Skip to content
2000
image of Research on Anti-tumor Pharmacodynamics of Multi-functional Magnetic Lipid Polymer with Specific Targeted Transmission of siRNA and its Toxicity Evaluation

Abstract

Introduction

Hepatocellular carcinoma (HCC) is the third leading cause of cancer deaths globally. Traditional treatments face limitations like low effectiveness, poor specificity, and significant side effects. Gene therapy, particularly siRNA-based, is promising for targeted gene regulation but requires effective delivery systems due to the instability and poor target delivery of unmodified siRNA.

Methods

This study examined the storage and biological stability of LP-PEI-SPION (LPS) and GPC3-LP-PEI-SPION (GLPS). The potential of these agents as tumor imaging contrast agents and the targeting ability of gene delivery carriers were assessed through organ fluorescence imaging and tumor magnetic resonance imaging (MRI). Antitumor efficacy was evaluated through tumor volume, protein blotting, immunohistochemistry, and TUNEL assays. safety was evaluated using HE staining, nude mouse weight changes, and blood biochemical indicators.

Results

LPS and GLPS both formed stable siRNA complexes. GLPS showed excellent tumor targeting . MRI results showed that the GPC3-targeting peptide effectively enhanced the MR imaging performance and diagnostic accuracy. Tumor volume and weight measurements demonstrated potent tumor inhibition by GLPS/siRNA. Immunoblotting and immunohistochemistry revealed significant GPC3 reduction in the GLPS/siRNA-targeted group. Safety evaluations confirmed good biocompatibility for both LPS/siRNA and GLPS/siRNA.

Discussion

GLPS/siRNA demonstrates superior transfection and anti-tumor efficacy compared to LPS/siRNA. It exhibits high tumor fluorescence signals, reduced MRI T2 relaxation time, and effective tumor enrichment, providing MRI imaging capability. Safety assessments, including HE staining, body weight, and blood biochemistry, indicate good biocompatibility. The development of siRNA-based therapeutics has progressed, yet challenges remain, such as siRNA's susceptibility to degradation and poor membrane permeability. While carriers like liposomes and polymers are used, they have limitations. Nanoparticles that enhance endosomal/lysosomal escape and promote cytoplasmic siRNA release are needed to improve delivery efficiency, reduce off-target effects, and enhance safety.

Conclusion

GLPS/siRNA demonstrates good stability, tumor targeting, imaging capability, and antitumor efficacy with favorable safety, positioning it as a promising theragnostic platform for HCC. This integrated system provides novel clinical tools for diagnosis and treatment, establishes a foundation for clinical translation, and enables simultaneous tumor imaging and gene therapy—offering innovative strategies for combined tumor theranostics.

© 2025 Bentham Science Publishers
Loading

Article metrics loading...

/content/journals/cpd/10.2174/0113816128395585250923122829
2025-10-17
2025-12-24

  • From This Site

    /content/journals/cpd/10.2174/0113816128395585250923122829
    dcterms_title,dcterms_subject,pub_keyword
    -contentType:Contributor -contentType:Concept -contentType:Institution
    10
    5
Loading full text...

Full text loading...

References

  1. Siegel R.L. Miller K.D. Fuchs H.E. Jemal A. Cancer statistics, 2022. CA Cancer J. Clin. 2022 72 1 7 33 10.3322/caac.21708 35020204
    [Google Scholar]
  2. Sung H. Ferlay J. Siegel R.L. Global cancer statistics 2020: Globocan estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin. 2021 71 3 209 249 10.3322/caac.21660 33538338
    [Google Scholar]
  3. Benson A.B. D’Angelica M.I. Abbott D.E. NCCN guidelines insights: Hepatobiliary cancers, version 1.2017. J. Natl. Compr. Canc. Netw. 2017 15 5 563 573 10.6004/jnccn.2017.0059 28476736
    [Google Scholar]
  4. Vogel A. Meyer T. Sapisochin G. Salem R. Saborowski A. Hepatocellular carcinoma. Lancet 2022 400 10360 1345 1362 10.1016/S0140‑6736(22)01200‑4 36084663
    [Google Scholar]
  5. Yang J.D. Hainaut P. Gores G.J. Amadou A. Plymoth A. Roberts L.R. A global view of hepatocellular carcinoma: Trends, risk, prevention and management. Nat. Rev. Gastroenterol. Hepatol. 2019 16 10 589 604 10.1038/s41575‑019‑0186‑y 31439937
    [Google Scholar]
  6. Park J.W. Chen M. Colombo M. Global patterns of hepatocellular carcinoma management from diagnosis to death: The BRIDGE Study. Liver Int. 2015 35 9 2155 2166 10.1111/liv.12818 25752327
    [Google Scholar]
  7. Dhir M. Melin A.A. Douaiher J. A review and update of treatment options and controversies in the management of hepatocellular carcinoma. Ann. Surg. 2016 263 6 1112 1125 10.1097/SLA.0000000000001556 26813914
    [Google Scholar]
  8. Yang T. Wang M.D. Xu X.F. Li C. Wu H. Shen F. Management of hepatocellular carcinoma in China: Seeking common grounds while reserving differences. Clin. Mol. Hepatol. 2023 29 2 342 344 10.3350/cmh.2023.0106 36924123
    [Google Scholar]
  9. Chakraborty E. Sarkar D. Emerging therapies for hepatocellular carcinoma (HCC). Cancers 2022 14 11 2798 10.3390/cancers14112798 35681776
    [Google Scholar]
  10. Chen J. Li S. Zhou Q. Near-infrared II fluorescence imaging highlights tumor angiogenesis in hepatocellular carcinoma with a VEGFR‐targeted probe. Small Methods 2025 9 3 2400904 10.1002/smtd.202400904 39428866
    [Google Scholar]
  11. Cesur-Ergün B. Demir-Dora D. Gene therapy in cancer. J. Gene Med. 2023 25 11 3550 10.1002/jgm.3550 37354071
    [Google Scholar]
  12. Kamimura K. Yokoo T. Abe H. Terai S. Gene therapy for liver cancers: Current status from basic to clinics. Cancers 2019 11 12 1865 10.3390/cancers11121865 31769427
    [Google Scholar]
  13. Yuan Y. Sun W. Xie J. RNA nanotherapeutics for hepatocellular carcinoma treatment. Theranostics 2025 15 3 965 992 10.7150/thno.102964 39776807
    [Google Scholar]
  14. Youssef E. Fletcher B. Palmer D. Enhancing precision in cancer treatment: The role of gene therapy and immune modulation in oncology. Front. Med. 2025 11 1527600 10.3389/fmed.2024.1527600 39871848
    [Google Scholar]
  15. Weiskirchen R. Weiskirchen S. Grassi C. Recent advances in optimizing siRNA delivery to hepatocellular carcinoma cells. Expert Opin. Drug Deliv. 2025 22 5 729 745 10.1080/17425247.2025.2484287 40126051
    [Google Scholar]
  16. Younis M. Harashima H. Understanding gene involvement in hepatocellular carcinoma: Implications for gene therapy and personalized medicine. Pharm. Genomics Pers. Med. 2024 17 193 213 10.2147/PGPM.S431346 38737776
    [Google Scholar]
  17. Mohd Abas M.D. Mohd Asri M.F. Yusafawi N.A.S. Advancements of gene therapy in cancer treatment: A comprehensive review. Pathol. Res. Pract. 2024 261 155509 10.1016/j.prp.2024.155509 39121791
    [Google Scholar]
  18. Luo R. Le H. Wu Q. Gong C. Nanoplatform‐based in vivo gene delivery systems for cancer therapy. Small 2024 20 30 2312153 10.1002/smll.202312153 38441386
    [Google Scholar]
  19. Elbashir S.M. Harborth J. Lendeckel W. Yalcin A. Weber K. Tuschl T. Duplexes of 21-nucleotide RNAs mediate RNA interference in cultured mammalian cells. Nature 2001 411 6836 494 498 10.1038/35078107 11373684
    [Google Scholar]
  20. Fire A. Xu S. Montgomery M.K. Kostas S.A. Driver S.E. Mello C.C. Potent and specific genetic interference by double-stranded RNA in Caenorhabditis elegans. Nature 1998 391 6669 806 811 10.1038/35888 9486653
    [Google Scholar]
  21. Setten R.L. Rossi J.J. Han S. The current state and future directions of RNAi-based therapeutics. Nat. Rev. Drug Discov. 2019 18 6 421 446 10.1038/s41573‑019‑0017‑4 30846871
    [Google Scholar]
  22. Morrissey D.V. Blanchard K. Shaw L. Activity of stabilized short interfering RNA in a mouse model of hepatitis B virus replication. Hepatology 2005 41 6 1349 1356 10.1002/hep.20702 15880588
    [Google Scholar]
  23. Whitehead K.A. Dahlman J.E. Langer R.S. Anderson D.G. Silencing or stimulation? siRNA delivery and the immune system. Annu. Rev. Chem. Biomol. Eng. 2011 2 1 77 96 10.1146/annurev‑chembioeng‑061010‑114133 22432611
    [Google Scholar]
  24. Dowdy S.F. Overcoming cellular barriers for RNA therapeutics. Nat. Biotechnol. 2017 35 3 222 229 10.1038/nbt.3802 28244992
    [Google Scholar]
  25. Song H. Hart S.L. Du Z. Assembly strategy of liposome and polymer systems for siRNA delivery. Int. J. Pharm. 2021 592 120033 10.1016/j.ijpharm.2020.120033 33144189
    [Google Scholar]
  26. Tan L. Wu S.J. Qiu Y. Preliminary investigation into ultrasound and MRI presentation of large-cell neuroendocrine carcinomas of the uterine cervix. BIO Integration 2023 4 4 180 10.15212/bioi‑2022‑0028
    [Google Scholar]
  27. Šimečková P. Hubatka F. Kotouček J. Gadolinium labelled nanoliposomes as the platform for MRI theranostics: In vitro safety study in liver cells and macrophages. Sci. Rep. 2020 10 1 4780 10.1038/s41598‑020‑60284‑z 32179785
    [Google Scholar]
  28. Skupin-Mrugalska P. Sobotta L. Warowicka A. Theranostic liposomes as a bimodal carrier for magnetic resonance imaging contrast agent and photosensitizer. J. Inorg. Biochem. 2018 180 1 14 10.1016/j.jinorgbio.2017.11.025 29223825
    [Google Scholar]
  29. Ye S. Liu Y. Lu Y. Cyclic RGD functionalized liposomes targeted to activated platelets for thrombosis dual-mode magnetic resonance imaging. J. Mater. Chem. B Mater. Biol. Med. 2020 8 3 447 453 10.1039/C9TB01834D 31833530
    [Google Scholar]
  30. Niesman M.R. Bacic G.G. Wright S.M. Swartz H.M. Magin R.L. Liposome encapsulated MnCl2 as a liver specific contrast agent for magnetic resonance imaging. Invest. Radiol. 1990 25 5 545 551 10.1097/00004424‑199005000‑00012 2345086
    [Google Scholar]
  31. Lv J. Roy S. Xie M. Yang X. Guo B. Contrast agents of magnetic resonance imaging and future perspective. Nanomaterials 2023 13 13 2003 10.3390/nano13132003 37446520
    [Google Scholar]
  32. Martínez-González R. Estelrich J. Busquets M. Liposomes loaded with hydrophobic iron oxide nanoparticles: Suitable T2 contrast agents for MRI. Int. J. Mol. Sci. 2016 17 8 1209 10.3390/ijms17081209 27472319
    [Google Scholar]
  33. Neuwelt A. Sidhu N. Hu C.A.A. Mlady G. Eberhardt S.C. Sillerud L.O. Iron-based superparamagnetic nanoparticle contrast agents for MRI of infection and inflammation. AJR Am. J. Roentgenol. 2015 204 3 W302-13 10.2214/AJR.14.12733 25714316
    [Google Scholar]
  34. Khalkhali M. Rostamizadeh K. Sadighian S. Khoeini F. Naghibi M. Hamidi M. The impact of polymer coatings on magnetite nanoparticles performance as MRI contrast agents: A comparative study. Daru 2015 23 1 45 10.1186/s40199‑015‑0124‑7 26381740
    [Google Scholar]
  35. Wu K. Su D. Liu J. Saha R. Wang J.P. Magnetic nanoparticles in nanomedicine: A review of recent advances. Nanotechnology 2019 30 50 502003 10.1088/1361‑6528/ab4241 31491782
    [Google Scholar]
  36. Wang Y.X. Xuan S. Port M. Idee J.M. Recent advances in superparamagnetic iron oxide nanoparticles for cellular imaging and targeted therapy research. Curr. Pharm. Des. 2013 19 37 6575 6593 10.2174/1381612811319370003 23621536
    [Google Scholar]
  37. Mok H. Zhang M. Superparamagnetic iron oxide nanoparticle-based delivery systems for biotherapeutics. Expert Opin. Drug Deliv. 2013 10 1 73 87 10.1517/17425247.2013.747507 23199200
    [Google Scholar]
  38. Yoffe S. Leshuk T. Everett P. Gu F. Superparamagnetic iron oxide nanoparticles (SPIONs): Synthesis and surface modification techniques for use with MRI and other biomedical applications. Curr. Pharm. Des. 2013 19 3 493 509 10.2174/138161213804143707 22934920
    [Google Scholar]
  39. Shimizu Y. Suzuki T. Yoshikawa T. Cancer immunotherapy-targeted glypican-3 or neoantigens. Cancer Sci. 2018 109 3 531 541 10.1111/cas.13485 29285841
    [Google Scholar]
  40. Schepers E.J. Glaser K. Zwolshen H.M. Hartman S.J. Bondoc A.J. Structural and functional impact of posttranslational modification of glypican-3 on liver carcinogenesis. Cancer Res. 2023 83 12 1933 1940 10.1158/0008‑5472.CAN‑22‑3895 37027004
    [Google Scholar]
  41. Haruyama Y. Kataoka H. Glypican-3 is a prognostic factor and an immunotherapeutic target in hepatocellular carcinoma. World J. Gastroenterol. 2016 22 1 275 283 10.3748/wjg.v22.i1.275 26755876
    [Google Scholar]
  42. Wang S. Chen N. Chen Y. Sun L. Li L. Liu H. Elevated GPC3 level promotes cell proliferation in liver cancer. Oncol. Lett. 2018 16 1 970 976 10.3892/ol.2018.8754 29963171
    [Google Scholar]
  43. Zhang Q. Han Z. Tao J. An innovative peptide with high affinity to GPC3 for hepatocellular carcinoma diagnosis. Biomater. Sci. 2019 7 1 159 167 10.1039/C8BM01016A 30417190
    [Google Scholar]
  44. Montalbano M. Rastellini C. McGuire J.T. Role of glypican-3 in the growth, migration and invasion of primary hepatocytes isolated from patients with hepatocellular carcinoma. Cell. Oncol. 2018 41 2 169 184 10.1007/s13402‑017‑0364‑2 29204978
    [Google Scholar]
  45. Shimizu Y. Mizuno S. Fujinami N. Plasma and tumoral glypican-3 levels are correlated in patients with hepatitis C virus-related hepatocellular carcinoma. Cancer Sci. 2020 111 2 334 342 10.1111/cas.14251 31774932
    [Google Scholar]
  46. Fu Y. Urban D.J. Nani R.R. Glypican-3-specific antibody drug conjugates targeting hepatocellular carcinoma. Hepatology 2019 70 2 563 576 10.1002/hep.30326 30353932
    [Google Scholar]
  47. Zhou M. Zhou Z. Hu L. Multiplex immunohistochemistry to explore the tumor immune microenvironment in HCC patients with different GPC3 expression. J. Transl. Med. 2025 23 1 88 10.1186/s12967‑025‑06106‑0 39838375
    [Google Scholar]
  48. Du K. Li Y. Liu J. A bispecific antibody targeting GPC3 and CD47 induced enhanced antitumor efficacy against dual antigen-expressing HCC. Mol. Ther. 2021 29 4 1572 1584 10.1016/j.ymthe.2021.01.006 33429083
    [Google Scholar]
  49. Sun D. Li X. Liu Y. Quan J. Jin G. Construction of GPC3-modified Lipopolymer SiRNA Delivery System. Curr. Pharm. Des. 2024 30 19 1507 1518 10.2174/0113816128258852231204102044 38644723
    [Google Scholar]
  50. Liu H. Wu D. In vivo near-infrared fluorescence tumor imaging using dir-loaded nanocarriers. Curr. Drug Deliv. 2016 13 1 40 48 10.2174/1567201812666150703114908 26138681
    [Google Scholar]
  51. Lázaro-Ibáñez E. Faruqu F.N. Saleh A.F. Selection of fluorescent, bioluminescent, and radioactive tracers to accurately reflect extracellular vesicle biodistribution in vivo. ACS Nano 2021 15 2 3212 3227 10.1021/acsnano.0c09873 33470092
    [Google Scholar]
  52. Ao H. Lu L. Li M. Han M. Guo Y. Wang X. Enhanced solubility and antitumor activity of annona squamosa seed oil via nanoparticles stabilized with tpgs: Preparation and in vitro and in vivo evaluation. Pharmaceutics 2022 14 6 1232 10.3390/pharmaceutics14061232 35745804
    [Google Scholar]
  53. Wu Y. Liu H. Ding H.G. GPC-3 in hepatocellular carcinoma: Current perspectives. J. Hepatocell. Carcinoma 2016 3 63 67 10.2147/JHC.S116513 27878117
    [Google Scholar]
  54. Lazic S.E. Semenova E. Williams D.P. Determining organ weight toxicity with Bayesian causal models: Improving on the analysis of relative organ weights. Sci. Rep. 2020 10 1 6625 10.1038/s41598‑020‑63465‑y 32313041
    [Google Scholar]
  55. Zhou J. Zhou Q. Shu G. Dual-effect of magnetic resonance imaging reporter gene in diagnosis and treatment of hepatocellular carcinoma. Int. J. Nanomedicine 2020 15 7235 7249 10.2147/IJN.S257628 33061378
    [Google Scholar]
  56. Sun J. Jin Z. Jin Y. Yuan H. Jin G. Quan J. MRI-based multifunctional nanoliposomes for enhanced hcc therapy and diagnosis. Mol. Pharm. 2025 22 2 787 807 10.1021/acs.molpharmaceut.4c00917 39809473
    [Google Scholar]
  57. Zhang Q. Lu Y. Xu X. Li S. Du Y. Yu R. MR molecular imaging of HCC employing a regulated ferritin gene carried by a modified polycation vector. Int. J. Nanomedicine 2019 14 3189 3201 10.2147/IJN.S191270 31118631
    [Google Scholar]
  58. Arami S. Mahdavi M. Rashidi M.R. Fathi M. Hejazi M.S. Samadi N. Multifunctional superparamagnetic nanoparticles: From synthesis to siRNA delivery. Curr. Pharm. Des. 2017 23 16 2400 2409 27799034
    [Google Scholar]
  59. Lam J.K.W. Chow M.Y.T. Zhang Y. Leung S.W.S. siRNA Versus miRNA as therapeutics for gene silencing. Mol. Ther. Nucleic Acids 2015 4 9 252 10.1038/mtna.2015.23 26372022
    [Google Scholar]
  60. Lee DJ He D Kessel E Tumoral gene silencing by receptortargeted combinatorial siRNA polyplexes J Control Release 2016 244 Pt B 280 91 10.1016/j.jconrel.2016.06.011 27287890
    [Google Scholar]
  61. Li N. Yang H. Yu Z. Nuclear-targeted siRNA delivery for long-term gene silencing. Chem. Sci. (Camb.) 2017 8 4 2816 2822 10.1039/C6SC04293G 28553519
    [Google Scholar]
  62. Alshaer W. Zureigat H. Al Karaki A. siRNA: Mechanism of action, challenges, and therapeutic approaches. Eur. J. Pharmacol. 2021 905 174178 10.1016/j.ejphar.2021.174178 34044011
    [Google Scholar]
  63. Barba A.A. Cascone S. Caccavo D. Engineering approaches in siRNA delivery. Int. J. Pharm. 2017 525 2 343 358 10.1016/j.ijpharm.2017.02.032 28213276
    [Google Scholar]
  64. Kim B. Park J.H. Sailor M.J. Rekindling RNAi therapy: Materials design requirements for in vivo sirna delivery. Adv. Mater. 2019 31 49 1903637 10.1002/adma.201903637 31566258
    [Google Scholar]
  65. Wittrup A. Ai A. Liu X. Visualizing lipid-formulated siRNA release from endosomes and target gene knockdown. Nat. Biotechnol. 2015 33 8 870 876 10.1038/nbt.3298 26192320
    [Google Scholar]
  66. Sahay G. Querbes W. Alabi C. Efficiency of siRNA delivery by lipid nanoparticles is limited by endocytic recycling. Nat. Biotechnol. 2013 31 7 653 658 10.1038/nbt.2614 23792629
    [Google Scholar]
  67. Eloy J.O. Petrilli R. Raspantini G.L. Lee R.J. Targeted liposomes for siRNA delivery to cancer. Curr. Pharm. Des. 2018 24 23 2664 2672 10.2174/1381612824666180807121935 30084323
    [Google Scholar]
  68. Vhora I. Patil S. Amrutiya J. Misra A. Liposomes and lipid envelope-type systems for systemic siRNA delivery. Curr. Pharm. Des. 2015 21 31 4541 4555 10.2174/138161282131151013185850 26486141
    [Google Scholar]
  69. Wu K. Wang J.P. Natekar N.A. Roadmap on magnetic nanoparticles in nanomedicine. Nanotechnology 2024 36 4 36 39395441
    [Google Scholar]
  70. Balasubramanian S. Girija A.R. Nagaoka Y. Curcumin and 5-fluorouracil-loaded, folate- and transferrin-decorated polymeric magnetic nanoformulation: A synergistic cancer therapeutic approach, accelerated by magnetic hyperthermia. Int. J. Nanomedicine 2014 9 437 459 24531392
    [Google Scholar]
  71. Frullano L. Meade T.J. Multimodal MRI contrast agents. J. Biol. Inorg. Chem. 2007 12 7 939 949 10.1007/s00775‑007‑0265‑3 17659368
    [Google Scholar]
  72. Sun C. Lee J.S.H. Zhang M. Magnetic nanoparticles in MR imaging and drug delivery. Adv. Drug Deliv. Rev. 2008 60 11 1252 1265 10.1016/j.addr.2008.03.018 18558452
    [Google Scholar]
  73. Luo G.F. Zhang X.Z. Magnetic nanoparticles for use in bioimaging. Biomater. Sci. 2024 12 24 6224 6236 10.1039/D4BM01145G 39498601
    [Google Scholar]
  74. Zhou Z. Yang L. Gao J. Chen X. Structure–relaxivity relationships of magnetic nanoparticles for magnetic resonance imaging. Adv. Mater. 2019 31 8 1804567 10.1002/adma.201804567 30600553
    [Google Scholar]
  75. Farzin A. Etesami S.A. Quint J. Memic A. Tamayol A. Magnetic nanoparticles in cancer therapy and diagnosis. Adv. Healthc. Mater. 2020 9 9 1901058 10.1002/adhm.201901058 32196144
    [Google Scholar]
/content/journals/cpd/10.2174/0113816128395585250923122829
Loading
Research on Anti-tumor Pharmacodynamics of Multi-functional Magnetic Lipid Polymer with Specific Targeted Transmission of siRNA and its Toxicity Evaluation
Bentham Science Publishers ; https://doi.org/10.2174/0113816128395585250923122829
/content/journals/cpd/10.2174/0113816128395585250923122829
/content/journals/cpd/10.2174/0113816128395585250923122829
Loading

Data & Media loading...


  • Article Type:     Research Article
Keywords: targeted therapy ; siRNA ; GPC3 ; MR imaging ; superparamagnetic iron oxide nanoparticles ; tumor

Most Cited Most Cited RSS feed

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error
Please enter a valid_number test