Y, Weiss HL, et al. Delivery of RNA nanoparticles into colorectal cancer metastases following systemic administration. ACS Nano. 2015; 9: 1108–1116. PubMed:
  33. Shu D, Li H, Shu Y, Xiong G, Carson WE, 3rd, et al. Systemic delivery of anti-miRNA for suppression of triple negative breast cancer utilizing RNA nanotechnology. ACS Nano. 2015; 9: 9731–9740. PubMed:
  34. Haussecker D. Current issues of RNAi therapeutics delivery and development. J Control Release. 2014; 195: 49–54. PubMed:
  35. Wang J, Lu Z, Wientjes MG, Au JLS. Delivery of siRNA therapeutics: barriers and carriers. AAPS J. 2010; 12: 492–503. PubMed:
  36. Hornung V, Guenthner-Biller M, Bourquin C, Ablasser A, Schlee M, et al. Sequence-specific potent induction of IFN-alpha by short interfering RNA in plasmacytoid dendritic cells through TLR7. Nat Med. 2005; 11: 263–270. PubMed:
  37. Judge AD, Sood V, Shaw JR, Fang D, McClintock K, et al. Sequencedependent stimulation of the mammalian innate immune response by synthetic siRNA. Nat Biotechnol. 2005; 23: 457–462. PubMed:
  38. Jackson AL, Burchard J, Schelter J, Chau BN, Cleary M, et al. Widespread siRNA “off-target” transcript silencing mediated by seed region sequence complementarity. RNA. 2006; 12: 1179–1187. PubMed:
  39. Hong H, Zhang Y, Cai WB. In vivo imaging of RNA Interference. J Nucl Med. 2010; 51: 169–172. PubMed:
  40. Willmann JK, van Bruggen N, Dinkelborg LM, Gambhir SS. Molecular imaging in drug development. Nat Rev Drug Discov. 2008; 7: 591–607. PubMed:
  41. Wu SY, Lopez-Berestein G, Calin GA, Sood AK. RNAi therapies: drugging the undruggable. Sci Transl Med. 2014; 6: 240–247. PubMed:
  42. Contag CH, Bachmann MH. Advances in in vivo bioluminescence imaging of gene expression. Annu Rev Biomed Eng. 2002; 4: 235–260. PubMed:
  43. Wang F, Song X, Li X, Xin J, Wang S, et al. Noninvasive visualization of microRNA-16 in the chemoresistance of gastric cancer using a dual reporter gene imaging system. PLoS ONE. 2013; 8: e61792. PubMed:
  44. Huang X, Lee S, Chen X. Design of “smart” probes for optical imaging of apoptosis. Am J Nucl Med Mol Imaging. 2011; 1: 3–17. PubMed:
  45. Sosnovik DE, Weissleder R. Emerging concepts in molecular MRI. Curr Opin Biotechnol. 2007; 18: 4–10. PubMed:
  46. Alauddin MM. Positron emission tomography (PET) imagingwith (18)F-based radiotracers. Am J Nucl Med Mol Imaging. 2012; 2: 55–76. PubMed:
  47. Bhargava P, He G, Samarghandi A, Delpassand ES. Pictorial review of SPECT/CT imaging applications in clinical nuclear medicine. Am J Nucl Med Mol Imaging. 2012; 2: 221–231. PubMed:
  48. Dayton PA, Rychak JJ. Molecular ultrasound imaging using microbubble contrast agents. Front Biosci. 2007; 12: 5124–5142. PubMed:
  49. Pai SI, Lin YY, Macaes B, Meneshian A, Hung CF, et al. Prospects of RNA interference therapy for cancer. Gene Ther. 2006; 13: 464–477. PubMed:  
  50. Rao DD, Wang ZH, Senzer N, Nemunaitis J. RNA Interference and personalized cancer therapy. Discov Med. 2013; 81: 101–110. PubMed:
  51. M.D.A.C. Center. EphA2 Gene Targeting Using Neutral Liposomal Small Interfering RNA Delivery (IND# 72924): A Phase I Clinical Trial.   
  52. C.C.C.o.W.F. University, A Phase 1, Open-Label, Dose-Ranging Study to Assess the Safety and Immunologic Activity of APN401.
  53. Pruitt S. Phase I Study of Active Immunotherapy of Metastatic Melanoma with Mature Autologous Dendritic Cells Transfected with Tumor Antigen RNA and Small Inhibitory RNAs to Alter Proteasomal Antigen Processing.
  54. S.T. GmbH, A Prospective, Open-label, Single Center, Dose Finding Phase I-Study with Atu027 (an siRNA Formulation) in Subjects with Advanced Solid Cancer.
  55. S. Ltd, Phase I—Escalating Dose Study of siG12D LODER (Local Drug EluteR) in Patients With Locally Advanced Adenocarcinoma of the Pancreas, and a Single Dose Study of siG12D LODER (Local Drug EluteR) in PatientsWith Non-operable Adenocarcinoma of the Pancreas.
  56. N.C.I. (NCI), A Phase 1 Dose Escalation Study of Hepatic Intra-Arterial Administration of TKM 080301 (Lipid Nanoparticles Containing siRNA Against the PLK1 Gene Product) in Patients with Colorectal, Pancreas, Gastric, Breast, Ovarian and Esophageal Cancers with Hepatic.
  57. N.D. Corporation, A Phase 1b/2, Open Label, Randomized, Repeat Dose, Dose Escalation Study to Evaluate the Safety, Tolerability, Biological Activity, and Pharmacokinetics of ND-L02-s0201 Injection, a Vitamin A-coupled Lipid Nanoparticle Containing siRNA Against HSP47, in Subjects with Moderate to Extensive Hepatic Fibrosis (METAVIR F3-4).
  58. Dicerna Pharmaceuticals, Phase I,Multicenter, Cohort Dose Escalation Trial to Determine the Safety, Tolerance, and Maximum Tolerated Dose of DCR-MYC, a Lipid Nanoparticle (LNP)-Formulated Small Inhibitory RNA (siRNA) Oligonucleotide Targeting MYC, in Patients with Refractory Locally Advanced or Metastatic Solid Tumor Malignancies, Multiple Myeloma, or Lymphoma.
  59. C. Pharmaceuticals, A Phase I, Dose-Escalating Study of the Safety of Intravenous CALAA-01 in Adults with Solid Tumors Refractory to Standard-of-Care Therapies.
  60. T.P. Corporation, A Phase 1/2 Dose Escalation Study to Determine the Safety, Pharmacokinetics, and Pharmacodynamics of Intravenous TKM-080301 in Patients with Advanced Solid Tumors.
  61. Pharmaceuticals, A Multi-Center, Open Label, Phase 1 Dose-Escalation Trial to Evaluate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Intravenous ALN-VSP02 in Patients with Advanced Solid Tumors with Liver Involvement.
  62. Pharmaceuticals, A Multi-center, Open-Label, Extension Study of ALN-VSP02 in Cancer Patients Who Have Responded to ALN-VSP02 Treatment.
  63. Aleku SM, Schulz P, Keil O, Santel A, Schaeper U, et al. Atu027, a liposomal small interfering RNA formulation targeting protein kinase N3, inhibits cancer progression. Cancer Res. 2008; 68: 9788–9798. PubMed:
  64. Aleku SM, Roder N, Mopert K, Durieux B, Janke O, et al. Atu027 prevents pulmonary metastasis in experimental and spontaneous mouse metastasis models. Clin Cancer Res. 2010; 16: 5469–5480. PubMed:
  65. Leenders F, Mopert K, Schmiedeknecht A, Santel A, Czauderna F, et al. PKN3 is required formalignant prostate cell growth downstream of activated PI 3-kinase. EMBO J. 2004; 23: 3303–3313. PubMed:
  66. Strumberg D, Schultheis B, Traugott U, Vank C, Santel A, et al. Phase I clinical development of Atu027, a siRNA formulation targeting PKN3 in patients with advanced solid tumors. Int J Clin Pharmacol Ther. 2012; 50: 76–78. PubMed:
  67. Schultheis B, Strumberg D, Santel A, Vank C, Gebhardt F, et al. First-in-human phase I study of the liposomal RNA Interference therapeutic Atu027 in patients with advanced solid tumors. J Clin Oncol. 2014; 32: 4141–4148. PubMed:
  68. Blangy A, Lane HA, d’Herin P, Harper M, Kress M, et al. Phosphorylation by p34cdc2 regulates spindle association of human Eg5, a kinesin-related motor essential for bipolar spindle formation in vivo. Cell. 1995; 83: 1159–1169. PubMed:
  69. Itakura J, Ishiwata T, Shen B, Kornmann M, Korc M. Concomitant overexpression of vascular endothelial growth factor and its receptors in pancreatic cancer. Int J Cancer. 2000; 85: 27–34. PubMed:
  70. Boocock CA, Charnockjones DS, Sharkey AM, Mclaren J, Barker PJ, et al. Expression of vascular endothelial growth-factor and its receptors Flt and Kdr in ovarian-carcinoma. J Natl Cancer Inst. 1995; 87: 506–516. PubMed:
  71. Ferrara N, Gerber HP, LeCouter J. The biology of VEGF and its receptors. Nat Med. 2003; 9: 669–676. PubMed:
  72. Duxbury MS, Ito H, Zinner MJ, Ashley SW, Whang EE. RNA interference targeting the M2 subunit of ribonucleotide reductase enhances pancreatic adenocarcinoma chemosensitivity to gemcitabine, Oncogene. 2004; 23: 1539–1548. PubMed:
  73. Wang YX, Ng CK. The impact of quantitative imaging in medicine and surgery: charting our course for the future. Quant Imaging Med Surg. 2011; 1: 1–3. PubMed:
  74. Tracy Zimmermann VK, Harrop J, Chan A, Chiesa J, Peters G, et al. Phase I First-in-Human Trial of ALN-TTRsc, a Novel RNA Interference Therapeutic for the Treatment of Familial Amyloidotic Cardiomyopathy (FAC).
  75. Buyens K, De Smedt SC, Braeckmans K, Demeester J, Peeters L, et al. Liposome based systems for systemic siRNA delivery: stability in blood sets the requirements for optimal carrier design. J Control Release. 2012; 158: 362–370. PubMed:
  76. Kanasty R, Dorkin JR, Vegas A, Anderson D. Delivery materials for siRNA therapeutics. Nat Mater. 2013; 12: 967–977.
  77. Oh YK, Park TG. siRNA delivery systems for cancer treatment. Adv Drug Deliv Rev. 2009; 61: 850–862. PubMed:
  78. Yin H, Kanasty RL, Eltoukhy AA, Vegas AJ, Dorkin JR, et al. Non-viral vectors for gene-based therapy. Nat Rev Genet. 2014; 15: 541–555. PubMed:
  79. Zhang P, Chen Y, Zeng Y, Shen C, Li R, et al. Virus-mimetic nanovesicles as a versatile antigen-delivery system. Proc Natl Acad Sci. U S A. 2015; 112: E6129–E6138. PubMed:
  80. Kobayashi H, Watanabe R, Choyke PL. Improving conventional enhanced permeability and retention (EPR) effects; what Is the appropriate Target? Theranostics. 2014; 4: 81–89. PubMed:
  81. Matsumura Y, Maeda H, A new concept for macromolecular therapeutics in cancer- chemotherapy—mechanism of tumoritropic accumulation of proteins and the antitumor agent Smancs. Cancer Res. 1996; 46: 6387–6392. PubMed:
  82. Moghimi SM, Hunter AC, Murray JC. Long-circulating and target-specific nanoparticles: theory to practice. Pharmacol Rev. 2001; 53: 283–318. PubMed:
  83. Cho KJ, Wang X, Nie SM, Chen Z, Shin DM. Therapeutic nanoparticles for drug delivery in cancer. Clin Cancer Res. 2008; 14: 1310–1316. PubMed:
  84. van Vlerken LE, Vyas TK, Amiji MM. Poly(ethylene glycol)-modified nanocarriers for tumor-targeted and intracellular delivery. Pharm Res. 2007; 24: 1405–1414. PubMed:
  85. Maclachlan I, Cullis P. Diffusible-PEG-lipid stabilized plasmid lipid particles. Adv Genet. 2005; 157: 188 53pa. PubMed:
  86. Vaupel P, Kallinowski F, Okunieff P. Blood-flow, oxygen and nutrient supply, and metabolic microenvironment of human-tumors—a review. Cancer Res. 1989; 49: 6449–6465. PubMed:
  87. Li L, Wang R, Wilcox D, Zhao X, Song J, et al. Tumor vasculature is a key determinant for the efficiency of nanoparticlemediated siRNA delivery. Gene Ther. 2012; 19: 775–780. PubMed:
  88. Huang K, Ma H, Liu J, Huo S, Kumar A, et al. Size-dependent localization and penetration of ultrasmall gold nanoparticles in cancer cells, multicellular spheroids, and tumors in vivo. ACS Nano. 2012; 6: 4483–4493.                         PubMed:
  89. Cunha L, Szigeti K, Mathe D, Metello LF. The role ofmolecular imaging inmodern drug development. Drug Discov Today. 2014; 19: 936–948. PubMed:
  90. Meade BR, Dowdy SF. Exogenous siRNA delivery using peptide transduction domains/ cell penetrating peptides. Adv Drug Deliv Rev. 2007; 59: 134–140. PubMed:
  91. Rozema DB, Lewis DL, Wakefield DH, Wong SC, Klein JJ, et al. Dynamic polyconjugates for targeted in vivo delivery of siRNA to hepatocytes. Proc Natl Acad Sci. U S A. 2007; 104: 12982–12987. PubMed:
  92. Cardoso AL, Simoes S, de Almeida LP, Pelisek J, Culmsee C, et al. siRNA delivery by a transferrin-associated lipid-based vector: a non-viral strategy to mediate gene silencing. J Gene Med. 2007; 9: 170–183. PubMed:
  93. Chu TC, Twu KY, Ellington AD, Levy M. Aptamer mediated siRNA delivery. Nucleic Acids Res. 2006; 34: e73 PubMed:
  94. Lorenzer C, Dirin M, Winkler AM, Baumann V, Winkler J. Going beyond the liver: progress and challenges of targeted delivery of siRNA therapeutics. J Control Release. 2015; 203: 1–15. PubMed:
  95. Gruenberg J, van der Goot FG. Mechanisms of pathogen entry through the endosomal compartments. Nat Rev Mol Cell Biol. 2006; 7: 495–504. PubMed:
  96. Sonawane ND, Szoka FC, Jr., Verkman AS. Chloride accumulation and swelling in endosomes enhances DNA transfer by polyamine-DNA polyplexes. J Biol Chem. 2003; 278: 44826–44831. PubMed:
  97. Boussif O, Lezoualc’h F, Zanta MA, Mergny MD, Scherman D, et al. A versatile vector for gene and oligonucleotide transfer into cells in culture and in vivo: polyethylenimine. Proc Natl Acad Sci. U S A. 1995; 92: 7297–7301. PubMed:
  98. Qiu S, Adema CM, Lane T. A computational study of off-target effects of RNA interference. Nucleic Acids Res. 2005; 33: 1834–1847. PubMed:
  99. Goodchild A, Nopper N, King A, Doan T, Tanudji M, et al. Sequence determinants of innate immune activation by short interfering RNAs. BMC Immunol. 2009; 10: 40. PubMed:
  100. Judge AD, Sood V, Shaw JR, Fang D, McClintock K, et al. Sequence dependent stimulation of the mammalian innate immune response by synthetic siRNA. Nat Biotechnol. 2005; 23: 457–462. PubMed:
  101. Sioud M. Does the understanding of immune activation by RNA predict the design of safe siRNAs? Front Biosci. 2008; 13: 4379–4392. PubMed:
  102. Sevick-Muraca EM, Houston JP, Gurfinkel M. Fluorescence-enhanced, near infrared diagnostic imaging with contrast agents. Curr Opin Chem Biol. 2002; 6: 642–650. PubMed:
  103. Frangioni JV. In vivo near-infrared fluorescence imaging. Curr Opin Chem Biol. 2003; 7: 626–634. PubMed:
  104. Zanzonico P. Noninvasive imaging for supporting basic research, Small Animal Imaging: Basics and Practical Guide. 2011; 3–16.
  105. Leblond F, Davis SC, Valdés PA, Pogue BW. Pre-clinical whole-body fluorescence imaging: review of instruments, methods and applications. J Photochem Photobiol. 2010; 98: 77–94. PubMed:
  106. Guo Z, Park S, Yoon J, Shin I. Recent progress in the development of near-infrared fluorescent probes for bioimaging applications. Chem Soc Rev. 2014; 43: 16–29.
  107. Kim SH, Jeong JH, Lee SH, Kim SW, Park TG. Local and systemic delivery of VEGF siRNA using polyelectrolyte complex micelles for effective treatment of cancer. J Control Release. 2008; 129: 107–116. PubMed:
  108. Gilleron J, Querbes W, Zeigerer A, Borodovsky A, Marsico G, et al. Image-based analysis of lipid nanoparticle-mediated siRNA delivery, intracellular trafficking and endosomal escape. Nat Biotechnol. 2013; 31: 638–646. PubMed:
  109. Chang E, Zhu MQ, Drezek R. Novel siRNA-based molecular beacons for dual imaging and therapy. Biotechnol J. 2007; 2: 422–425. PubMed:
  110. Christie RJ, Matsumoto Y, Miyata K, Nomoto T, Fukushima S, et al. Targeted polymeric micelles for siRNA treatment of experimental cancer by intravenous injection. ACS Nano. 2012; 6: 5174–5189. PubMed:
  111. Christie RJ, Miyata K, Matsumoto Y, Nomoto T, Menasco D, et al. Effect of polymer structure on micelles formed between siRNA and cationic block copolymer comprising thiols and amidines. Biomacromolecules. 2011; 12: 3174–3185.  PubMed:
  112. Oe Y, Christie RJ, Naito M, Low SA, Fukushima S, et al. Actively-targeted polyion complex micelles stabilized by cholesterol and disulfide cross-linking for systemic delivery of siRNA to solid tumors. Biomaterials. 2014; 35: 7887–7895. PubMed:
  113. Chen AA, Derfus AM, Khetani SR, Bhatia SN. Quantum dots tomonitor RNAi delivery and improve gene silencing. Nucleic Acids Res. 2005; 33: e190. PubMed:
  114. Wang J, Zhang P, Huang C, Liu G, Leung KC, et al. High performance photoluminescent carbon dots for In Vitro and In vivo bioimaging: effect of nitrogen doping ratios. Langmuir. 2015; 31: 8063–8073. PubMed:
  115. Jiang S, Zhang Y, Lim KM, Sim EKW, Ye L. NIR-to-visible upconversion nanoparticles for fluorescent labeling and targeted delivery of siRNA. Nanotechnology. 2009; 20: e155101. PubMed:
  116. Jung J, Solanki A, Memoli KA, Kamei K, Kim H, et al. Selective inhibition of human brain tumor cells through multifunctional quantum-dot-based siRNA delivery. Angew Chem Int Ed. 2010; 49: 103–107. PubMed:
  117. Wang J, Liu G, Leung KC, Loffroy R, Lu PX, et al. Opportunities and challenges of fluorescent carbon dots in translational optical imaging. Curr Pharm Des. 2015; 21: 5401–5416. PubMed:
  118. Wang L, Wang X, Bhirde A, Cao J, Zeng Y, et al. Carbon- dot-based two-photon visible nanocarriers for safe and highly efficient delivery of siRNA and DNA. Adv Health Mater. 2014; 3: 1203–1209. PubMed:
  119. Chatterjee DK, Gnanasammandhan Y, Fau-Zhang MK, Zhang Y. Small upconverting fluorescent nanoparticles for biomedical applications. Small. 2010; 6: 2781–2795. PubMed:
  120. Wang L, Liu J, Dai Y, Yang Q, Zhang Y, et al. Efficient gene delivery and multimodal imaging by lanthanide-based upconversion nanoparticles. Langmuir. 2014; 30: 13042–13051. PubMed:
  121. Nayak TR, Krasteva LK, Cai W. Multimodality imaging of RNA Interference. Curr Med Chem. 2013; 20: 3664–3675. PubMed:
  122. McCaffrey AP, Meuse L, Pham TT, Conklin DS, Hannon GJ, et al. RNA interference in adult mice. Nature. 2002; 418: 38–39. PubMed:
  123. Lewis DL, Hagstrom JE, Loomis AG, Wolff JA, Herweijer H. Efficient delivery of siRNA for inhibition of gene expression in postnatal mice. Nat Genet. 2002; 32: 107–108. PubMed:
  124. Pichler A, Zelcer N, Prior JL, Kuil AJ, Piwnica-Worms D. In vivo RNA interference-mediated ablation of MDR1 P-glycoprotein. Clin Cancer Res. 2005; 11: 4487–4494. PubMed:
  125. Pittella F, Cabral H, Maeda Y, Mi P, Watanabe S, et al. Systemic siRNA delivery to a spontaneous pancreatic tumor model in transgenic mice by PEGylated calcium phosphate hybrid micelles. J Control Release. 2014; 178: 18–24. PubMed:
  126. Bartlett DW, Davis ME. Insights into the kinetics of siRNA-mediated gene silencing from live-cell and live-animal bioluminescent imaging. Nucleic Acids Res. 2006; 34: 322–333. PubMed:
  127. Kim SH, Mok H, Jeong JH, Kim SW, Park TG. Comparative evaluation of targetspecific GFP gene silencing efficiencies for antisense ODN, synthetic siRNA, and siRNA plasmid complexed with PEI-PEG-FOL conjugate. Bioconjug Chem. 2006; 17: 241–244. PubMed:
  128. Huschka R, Barhoumi A, Liu Q, Roth JA, Ji L, et al. Gene silencing by gold nanoshell-mediated delivery and laser-triggered release of antisense oligonucleotide and siRNA. ACS Nano. 2012; 6: 7681–7691. PubMed:
  129. James ML, Gambhir SS. A molecular imaging primer: modalities, imaging agents, and applications. Physiol Rev. 2012; 92: 897–965. PubMed:
  130. Phelps ME. Positron emission tomography provides molecular imaging of biological processes. Proc Natl Acad Sci U S A. 2000; 97: 9226–9233. PubMed:
  131. Ziegler SI. Positron emission tomography: principles, technology, and recent developments. Nucl Phys A. 2005; 752: 679c–687c.
  132. Lammers T, Aime S, Hennink WE, Storm G, Kiessling F. Theranostic nanomedicine. Acc Chem Res. 2011; 44: 1029–1038. PubMed:
  133. Lu W, Zhang G, Zhang R, Flores LG,2nd, Huang Q, et al. Tumor sitespecific silencing of NF-kappaB p65 by targeted hollow gold nanosphere-mediated photothermal transfection. Cancer Res. 2010; 70: 3177–3188. PubMed:
  134. Nayak TR, Krasteva LK, Cai W. Multimodality imaging of RNA interference. Curr Med Chem. 2013; 20: 3664–3675. PubMed:
  135. Hatanaka K, Asai T, Koide H, Kenjo E, Tsuzuku T, et al. Development of double-stranded siRNA labeling method using positron emitter and its in vivo trafficking analyzed by positron emission tomography. Bioconjug Chem. 2010; 21: 756–763.
  136. Lu FM, Yuan Z. PET/SPECT molecular imaging in clinical neuroscience: recent advances in the investigation of CNS diseases. Quant Imaging Med Surg. 2015; 5: 433–447. PubMed:
  137. Liu N, Ding H, Vanderheyden JL, Zhu Z, Zhang Y. Radiolabeling small RNA with technetium-99 m for visualizing cellular delivery and mouse biodistribution. Nucl Med Biol. 2007; 34: 399–404. PubMed:
  138. Merkel OM, Librizzi D, Pfestroff A, Schurrat T, Behe M, et al. In vivo SPECT and real-time gamma camera imaging of biodistribution and pharmacokinetics of siRNA delivery using an optimized radiolabeling and purification procedure. Bioconjug Chem. 2009; 20: 174–182. PubMed:
  139. Faulkner W. Basic Principles of MRIOutSource 1996.
  140. Wang YX. Super paramagnetic iron oxide based MRI contrast agents: current status of clinical application. Quant Imaging Med Surg. 2011; 1: 35–40. PubMed:
  141. Mok H, Veiseh O, Fang C, Kievit FM, Wang FY, et al. pH-sensitive siRNA nanovector for targeted gene silencing and cytotoxic effect in cancer cells. Mol Pharm. 2010; 7: 1930–1939. PubMed:
  142. Shen M, Gong F, Pang P, Zhu K, Meng X, et al. An MRI-visible non-viral vector for targeted Bcl-2 siRNA delivery to neuroblastoma. Int J Nanomed. 2012; 7: 3319–3332. PubMed:
  143. Li C, Penet MF, Wildes F, Takagi T, Chen ZH, et al. Nanoplex delivery of siRNA and prodrug enzyme for multimodality image-guided molecular pathway targeted cancer therapy. ACS Nano. 2010; 4: 6707–6716.  PubMed:
  144. Bae KH, Lee K, Kim C, Park TG. Surface functionalized hollow manganese oxide nanoparticles for cancer targeted siRNA delivery and magnetic resonance imaging. Biomaterials. 2011; 32: 176–184. PubMed:
  145. Zhou Z, Huang D, Bao J, Chen Q, Liu G, et al. A synergistically enhanced T(1)–T(2) dual-modal contrast agent. Adv Mater. 2012; 24: 6223–6228. PubMed:
  146. Wang X, Zhou Z, Wang Z, Xue Y, Zeng Y, et al. Gadolinium embedded iron oxide nanoclusters as T1–T2 dual-modal MRI-visible vectors for safe and efficient siRNA delivery. Nanoscale. 2013; 5: 8098–8104. PubMed:
  147. Liang HD, Blomley MJK. The role of ultrasound inmolecular imaging. Br J Radiol. 2003; 76: S140–S150. PubMed:
  148. Shim MS, Kwon YJ. Stimuli-responsive polymers and nanomaterials for gene delivery and imaging applications. Adv Drug Deliv Rev. 2012; 64: 1046–1059. PubMed:
  149. Unger, Porter T, Lindner J, Grayburn P. Cardiovascular drug delivery with ultrasound and microbubbles. Adv Drug Deliv Rev. 2014; 72: 110–126. PubMed:
  150. Martin KH, Dayton PA. Current status and prospects for microbubbles in ultrasound theranostics, Wiley Interdiscip. Rev Nanomed Nanobiotechnol. 2013; 5: 329–345. PubMed:
  151. Florinas S, Kim J, Nam K, Janat-Amsbury MM, Kim SW. Ultrasound-assisted siRNA delivery via arginine-grafted bioreducible polymer and microbubbles targeting VEGF for ovarian cancer treatment. J Control Release. 183: 1–8. PubMed:
  152. Vandenbroucke RE, Lentacker I, Demeester J, De Smedt SC, et al. Ultrasound assisted siRNA delivery using PEG-siPlex loaded microbubbles. J Control Release. 2008; 126: 265–273. PubMed:
  153. Liu Y, Miyoshi H, Nakamura M. Encapsulated ultrasound microbubbles: therapeutic application in drug/gene delivery. J Control Release. 2006; 114: 89–99. PubMed:
  154. Chen CC, Sheeran PS, Wu SY, Olumolade OO, Dayton PA, et al. Targeted drug delivery with focused ultrasound-induced blood–brain barrier opening using acoustically-activated nanodroplets. J Control Release. 2013; 172: 795–804. PubMed:
  155. Cheng X, Li H, Chen Y, Luo B, Liu X, et al. Ultrasound-triggered phase transition sensitive magnetic fluorescent nanodroplets as a multimodal imaging contrast agent in rat and mouse model. PLoS ONE. 2013; 8: e85003. PubMed:
  156. Dayton PA, Zhao S, Bloch SH, Schumann P, Penrose K, et al. Application of ultrasound to selectively localize nanodroplets for targeted imaging and therapy. Mol Imaging. 2006; 5: 160–174. PubMed:
  157. Jian J, Liu C, Gong Y, Su L, Zhang B, et al. India ink incorporated multifunctional phase-transition nanodroplets for photoacoustic/ultrasound dual-modality imaging and photoacoustic effect based tumor therapy. Theranostics. 2014; 4: 1026–1038. PubMed:
  158. Horie S, Watanabe Y, Ono M, Mori S, Kodama T. Evaluation of antitumor effects following tumor necrosis factor-alpha gene delivery using nanobubbles and ultrasound. Cancer Sci. 2011; 102: 2082–2089. PubMed:
  159. Wang CH, Huang YF, Yeh CK. Aptamer-conjugated nanobubbles for targeted ultrasound molecular imaging. Langmuir. 2011; 27: 6971–6976. PubMed:
  160. Yin T, Wang P, Li J, Wang Y, Zheng B, et al. Tumorpenetrating codelivery of siRNA and paclitaxel with ultrasound-responsive nanobubbles hetero-assembled from polymeric micelles and liposomes. Biomaterials. 2014; 35: 5932–5943. PubMed:
  161. Chen Z, Liang K, Liu J, Xie M, Wang X, et al. Enhancement of survivin gene downregulation and cell apoptosis by a novel combination: liposome microbubbles and ultrasound exposure. Med Oncol. 2009; 26: 491–500. PubMed:
  162. Castle J, Butts M, Healey A, Kent K, Marino M, et al.Ultrasoundmediated targeted drug delivery: recent success and remaining challenges. Am J Physiol Heart Circ Physiol. 2013; 304: H350–H357. PubMed:
  163. Kaneko OF, Willmann JK. Ultrasound for molecular imaging and therapy in cancer. Quant Imaging Med Surg. 2012; 2: 87–97. PubMed:
  164. Son S, Min HS, You DG, Kim BS, Kwon IC. Echogenic nanoparticles for ultrasound technologies: evolution from diagnostic imaging modality to multimodal theranostic agent. Nano Today. 2012; 9: 525–540. PubMed:
  165. Sboros V. Response of contrast agents to ultrasound. Adv Drug Deliv Rev. 2008; 60: 1117–1136. PubMed:
  166. Carson AR, McTiernan CF, Lavery L, Grata M, Leng X, et al. Ultrasound-targeted microbubble destruction to deliver siRNA cancer therapy. Cancer Res. 2012; 72: 6191–6199. PubMed:
  167. Zhou QL, Chen ZY, Wang YX, Yang F, Lin Y, et al. Ultrasound-mediated local drug and gene delivery using nanocarriers. Biomed Res Int. 2014; e963891. PubMed:
  168. Yin T, Wang P, Li J, Zheng R, Zheng B, et al. Ultrasoundsensitive siRNA-loaded nanobubbles formed by hetero-assembly of polymeric micelles and liposomes and their therapeutic effect in gliomas. Biomaterials. 2013; 34: 4532–4543. PubMed:
  169. Lee DE, Koo H, Sun IC, Ryu TH, Kim K, et al. Multifunctional nanoparticles for multimodal imaging and theragnosis. Chem Soc Rev. 2012; 41: 2656–2672. PubMed:
  170. Choi HS, Frangioni JV. Nanoparticles for biomedical imaging: fundamentals of clinical translation. Mol Imaging. 2010; 9: 291–310. PubMed:
  171. Louie AY. Multimodality imaging probes: design and challenges. Chem Rev. 2010; 110: 3146–3195. PubMed:
  172. Boerman OC, Oyen WJG. Multimodality probes: amphibian cars for molecular imaging. J Nucl Med. 2008; 49: 1213–1214. PubMed:
  173. Idee JM, Louguet S, Ballet S, Corot C0 Theranostics and contrast-agents for medical imaging: a pharmaceutical company viewpoint. Quant Imaging Med Surg. 2013; 3: 292–297. PubMed:
  174. Wang YX. Physical scientists research biomedicine: a call for caution. Chin J Cancer Res. 2015; 27: 94–95. PubMed:
  175. Medarova Z, Pham W, Farrar C, Petkova V, Moore A. In vivo imaging of siRNA delivery and silencing in tumors. Nat Med. 2007; 13: 372–377. PubMed:
  176. Mikhaylova M, Stasinopoulos I, Kato Y, Artemov D, Bhujwalla ZM, Imaging of cationic multifunctional liposome-mediated delivery of COX-2 siRNA. Cancer Gene Ther. 2009; 16: 217–226. PubMed:
  177. Bartlett DW, Su H, Hildebrandt IJ, Weber WA, Davis ME. Impact of tumorspecific targeting on the biodistribution and efficacy of siRNA nanoparticles measured by multimodality in vivo imaging. Proc Natl Acad Sci U S A. 2007; 104: 15549–15554. PubMed:
  178. Lammers T, Aime S, Hennink WE, Storm G, Kiessling F. Theranostic nanomedicine. Acc Chem Res. 2011; 44: 1029–1038. PubMed:
  179. Ma X, Zhao Y, Liang XJ, Theranostic nanoparticles engineered for clinic and pharmaceutics. Acc Chem Res. 2011; 44: 1114–1122. PubMed:
  180. Ryu JH, Koo H, Sun IC, Yuk SH, Choi K, et al. Tumor targeting multifunctional nanoparticles for theragnosis: new paradigm for cancer therapy. Adv Drug Deliv Rev. 2012; 64: 1447–1458. PubMed:
  181. Lee DE, Koo H, Sun IC, Ryu JH, Kim K, et al. Multifunctional nanoparticles for multimodal imaging and theragnosis. Chem Soc Rev. 2012; 41: 2656–2672. PubMed:
  182. Lee N, Choi SH, Hyeon T. Nano-sized CT contrast agents. Adv Mater. 2013; 25: 2641–2660.
  183. Hallouard F, Anton N, Choquet P, Constantinesco A, Vandamme T. Iodinated blood pool contrast media for preclinical X-ray imaging applications–a review. Biomaterials. 2010; 31: 6249–6268. PubMed:
  184. Liu Y, Ai K, Lu L. Nanoparticulate X-ray computed tomography contrast agents: from design validation to in vivo applications. Acc Chem Res. 2012; 45: 1817–1827.
  185. Lusic H, Grinstaff MW. X-ray-computed tomography contrast agents. Chem Rev. 2012; 113: 1641–1666. PubMed:
  186. Jin E, Lu ZR. Biodegradable iodinated polydisulfides as contrast agents for CT angiography. Biomaterials. 2014; 35: 5822–5829. PubMed:
  187. Choi KY, Liu G, Lee S, Chen X. Theranostic nanoplatforms for simultaneous cancer imaging and therapy: current approaches and future perspectives. Nanoscale. 2012; 4: 330–342. PubMed:
  188. Anton N, Vandamme TF. Nanotechnology for computed tomography: a real potential recently disclosed. Pharm Res. 2012; 31: 20–34. PubMed:
  189. Cormode DP, Naha PC, Fayad ZA. Nanoparticle contrast agents for computed tomography: a focus on micelles. Contrast Media Mol Imaging. 2014; 9: 37–52. PubMed:
  190. Li X, Anton N, Zuber G, Vandamme T. Contrast agents for preclinical targeted X-ray imaging. Adv Drug Deliv Rev. 2014; 76: 116–133. PubMed:
  191. Lee JY, Chung SJ, Cho HJ, Kim DD. Iodinated hyaluronic acid oligomer-based nanoassemblies for tumor-targeted drug delivery and cancer imaging. Biomaterials. 2016; 85: 218–231. PubMed:
  192. Deng H, Zhong Y, Du M, Liu Q, Fan Z, et al. Theranostic self-assembly structure of gold nanoparticles for NIR photothermal therapy and X-ray computed tomography imaging. Theranostics. 2014; 4: 904–918. PubMed:
  193. Zhu J, Zheng L, Wen S, Tang Y, Shen M, et al. Targeted cancer theranostics using alpha-tocopheryl succinate-conjugated multifunctional dendrimer-entrapped gold nanoparticles. Biom-aterials. 2014; 35: 7635–7646. PubMed:
  194. Jiang Y, Chen J, Deng C, Suuronen EJ, Zhong Z. Click hydrogels, microgels and nanogels: emerging platforms for drug delivery and tissue engineering. Biomaterials. 2011; 35: 4969–4985. PubMed:
  195. Kabanov AV, Vinogradov SV. Nanogels as pharmaceutical carriers: finite networks of infinite capabilities. Angew Chem Int Ed. 2009; 48: 5418–5429. PubMed:
  196. Zhang X, Malhotra S, Molina M, Haag R. Micro-and nanogels with labile crosslinksfrom synthesis to biomedical applications. Chem Soc Rev. 2015; 44: 1948–1973.
  197. Chen W, Achazi K, Schade B, Haag R. Charge-conversional and reduction-sensitive poly (vinyl alcohol) nanogels for enhanced cell uptake and efficient intracellular doxorubicin release. J Control Release. 2015; 205: 15–24. PubMed:
  198. Morimoto N, Hirano S, Takahashi H, Loethen S, Thompson DH, et al. Selfassembled pH-sensitive cholesteryl pullulan nanogel as a protein delivery vehicle. Biomacromolecules. 2013; 14: 56–63. PubMed:
  199. Jiang L, Zhou Q, Mu K, Xie H, Zhu Y, et al. pH/temperature sensitive magnetic nanogels conjugated with Cy5.5-labled lactoferrin for MR and fluorescence imaging of glioma in rats. Biomaterials. 2013; 34: 7418–7428. PubMed:
  200. Steinhilber D, Witting M, Zhang X, Staegemann M, Paulus F, et al. Surfactant free preparation of biodegradable dendritic polyglycerol nanogels by inverse nanoprecipitation for encapsulation and release of pharmaceutical biomacromolecules. J Control Release. 2013; 169: 289–295. PubMed:
  201. Yang H, Wang Q, Chen W, Zhao Y, Yong T, et al. Hydrophilicity/ hydrophobicity reversable and redox-sensitive nanogels for anticancer drug delivery. Mol Pharm. 2015; 12: 1636–1647. PubMed:
  202. Zhang X, Achazi K, Steinhilber D, Kratz F, Dernedde J, et al. A facile approach for dual-responsive prodrug nanogels based on dendritic polyglycerols with minimal leaching. J Control Release. 2014; 174: 209–216. PubMed:
  203. Yang C, Wang X, Yao X, Zhang Y, Wu W, et al. Hyaluronic acid nanogels with enzyme-sensitive cross-linking group for drug delivery. J Control Release. 2015; 205: 206–217. PubMed:
  204. Chen W, Zheng M, Meng F, Cheng R, Deng C, et al. In situ forming reduction-sensitive degradable nanogels for facile loading and triggered intracellular release of proteins. Biomacromolecules. 3; 14: 1214–1222. PubMed:
  205. Wei X, Senanayake TH, Warren G, Vinogradov SV. Hyaluronic acid-based nanogel-drug conjugates with enhanced anticancer activity designed for the targeting of CD44-positive and drug-resistant tumors. Bioconjug Chem. 2013; 24: 658–668. PubMed:
  206. Stefanello TF, Szarpak-Jankowska A, Appaix F, Louage B, Hamard L, et al. Thermoresponsive hyaluronic acid nanogels as hydrophobic drug carrier to macrophages. Acta Biomater. 2014; 10: 4750–4758. PubMed:
  207. Liang K, Ng S, Lee F, Lim J, Chung JE, et al. Targeted intracellular protein delivery based on hyaluronic acid-green tea catechin nanogels. Acta Biomater. 2016; 33: 142–152. PubMed:
  208. Water JJ, Kim Y, Maltesen MJ, Franzyk H, Foged C, et al. Hyaluronic acidbased nanogels produced by microfluidics-facilitated self-assembly improves the safety profile of the cationic host defense peptide novicidin. Pharm Res. 2015; 32: 2727–2735. PubMed:
  209. Park K, Lee MY, Kim KS, Hahn SK. Target specific tumor treatment by VEGF siRNA complexed with reducible polyethyleneimine-hyaluronic acid conjugate. Biomaterials. 2010; 31: 5258–5265. PubMed:
  210. Zhong Y, Zhang J, Cheng R, Deng C, Meng F, et al. Reversibly crosslinked hyaluronic acid nanoparticles for active targeting and intelligent delivery of doxorubicin to drug resistant CD44+ human breast tumor xenografts. J Control Release. 2015; 205: 144–154. PubMed:
  211. Oh EJ, Park K, Kim KS, Kim J, Yang JA, et al. Target specific and long-acting delivery of protein, peptide, and nucleotide therapeutics using hyaluronic acid derivatives. J Control Release. 2010; 141: 2–12. PubMed:
  212. Park JK, Shim JH, Kang KS, Yeom J, Jung HS, et al. Solid free-form fabrication of tissue-engineering scaffolds with a poly (lactic-co-glycolic acid) grafted hyaluronic acid conjugate encapsulating an intact bone morphogenetic protein-2/poly (ethylene glycol) complex. Adv Funct Mater. 2011; 21: 2906–2912.
  213. Fan Y, Deng C, Cheng R, Meng F, Zhong Z. In situ forming hydrogels via catalystfree and bioorthogonal “tetrazole-alkene” photo-click chemistry. Biomacromolecules. 2013; 14: 2814–2821.
  214. Song W, Wang Y, Qu J, Lin Q. Selective functionalization of a genetically encoded alkene-containing protein via “photoclick chemistry” in bacterial cells. J Am Chem Soc. 2008; 130: 9654–9655. PubMed:
  215. Ganesh S, Iyer AK, Gattacceca F, Morrissey DV, Amiji MM. In vivo biodistribution of siRNA and cisplatin administered using CD44-targeted hyaluronic acid nanoparticles. J Control Release. 2013; 172: 699–706. PubMed:  
  216. Li J, Huo M, Wang J, Zhou J, Mohammad JM, et al. Redox-sensitive micelles self-assembled from amphiphilic hyaluronic aciddeoxycholic acid conjugates for targeted intracellular delivery of paclitaxel. Biomaterials. 2012; 33: 2310–2320. PubMed:
  217. Yao HJ, Zhang YG, Sun L, Liu Y. The effect of hyaluronic acid functionalized carbon nanotubes loaded with salinomycin on gastric cancer stem cells. Biomaterials. 2014; 35: 9208–9223. PubMed:
  218. Kesharwani P, Banerjee S, Padhye S, Sarkar FH, Iyer AK. Hyaluronic acid engineered nanomicelles loaded with 3,4-difluorobenzylidene curcumin for targeted killing of CD44+ stem-like pancreatic cancer cells. Biomacromolecules. 2015; 16: 3042–3053. PubMed:
  219. Wang X, Zhang J, Cheng R, Meng F, Deng C, et al. Facile synthesis of reductively degradable biopolymers using cystamine diisocyanate as a coupling agent. Biomacromolecules. 2016; 17: 882–890.
  220. Yu Z, Ho LY, Lin Q. Rapid, photoactivatable turn-on fluorescent probes based on an intramolecular photoclick reaction. J Am Chem Soc. 2011; 133: 11912–11915. PubMed:
  221. Peng J, Qi T, Liao J, Fan M, Luo F, et al. Synthesis and characterization of novel dual-responsive nanogels and their application as drug delivery systems. Nanoscale. 2012; 4: 2694–2704.
  222. Shi Y, van Steenbergen MJ, Teunissen EA, Novo LS, Gradmann S, et al. π–π stacking increases the stability and loading capacity of thermosensitive polymeric micelles for chemotherapeutic drugs. Biomacromolecules. 2013; 14: 1826-1837. PubMed:
  223. Zhu Y, Wang XX, Chen J, Zhang J, Meng F, et al. Bioresponsive and fluorescent hyaluronic acid-iodixanol nanogels for targeted X-ray computed tomography imaging and chemotherapy of breast tumors. J Control Release. 2016; 244: 229–239. PubMed:
  224. Kobayashi H, Choyke PL. Target-cancer-cell-specific activatable fluorescence imaging probes: rational design and in vivo applications. Acc Chem Res. 2010; 44: 83–90. PubMed:
  225. Chauhan VP, Jain RK. Strategies for advancing cancer nanomedicine. Nat Mater. 2013; 12: 958–962. PubMed:
  226. Jain RK, Stylianopoulos T. Delivering nanomedicine to solid tumors. Nat Rev Clin Oncol. 2010; 7: 653–664. PubMed:
  227. Liang L, Lin SW, Dai W, Lu JK, Yang TY, et al.Novel cathepsin B-sensitive paclitaxel conjugate: higher water solubility, better efficacy and lower toxicity. J Control Release. 2012; 160: 618–629. PubMed:
  228. Zou Y, Song Y, Yang W, Meng F, Liu H, et al. Galactose-installed photocrosslinked pH-sensitive degradable micelles for active targeting chemotherapy of hepatocellular carcinoma in mice. J Control Release. 2014; 193: 154–161.             PubMed:
  229. Loutfy H. Madkour Book: Reactive Oxygen Species (ROS), Nanoparticles, and Endoplasmic Reticulum (ER) Stress-Induced Cell Death Mechanisms. Paperback.
  230. Xu A, Chen J, Peng H, Han G, Cai H. Simultaneous interrogation of cancer omics to identify subtypes with significant clinical differences[J]. Front Genet. 2019; 10: 236. PubMed:
  231. Madkour LH. Book. Nanoparticles Induce Oxidative and Endoplasmic Reticulum Antioxidant Therapeutic Defenses. 
  232. Chen J, Han G, Xu A, et al. Identification of Multidimensional Regulatory Modules through. Multi-graph Matching with Network Constraints [J]. IEEE Transactions on Biomedical Engineering. 2019.
  233. Madkour LH. Book: Nucleic Acids as Gene Anticancer Drug Delivery Therapy. 1st Edition.
  234. Madkour LH. Book: Nanoelectronic Materials: Fundamentals and Applications (Advanced Structured Materials) 1st ed. 2019.
  235. Wang YXJ, Choi Y, Chen ZY, Laurent S, Gibbs SL. Molecular imaging: from bench to clinic. Biomed Res Int. 2014; 357258. PubMed:
  236. Wang J, Mi P, Lin G, Xiáng Y, Wáng J, et al. Imaging-guided delivery of RNAi for anticancer treatment. Adv Drug Deliv Rev. 2016; 104: 44–60. PubMed: