Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Comparison of two methods for tumour-targeting peptide modification of liposomes

Abstract

Liposomes decorated with tumour-targeting cell-penetrating peptides can enhance specific drug delivery at the tumour site. The TR peptide, c(RGDfK)-AGYLLGHINLHHLAHL(Aib)HHIL, is pH-sensitive and actively targets tumour cells that overexpress integrin receptor αvβ3, such as B16F10 melanoma cells. Liposomes can be modified with the TR peptide by two different methods: utilization of the cysteine residue on TR to link DSPE-PEG2000-Mal contained in the liposome formula (LIPTR) or decoration of TR with a C18 stearyl chain (C18-TR) for direct insertion into the liposomal phospholipid bilayer through electrostatic and hydrophobic interactions (LIPC18-TR). We found that both TR and C18-TR effectively reversed the surface charge of the liposomes when the systems encountered the low pH of the tumour microenvironment, but LIPC18-TR exhibited a greater increase in the charge, which led to higher cellular uptake efficiency. Correspondingly, the IC50 values of PTX-LIPTR and PTX-LIPC18-TR in B16F10 cells in vitro were 2.1-fold and 2.5-fold lower than that of the unmodified PTX-loaded liposomes (PTX-LIP), respectively, in an acidic microenvironment (pH 6.3). In B16F10 tumour-bearing mice, intravenous administration of PTX-LIPTR and PTX-LIPC18-TR (8 mg/kg PTX every other day for a total of 4 injections) caused tumour reduction ratios of 39.4% and 56.1%, respectively, compared to 20.8% after PTX-LIP administration. Thus, we demonstrated that TR peptide modification could improve the antitumour efficiency of liposomal delivery systems, with C18-TR presenting significantly better results. After investigating different modification methods, our data show that selecting an adequate method is vital even when the same molecule is used for decoration.

This is a preview of subscription content, access via your institution

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Scheme 1: Basic structures of PTX-LIPC18-TR and PTX-LIPTR.
Fig. 1: Characterization of fabricated liposomal carriers.
Fig. 2: Drug release profile and stability of different liposomes.
Fig. 3: Cellular studies of different formulations.
Fig. 4: Tumour-targeting ability of different peptide-modified liposomes.
Fig. 5: In vivo antitumour efficiency of prepared drug delivery systems.

References

  1. Vaupel P, Kallinowski F, Okunieff P. Blood flow, oxygen and nutrient supply, and metabolic microenvironment of human tumors: a review. Cancer Res. 1989;49:6449–65.

    CAS  PubMed  Google Scholar 

  2. Tannock IF, Rotin D. Acid pH in tumors and its potential for therapeutic exploitation. Cancer Res. 1989;49:4373–84.

    CAS  PubMed  Google Scholar 

  3. Wojtkowiak JW, Verduzco D, Schramm KJ, Gillies RJ. Drug resistance and cellular adaptation to tumor acidic pH microenvironment. Mol Pharm. 2011;8:2032–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Tian L, Bae YH. Cancer nanomedicines targeting tumor extracellular pH. Colloids Surf B Biointerfaces. 2012;99:116–26.

    Article  CAS  PubMed  Google Scholar 

  5. Béduneau A, Saulnier P, Benoit JP. Active targeting of brain tumors using nanocarriers. Biomaterials. 2007;28:4947–67.

    Article  PubMed  Google Scholar 

  6. Sudimack J, Lee RJ. Targeted drug delivery via the folate receptor. Adv Drug Deliv Rev. 2000;41:147–62.

    Article  CAS  PubMed  Google Scholar 

  7. Vugrin D, Whitmore WF Jr, Sogani PC, Bains M, Herr HW, Golbey RB. Combined chemotherapy and surgery in treatment of advanced germ-cell tumors. Cancer. 1981;47:2228–31.

    Article  CAS  PubMed  Google Scholar 

  8. Tormey DC. Combined chemotherapy and surgery in breast cancer: a review. Cancer. 1975;36:881–92.

    Article  CAS  PubMed  Google Scholar 

  9. Morise Z, Sugioka A, Tokoro T, Tanahashi Y, Okabe Y, Kagawa T, et al. Surgery and chemotherapy for intrahepatic cholangiocarcinoma. World J Hepatol. 2010;2:58–64.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Markman M, Mekhail TM. Paclitaxel in cancer therapy. Expert Opin Pharmacother. 2002;3:755–66.

    Article  PubMed  Google Scholar 

  11. Rowinsky EK, Donehower RC. Paclitaxel (taxol). N. Engl J Med. 1995;332:1004–14.

    Article  CAS  PubMed  Google Scholar 

  12. Spencer CM, Faulds D. Paclitaxel. Drugs. 1994;48:794–847.

    Article  CAS  PubMed  Google Scholar 

  13. Wang LY, Zhou BJ, Huang SQ, Qu MK, Lin Q, Gong T, et al. Novel fibronectin-targeted nanodisk drug delivery system displayed superior efficacy against prostate cancer compared with nanospheres. Nano Res. 2019;12:2451–9.

    Article  CAS  Google Scholar 

  14. Yang T, Cui FD, Choi MK, Cho JW, Chung SJ, Shim CK, et al. Enhanced solubility and stability of PEGylated liposomal paclitaxel: in vitro and in vivo evaluation. Int J Pharm. 2007;338:317–26.

    Article  CAS  PubMed  Google Scholar 

  15. Koudelka Š, Turánek J. Liposomal paclitaxel formulations. J Control Rel. 2012;163:322–34.

    Article  CAS  Google Scholar 

  16. Koren E, Torchilin VP. Cell-penetrating peptides: breaking through to the other side. Trends Mol Med. 2012;18:385–93.

    Article  CAS  PubMed  Google Scholar 

  17. Juliano RL, Alam R, Dixit V, Kang HM. Cell-targeting and cell-penetrating peptides for delivery of therapeutic and imaging agents. Wiley Interdiscip Rev Nanomed Nanobiotechnol. 2009;1:324–35.

    Article  CAS  PubMed  Google Scholar 

  18. Copolovici DM, Langel K, Eriste E, Langel Ü. Cell-penetrating peptides: design, synthesis, and applications. ACS Nano. 2014;8:1972–94.

    Article  CAS  PubMed  Google Scholar 

  19. Torchilin VP. Cell-penetrating peptide-modified pharmaceutical nanocarriers for intracellular drug and gene delivery. Biopolymers. 2008;90:604–10.

    Article  CAS  PubMed  Google Scholar 

  20. Snyder EL, Dowdy SF. Cell-penetrating peptides in drug delivery. Pharm Res. 2004;21:389–93.

    Article  CAS  PubMed  Google Scholar 

  21. Torchilin VP, Lukyanov AN. Peptide and protein drug delivery to and into tumors: challenges and solutions. Drug Discov Today. 2003;8:259–66.

    Article  CAS  PubMed  Google Scholar 

  22. Fonseca SB, Pereira MP, Kelley SO. Recent advances in the use of cell-penetrating peptides for medical and biological applications. Adv Drug Deliv Rev. 2009;61:953–64.

    Article  CAS  PubMed  Google Scholar 

  23. Mondal G, Barui S, Chaudhuri A. The relationship between the cyclic-RGDfK ligand and αvβ3 integrin receptor. Biomaterials. 2013;34:6249–60.

    Article  CAS  PubMed  Google Scholar 

  24. Sakurai Y, Hatakeyama H, Sato Y, Hyodo M, Akita H, Ohga N, et al. RNAi-mediated gene knockdown and anti-angiogenic therapy of RCCs using a cyclic RGD-modified liposomal-siRNA system. J Control Rel. 2014;173:110–8.

    Article  CAS  Google Scholar 

  25. Shi KR, Li JP, Cao ZL, Yang P, Qiu Y, Yang B, et al. A pH-responsive cell-penetrating peptide-modified liposomes with active recognizing of integrin αvβ3 for the treatment of melanoma. J Control Rel. 2015;217:138–50.

    Article  CAS  Google Scholar 

  26. Song WT, Tang ZH, Zhang DW, Zhang Y, Yu HY, Li MQ, et al. Anti-tumor efficacy of c (RGDfK)-decorated polypeptide-based micelles co-loaded with docetaxel and cisplatin. Biomaterials. 2014;35:3005–14.

    Article  CAS  PubMed  Google Scholar 

  27. Wang LY, Qu MK, Huang SQ, Fu Y, Yang LQ, He SS, et al. A novel α-enolase-targeted drug delivery system for high efficacy prostate cancer therapy. Nanoscale. 2018;10:13673–83.

    Article  CAS  PubMed  Google Scholar 

  28. Jiang TY, Mo R, Bellotti A, Zhou JP, Gu Z. Gel–liposome-mediated co-delivery of anticancer membrane-associated proteins and small-molecule drugs for enhanced therapeutic efficacy. Adv Funct Mater. 2014;24:2295–304.

    Article  CAS  Google Scholar 

  29. Jiang TY, Wang T, Li T, Ma YD, Shen SY, He BF, et al. Enhanced transdermal drug delivery by transfersome-embedded oligopeptide hydrogel for topical chemotherapy of melanoma. ACS Nano. 2018;12:9693–701.

    Article  CAS  PubMed  Google Scholar 

  30. Song X, Wan ZY, Chen TJ, Fu Y, Jiang KJ, Yi XL, et al. Development of a multi-target peptide for potentiating chemotherapy by modulating tumor microenvironment. Biomaterials. 2016;108:44–56.

    Article  CAS  PubMed  Google Scholar 

  31. Zhang XM, Zhang Q, Peng Q, Zhou J, Liao LF, Sun X, et al. Hepatitis B virus preS1-derived lipopeptide functionalized liposomes for targeting of hepatic cells. Biomaterials. 2014;35:6130–41.

    Article  CAS  PubMed  Google Scholar 

  32. Zhang QY, Tang J, Fu L, Ran R, Liu YY, Yuan MQ, et al. A pH-responsive α-helical cell-penetrating peptide-mediated liposomal delivery system. Biomaterials. 2013;34:7980–93.

    Article  CAS  PubMed  Google Scholar 

  33. Yang T, Choi MK, Cui FD, Kim JS, Chung SJ, Shim CK, et al. Preparation and evaluation of paclitaxel-loaded PEGylated immunoliposome. J Control Rel. 2007;120:169–77.

    Article  CAS  Google Scholar 

  34. Qu MK, Lin Q, He SS, Wang LY, Fu Y, Zhang ZR, et al. A brain targeting functionalized liposomes of the dopamine derivative N-3, 4-bis (pivaloyloxy)-dopamine for treatment of Parkinson’s disease. J Control Rel. 2018;277:173–82.

    Article  CAS  Google Scholar 

  35. Huang SQ, Deng L, Zhang HM, Wang LY, Zhang YC, Lin Q, et al. Co-delivery of TRAIL and paclitaxel by fibronectin-targeting liposomal nanodisk for effective lung melanoma metastasis treatment. Nano Res. 2022;15:728–37.

    Article  CAS  Google Scholar 

  36. Khalil IA, Kogure K, Futaki S, Hama S, Akita H, Ueno M, et al. Octaarginine-modified multifunctional envelope-type nanoparticles for gene delivery. Gene Ther. 2007;14:682.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Jang B, Park JY, Tung CH, Kim IH, Choi Y. Gold nanorod-photosensitizer complex for near-infrared fluorescence imaging and photodynamic/photothermal therapy in vivo. ACS Nano. 2011;5:1086–94.

    Article  CAS  PubMed  Google Scholar 

  38. Lammers T, Kiessling F, Hennink WE, Storm G. Drug targeting to tumors: principles, pitfalls and (pre-) clinical progress. J Control Rel. 2012;161:175–87.

    Article  CAS  Google Scholar 

  39. Bigini P, Previdi S, Casarin E, Silvestri D, Violatto MB, Facchin S, et al. In vivo fate of avidin-nucleic acid nanoassemblies as multifunctional diagnostic tools. ACS Nano. 2014;8:175–87.

    Article  CAS  PubMed  Google Scholar 

  40. Gao YJ, Zhou YX, Zhao L, Zhang C, Li YS, Li JW, et al. Enhanced antitumor efficacy by cyclic RGDyK-conjugated and paclitaxel-loaded pH-responsive polymeric micelles. Acta Biomater. 2015;23:127–35.

    Article  CAS  PubMed  Google Scholar 

  41. Al-Jamal KT, Al-Jamal WT, Wang JT, Rubio N, Buddle J, Gathercole D, et al. Cationic poly-L-lysine dendrimer complexes doxorubicin and delays tumor growth in vitro and in vivo. ACS Nano. 2013;7:1905–17.

    Article  CAS  PubMed  Google Scholar 

  42. Xu ZH, Wang YH, Zhang L, Huang L. Nanoparticle-delivered transforming growth factor-beta siRNA enhances vaccination against advanced melanoma by modifying tumor microenvironment. ACS Nano. 2014;8:3636–45.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Huang SQ, Zhang YC, Wang LY, Liu W, Xiao LY, Lin Q, et al. Improved melanoma suppression with target-delivered TRAIL and Paclitaxel by a multifunctional nanocarrier. J Control Rel. 2020;325:10–24.

    Article  CAS  Google Scholar 

  44. Salvati A, Pitek AS, Monopoli MP, Prapainop K, Bombelli FB, Hristov DR, et al. Transferrin-functionalized nanoparticles lose their targeting capabilities when a biomolecule corona adsorbs on the surface. Nat Nanotechnol. 2013;8:137–43.

    Article  CAS  PubMed  Google Scholar 

  45. Spinks CB, Zidan AS, Khan MA, Habib MJ, Faustino PJ. Pharmaceutical characterization of novel tenofovir liposomal formulations for enhanced oral drug delivery: in vitro pharmaceutics and Caco-2 permeability investigations. Clin Pharmacol. 2017;9:29.

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Lainé AL, Gravier J, Henry M, Sancey L, Béjaud J, Pancani E, et al. Conventional versus stealth lipid nanoparticles: Formulation and in vivo fate prediction through FRET monitoring. J Control Rel. 2014;188:1–8.

    Article  Google Scholar 

  47. Xiao D, Jia HZ, Ma N, Zhuo RX, Zhang XZ. A redox-responsive mesoporous silica nanoparticle capped with amphiphilic peptides by self-assembly for cancer-targeting drug delivery. Nanoscale. 2015;7:10071–7.

    Article  CAS  PubMed  Google Scholar 

  48. Yu YC, Tirrell M, Fields GB. Minimal lipidation stabilizes protein-like molecular architecture. J Am Chem Soc. 1998;120:9979–87.

    Article  CAS  Google Scholar 

  49. Forns P, Lauer‐Fields JL, Gao S, Fields GB. Induction of protein-like molecular architecture by monoalkyl hydrocarbon chains. Biopolymers. 2000;54:531–46.

    Article  CAS  PubMed  Google Scholar 

  50. Han J, Huang X, Sun LD, Li Z, Qian H, Huang WL. Novel fatty chain-modified glucagon-like peptide-1 conjugates with enhanced stability and prolonged in vivo activity. Biochem Pharmacol. 2013;86:297–308.

    Article  CAS  PubMed  Google Scholar 

  51. Zhang HY, Schneider SE, Bray BL, Friedrich PE, Tvermoes NA, Mader CJ, et al. Process development of TRI-999, a fatty-acid-modified HIV fusion inhibitory peptide. Org Process Res Dev. 2008;12:101–10.

    Article  Google Scholar 

Download references

Acknowledgements

This work was supported by the National Natural Science Foundation of China (Nos. 81690261, 82022070 and 81872824) and the Medico-Engineering Cooperation Programme from the Med-X Center for Materials, Sichuan University (MCM202103).

Author information

Authors and Affiliations

Authors

Contributions

ZRZ and LZ designed the research; SQH, HMZ and YCZ performed the research; ZRZ and LZ contributed new reagents or analytical tools; SQH and LYW analysed the data, and SQH and LZ wrote the paper.

Corresponding author

Correspondence to Ling Zhang.

Ethics declarations

Competing interests

The authors declare no competing interests.

Rights and permissions

Springer Nature or its licensor holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Huang, Sq., Zhang, Hm., Zhang, Yc. et al. Comparison of two methods for tumour-targeting peptide modification of liposomes. Acta Pharmacol Sin (2022). https://doi.org/10.1038/s41401-022-01011-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1038/s41401-022-01011-4

Keywords

  • liposomes
  • C18-TR
  • TR
  • tumour-targeting
  • cell-penetrating peptides
  • B16F10 melanoma cells

Search

Quick links