Online first
Review paper
Published online: 2024-11-18

open access

Page views 55
Article views/downloads 25
Get Citation

Connect on Social Media

Connect on Social Media

Targeted nanodelivery systems for personalized cancer therapy

Szymon Roszkowski1, Zofia Durczynska2, Sylwia Szablewska2

Abstract

Conventional cancer therapies such as chemotherapy face challenges such as poor tumor targeting, systemic toxicity, and drug resistance. Nanotechnology offers solutions through advanced drug delivery systems that preferentially accumulate in tumors while avoiding healthy tissues. Recent innovations have enabled the optimization of engineered nanocarriers for extended circulation and tumor localization via both passive and active targeting mechanisms. Passive accumulation exploits the leaky vasculature of tumors, whereas active strategies use ligands to selectively bind cancer cell receptors. Multifunctional nanoparticles also allow the combination of imaging, multiple therapeutic modalities and on-demand drug release within a single platform. Overall, precisely tailored nanotherapeutics that leverage unique pathophysiological traits of malignancies provide opportunities to overcome the limitations of traditional treatment regimens. This emerging field promises more effective and personalized nanomedicine approaches to detect and treat cancer.

The key aspects highlighted in this review include the biological barriers associated with nanoparticles, rational design principles to optimize nanocarrier pharmacokinetics and tumor uptake, passive and active targeting strategies, multifunctionality, and reversal of multidrug resistance.

 

Article available in PDF format

View PDF Download PDF file

References

  1. Minelli C, Lowe SB, Stevens MM. Engineering nanocomposite materials for cancer therapy. Small. 2010; 6(21): 2336–2357.
  2. Blanco E, Shen H, Ferrari M. Principles of nanoparticle design for overcoming biological barriers to drug delivery. Nat Biotechnol. 2015; 33(9): 941–951.
  3. Maeda H, Wu J, Sawa T, et al. Tumor vascular permeability and the EPR effect in macromolecular therapeutics: a review. J Control Release. 2000; 65(1-2): 271–284.
  4. Alexis F, Pridgen E, Molnar LK, et al. Factors affecting the clearance and biodistribution of polymeric nanoparticles. Mol Pharm. 2008; 5(4): 505–515.
  5. Estrella V, Chen T, Lloyd M, et al. Acidity generated by the tumor microenvironment drives local invasion. Cancer Res. 2013; 73(5): 1524–1535.
  6. Peer D, Karp JM, Hong S, et al. Nanocarriers as an emerging platform for cancer therapy. Nat Nanotechnol. 2007; 2(12): 751–760.
  7. Danhier F. To exploit the tumor microenvironment: Since the EPR effect fails in the clinic, what is the future of nanomedicine? J Control Release. 2016; 244(Pt A): 108–121.
  8. Jones DS, Silverman AP, Cochran JR. Developing therapeutic proteins by engineering ligand-receptor interactions. Trends Biotechnol. 2008; 26(9): 498–505.
  9. Qian ZM, Li H, Sun H, et al. Targeted drug delivery via the transferrin receptor-mediated endocytosis pathway. Pharmacol Rev. 2002; 54(4): 561–587.
  10. Farokhzad OC, Cheng J, Teply BA, et al. Targeted nanoparticle-aptamer bioconjugates for cancer chemotherapy in vivo. Proc Natl Acad Sci U S A. 2006; 103(16): 6315–6320.
  11. Bertrand N, Wu J, Xu X, et al. Cancer nanotechnology: the impact of passive and active targeting in the era of modern cancer biology. Adv Drug Deliv Rev. 2014; 66: 2–25.
  12. Shi J, Kantoff PW, Wooster R, et al. Cancer nanomedicine: progress, challenges and opportunities. Nat Rev Cancer. 2017; 17(1): 20–37.
  13. Maeda H. The enhanced permeability and retention (EPR) effect in tumor vasculature: the key role of tumor-selective macromolecular drug targeting. Adv Enzyme Regul. 2001; 41: 189–207.
  14. Cabral H, Matsumoto Y, Mizuno K, et al. Accumulation of sub-100 nm polymeric micelles in poorly permeable tumours depends on size. Nat Nanotechnol. 2011; 6(12): 815–823.
  15. Gaumet M, Vargas A, Gurny R, et al. Nanoparticles for drug delivery: the need for precision in reporting particle size parameters. Eur J Pharm Biopharm. 2008; 69(1): 1–9.
  16. Nguyen PV, Hervé-Aubert K, Chourpa I, et al. Active targeting strategy in nanomedicines using anti-EGFR ligands - A promising approach for cancer therapy and diagnosis. Int J Pharm. 2021; 609: 121134.
  17. Talekar M, Kendall J, Denny W, et al. Targeting of nanoparticles in cancer: drug delivery and diagnostics. Anticancer Drugs. 2011; 22(10): 949–962.
  18. Singla AK, Garg A, Aggarwal D. Paclitaxel and its formulations. Int J Pharm. 2002; 235(1-2): 179–192.
  19. Yuan H, Guo H, Luan X, et al. Albumin Nanoparticle of Paclitaxel (Abraxane) Decreases while Taxol Increases Breast Cancer Stem Cells in Treatment of Triple Negative Breast Cancer. Mol Pharm. 2020; 17(7): 2275–2286.
  20. Moreno-Aspitia A, Perez EA. Nanoparticle albumin-bound paclitaxel (ABI-007): a newer taxane alternative in breast cancer. Future Oncol. 2005; 1(6): 755–762.
  21. Montané X, Bajek A, Roszkowski K, et al. Encapsulation for Cancer Therapy. Molecules. 2020; 25(7).
  22. Janib SM, Moses AS, MacKay JA. Imaging and drug delivery using theranostic nanoparticles. Adv Drug Deliv Rev. 2010; 62(11): 1052–1063.
  23. Bae Y, Nishiyama N, Fukushima S, et al. Preparation and biological characterization of polymeric micelle drug carriers with intracellular pH-triggered drug release property: tumor permeability, controlled subcellular drug distribution, and enhanced in vivo antitumor efficacy. Bioconjug Chem. 2005; 16(1): 122–130.
  24. Allen TM, Cullis PR. Drug delivery systems: entering the mainstream. Science. 2004; 303(5665): 1818–1822.
  25. Camorani S, Tortorella S, Agnello L, et al. Aptamer-Functionalized Nanoparticles Mediate PD-L1 siRNA Delivery for Effective Gene Silencing in Triple-Negative Breast Cancer Cells. Pharmaceutics. 2022; 14(10).
  26. Eljack S, David S, Chourpa I, et al. Formulation of Lipid-Based Nanoparticles for Simultaneous Delivery of Lapatinib and Anti-Survivin siRNA for HER2+ Breast Cancer Treatment. Pharmaceuticals (Basel). 2022; 15(12).
  27. Yang T, Han H, Chen Y, et al. Study the lipidoid nanoparticle mediated genome editing protein delivery using 3D intestinal tissue model. Bioact Mater. 2021; 6(11): 3671–3677.
  28. Richter F, Leer K, Martin L, et al. The impact of anionic polymers on gene delivery: how composition and assembly help evading the toxicity-efficiency dilemma. J Nanobiotechnology. 2021; 19(1): 292.
  29. Terada T, Kulkarni JA, Huynh A, et al. Characterization of Lipid Nanoparticles Containing Ionizable Cationic Lipids Using Design-of-Experiments Approach. Langmuir. 2021; 37(3): 1120–1128.
  30. Chelakkot C, Ghim J, Ryu SHo. Mechanisms regulating intestinal barrier integrity and its pathological implications. Exp Mol Med. 2018; 50(8): 1–9.
  31. Lin CH, Chen CH, Lin ZC, et al. Recent advances in oral delivery of drugs and bioactive natural products using solid lipid nanoparticles as the carriers. J Food Drug Anal. 2017; 25(2): 219–234.
  32. Ensign LM, Cone R, Hanes J. Oral drug delivery with polymeric nanoparticles: the gastrointestinal mucus barriers. Adv Drug Deliv Rev. 2012; 64(6): 557–570.
  33. Lai SK, Wang YY, Hanes J. Mucus-penetrating nanoparticles for drug and gene delivery to mucosal tissues. Adv Drug Deliv Rev. 2009; 61(2): 158–171.
  34. Bailey MM, Berkland CJ. Nanoparticle formulations in pulmonary drug delivery. Med Res Rev. 2009; 29(1): 196–212.
  35. Hashemi Goradel N, Ghiyami-Hour F, Jahangiri S, et al. Nanoparticles as new tools for inhibition of cancer angiogenesis. J Cell Physiol. 2018; 233(4): 2902–2910.
  36. Harrison L, Blackwell K. Hypoxia and anemia: factors in decreased sensitivity to radiation therapy and chemotherapy? Oncologist. 2004; 9 Suppl 5: 31–40.
  37. Keereweer S, Van Driel PB, Snoeks TJA, et al. Optical image-guided cancer surgery: challenges and limitations. Clin Cancer Res. 2013; 19(14): 3745–3754.
  38. Wong C, Stylianopoulos T, Cui J, et al. Multistage nanoparticle delivery system for deep penetration into tumor tissue. Proc Natl Acad Sci U S A. 2011; 108(6): 2426–2431.
  39. Torchilin V. Tumor delivery of macromolecular drugs based on the EPR effect. Adv Drug Deliv Rev. 2011; 63(3): 131–135.
  40. Irvine DJ, Hanson MC, Rakhra K, et al. Synthetic Nanoparticles for Vaccines and Immunotherapy. Chem Rev. 2015; 115(19): 11109–11146.
  41. Cruz LJ, Rosalia RA, Kleinovink JW, et al. Targeting nanoparticles to CD40, DEC-205 or CD11c molecules on dendritic cells for efficient CD8(+) T cell response: a comparative study. J Control Release. 2014; 192: 209–218.
  42. Stephan MT, Moon JJ, Um SHo, et al. Therapeutic cell engineering with surface-conjugated synthetic nanoparticles. Nat Med. 2010; 16(9): 1035–1041.
  43. Buschow SI, Lasonder E, van Deutekom HWM, et al. Dominant processes during human dendritic cell maturation revealed by integration of proteome and transcriptome at the pathway level. J Proteome Res. 2010; 9(4): 1727–1737.
  44. Rosalia RA, Cruz LJ, van Duikeren S, et al. CD40-targeted dendritic cell delivery of PLGA-nanoparticle vaccines induce potent anti-tumor responses. Biomaterials. 2015; 40: 88–97.
  45. Fang J, Islam W, Maeda H. Exploiting the dynamics of the EPR effect and strategies to improve the therapeutic effects of nanomedicines by using EPR effect enhancers. Adv Drug Deliv Rev. 2020; 157: 142–160.
  46. Nel A, Ruoslahti E, Meng H. New Insights into "Permeability" as in the Enhanced Permeability and Retention Effect of Cancer Nanotherapeutics. ACS Nano. 2017; 11(10): 9567–9569.
  47. Toy R, Peiris PM, Ghaghada KB, et al. Shaping cancer nanomedicine: the effect of particle shape on the in vivo journey of nanoparticles. Nanomedicine (Lond). 2014; 9(1): 121–134.
  48. Kibria G, Hatakeyama H, Harashima H. Cancer multidrug resistance: mechanisms involved and strategies for circumvention using a drug delivery system. Arch Pharm Res. 2014; 37(1): 4–15.
  49. Byrne JD, Betancourt T, Brannon-Peppas L. Active targeting schemes for nanoparticle systems in cancer therapeutics. Adv Drug Deliv Rev. 2008; 60(15): 1615–1626.
  50. Jaracz S, Chen J, Kuznetsova LV, et al. Recent advances in tumor-targeting anticancer drug conjugates. Bioorg Med Chem. 2005; 13(17): 5043–5054.
  51. Elias DR, Poloukhtine A, Popik V, et al. Effect of ligand density, receptor density, and nanoparticle size on cell targeting. Nanomedicine. 2013; 9(2): 194–201.
  52. Parveen S, Sahoo SK. Polymeric nanoparticles for cancer therapy. J Drug Target. 2008; 16(2): 108–123.
  53. Saptarshi SR, Duschl A, Lopata AL. Interaction of nanoparticles with proteins: relation to bio-reactivity of the nanoparticle. J Nanobiotechnology. 2013; 11: 26.
  54. Shi J, Votruba AR, Farokhzad OC, et al. Nanotechnology in drug delivery and tissue engineering: from discovery to applications. Nano Lett. 2010; 10(9): 3223–3230.
  55. Dreaden EC, Austin LA, Mackey MA, et al. Size matters: gold nanoparticles in targeted cancer drug delivery. Ther Deliv. 2012; 3(4): 457–478.
  56. Cruz E, Kayser V. Synthesis and Enhanced Cellular Uptake In Vitro of Anti-HER2 Multifunctional Gold Nanoparticles. Cancers (Basel). 2019; 11(6).
  57. Huang X, El-Sayed IH, Qian W, et al. Cancer cell imaging and photothermal therapy in the near-infrared region by using gold nanorods. J Am Chem Soc. 2006; 128(6): 2115–2120.
  58. Liong M, Lu J, Kovochich M, et al. Multifunctional inorganic nanoparticles for imaging, targeting, and drug delivery. ACS Nano. 2008; 2(5): 889–896.
  59. Chen L, Zhou X, Nie W, et al. Multifunctional Redox-Responsive Mesoporous Silica Nanoparticles for Efficient Targeting Drug Delivery and Magnetic Resonance Imaging. ACS Appl Mater Interfaces. 2016; 8(49): 33829–33841.
  60. Huang G, Chen H, Dong Y, et al. Superparamagnetic iron oxide nanoparticles: amplifying ROS stress to improve anticancer drug efficacy. Theranostics. 2013; 3(2): 116–126.
  61. Nance E, Timbie K, Miller GW, et al. Non-invasive delivery of stealth, brain-penetrating nanoparticles across the blood-brain barrier using MRI-guided focused ultrasound. J Control Release. 2014; 189: 123–132.
  62. Xie J, Lee S, Chen X. Nanoparticle-based theranostic agents. Adv Drug Deliv Rev. 2010; 62(11): 1064–1079.
  63. Lammers T, Aime S, Hennink WE, et al. Theranostic nanomedicine. Acc Chem Res. 2011; 44(10): 1029–1038.
  64. Khatun Z, Nurunnabi Md, Nafiujjaman Md, et al. Photoluminescent graphene nanoparticles for cancer phototherapy and imaging. ACS Appl Mater Interfaces. 2014; 6(15): 12413–12421.
  65. Robinson JT, Tabakman SM, Liang Y, et al. Ultrasmall reduced graphene oxide with high near-infrared absorbance for photothermal therapy. J Am Chem Soc. 2011; 133(17): 6825–6831.
  66. Yang K, Zhang S, Zhang G, et al. Graphene in mice: ultrahigh in vivo tumor uptake and efficient photothermal therapy. Nano Lett. 2010; 10(9): 3318–3323.
  67. Mamaeva V, Sahlgren C, Lindén M. Mesoporous silica nanoparticles in medicine--recent advances. Adv Drug Deliv Rev. 2013; 65(5): 689–702.
  68. Slowing II, Vivero-Escoto JL, Wu CW, et al. Mesoporous silica nanoparticles as controlled release drug delivery and gene transfection carriers. Adv Drug Deliv Rev. 2008; 60(11): 1278–1288.
  69. Hom C, Lu J, Liong M, et al. Mesoporous silica nanoparticles facilitate delivery of siRNA to shutdown signaling pathways in mammalian cells. Small. 2010; 6(11): 1185–1190.
  70. Choi KiY, Min KH, Yoon HY, et al. PEGylation of hyaluronic acid nanoparticles improves tumor targetability in vivo. Biomaterials. 2011; 32(7): 1880–1889.
  71. Hossann M, Wang T, Wiggenhorn M, et al. Size of thermosensitive liposomes influences content release. J Control Release. 2010; 147(3): 436–443.
  72. Farokhzad OC, Jon S, Khademhosseini A, et al. Nanoparticle-aptamer bioconjugates: a new approach for targeting prostate cancer cells. Cancer Res. 2004; 64(21): 7668–7672.
  73. Wang AZ, Bagalkot V, Vasilliou CC, et al. Superparamagnetic iron oxide nanoparticle-aptamer bioconjugates for combined prostate cancer imaging and therapy. ChemMedChem. 2008; 3(9): 1311–1315.
  74. Sahay G, Querbes W, Alabi C, et al. Efficiency of siRNA delivery by lipid nanoparticles is limited by endocytic recycling. Nat Biotechnol. 2013; 31(7): 653–658.
  75. Yin H, Kanasty RL, Eltoukhy AA, et al. Non-viral vectors for gene-based therapy. Nat Rev Genet. 2014; 15(8): 541–555.
  76. Niculescu AG, Grumezescu AM. Novel Tumor-Targeting Nanoparticles for Cancer Treatment-A Review. Int J Mol Sci. 2022; 23(9).
  77. Khan MdI, Hossain MI, Hossain MK, et al. Recent Progress in Nanostructured Smart Drug Delivery Systems for Cancer Therapy: A Review. ACS Appl Bio Mater. 2022; 5(3): 971–1012.
  78. Gottesman MM, Fojo T, Bates SE. Multidrug resistance in cancer: role of ATP-dependent transporters. Nat Rev Cancer. 2002; 2(1): 48–58.
  79. Brigger I, Dubernet C, Couvreur P, et al. Tamoxifen encapsulation within polyethylene glycol-coated nanospheres. A new antiestrogen formulation. Int J Pharm. 2001; 214(1-2): 37–42.
  80. Dai Q, Wilhelm S, Ding D, et al. Quantifying the Ligand-Coated Nanoparticle Delivery to Cancer Cells in Solid Tumors. ACS Nano. 2018; 12(8): 8423–8435.
  81. Maeda H. Vascular permeability in cancer and infection as related to macromolecular drug delivery, with emphasis on the EPR effect for tumor-selective drug targeting. Proc Jpn Acad Ser B Phys Biol Sci. 2012; 88(3): 53–71.
  82. Zhang D, Liu L, Wang J, et al. Drug-loaded PEG-PLGA nanoparticles for cancer treatment. Front Pharmacol. 2022; 13: 990505.
  83. Dean M, Hamon Y, Chimini G. The human ATP-binding cassette (ABC) transporter superfamily. J Lipid Res. 2001; 42(7): 1007–1017.
  84. Scotto KW. Transcriptional regulation of ABC drug transporters. Oncogene. 2003; 22(47): 7496–7511.
  85. Ambudkar SV, Kimchi-Sarfaty C, Sauna ZE, et al. P-glycoprotein: from genomics to mechanism. Oncogene. 2003; 22(47): 7468–7485.
  86. Gottesman MM, Fojo T, Bates SE. Multidrug resistance in cancer: role of ATP-dependent transporters. Nat Rev Cancer. 2002; 2(1): 48–58.
  87. Fletcher JI, Haber M, Henderson MJ, et al. ABC transporters in cancer: more than just drug efflux pumps. Nat Rev Cancer. 2010; 10(2): 147–156.
  88. Sangtani A, Petryayeva E, Susumu K, et al. Nanoparticle-Peptide-Drug Bioconjugates for Unassisted Defeat of Multidrug Resistance in a Model Cancer Cell Line. Bioconjug Chem. 2019; 30(3): 525–530.
  89. Huszthy PC, Giroglou T, Tsinkalovsky O, et al. Remission of invasive, cancer stem-like glioblastoma xenografts using lentiviral vector-mediated suicide gene therapy. PLoS One. 2009; 4(7): e6314.
  90. Wang K, Kievit FM, Zhang M. Nanoparticles for cancer gene therapy: Recent advances, challenges, and strategies. Pharmacol Res. 2016; 114: 56–66.
  91. Tzeng SY, Patel KK, Wilson DR, et al. In situ genetic engineering of tumors for long-lasting and systemic immunotherapy. Proc Natl Acad Sci U S A. 2020; 117(8): 4043–4052.
  92. Varlamova EG, Goltyaev MV, Mal'tseva VN, et al. Mechanisms of the Cytotoxic Effect of Selenium Nanoparticles in Different Human Cancer Cell Lines. Int J Mol Sci. 2021; 22(15).
  93. Mazumdar S, Chitkara D, Mittal A. Exploration and insights into the cellular internalization and intracellular fate of amphiphilic polymeric nanocarriers. Acta Pharm Sin B. 2021; 11(4): 903–924.
  94. Bechet D, Couleaud P, Frochot C, et al. Nanoparticles as vehicles for delivery of photodynamic therapy agents. Trends Biotechnol. 2008; 26(11): 612–621.
  95. Allison RR, Sibata CH. Oncologic photodynamic therapy photosensitizers: a clinical review. Photodiagnosis Photodyn Ther. 2010; 7(2): 61–75.
  96. Ricci-Júnior E, Marchetti JM, Ricci-Júnior E, et al. Zinc(II) phthalocyanine loaded PLGA nanoparticles for photodynamic therapy use. Int J Pharm. 2006; 310(1-2): 187–195.
  97. Master AM, Sen Gupta A. EGF receptor-targeted nanocarriers for enhanced cancer treatment. Nanomedicine (Lond). 2012; 7(12): 1895–1906.
  98. Wong HoL, Rauth AM, Bendayan R, et al. A new polymer-lipid hybrid nanoparticle system increases cytotoxicity of doxorubicin against multidrug-resistant human breast cancer cells. Pharm Res. 2006; 23(7): 1574–1585.