Skip to main content

Advertisement

SpringerLink
Log in

Co-delivery of gemcitabine and cisplatin via Poly (L-glutamic acid)-g-methoxy poly (ethylene glycol) micelle to improve the in vivo stability and antitumor effect

  • Research Paper
  • Published:
Pharmaceutical Research Aims and scope Submit manuscript

Abstract

Purpose

The intention of the study was to co-delivery gemcitabine and cisplatin with totally different nature by prodrug and micelle strategy to improve its in vivo stability and antitumor effect.

Methods

A prodrug of gemcitabine (mPEG-PLG-GEM) was synthesized through the covalent conjugation between the primary amino group of gemcitabine and the carboxylic group of poly (L-glutamic acid)-g-methoxy poly (ethylene glycol) (mPEG-PLG). It was prepared into micelles by a solvent diffusion method, and then combined with cisplatin through chelation to prepare gemcitabine and cisplatin co-loaded mPEG-PLG micelles (mPEG-PLG-GEM@CDDP micelles).

Results

Gemcitabine and cisplatin in each micelle group were released more slowly than in solutions. In addition, pharmacokinetics behaviors of them were improved after encapsulated in prodrug micelles. T1/2z of gemcitabine and cisplatin encapsulated in micelles were prolonged to 6.357 h (mPEG-PLG-GEM), 10.490 h (mPEG-PLG@CDDP), 5.463 h and 12.540 h (mPEG-PLG-GEM@CDDP) compared with GEM@CDDP solutions (T1/2z = 1.445 h and 7.740 h). The ratio of synergy between gemcitabine and cisplatin (3:1 ~ 1:1(n/n)) was guaranteed in the systemic circulation, thus improving its antitumor effect. The results of biochemical analysis showed that GEM@CDDP-Sol was more toxic to kidneys and marrow compared with mPEG-PLG-GEM@CDDP micelles.

Conclusions

By prodrug strategy, gemcitabine and cisplatin with totally different nature were prepared into micelles and obtained a better pharmacokinetic behavior. And the dual drug delivery system performed a better in vivo stability and antitumor effect compared with each single drug delivery system in the experiment.

Graphical abstract

Scheme. Schematic of mPEG-PLG-GEM@CDDP micelles’ formation and action process.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8

Similar content being viewed by others

Abbreviations

GEM:

Gemcitabine hydrochloride

dFdCDP:

Nucleoside diphosphate

dFdCTP:

Nucleoside triphosphate

dCTP:

Deoxynucleotide

CDDP:

Cisplatin

EDC·HCL:

1-Ethyl-3-[3-dimethylaminopropyl] carbodiimide hydrochloride

NHS:

N-Hydroxysuccinimide

DLC:

Drug loading content

DLE:

Drug loading efficiency

PDI:

Polydispersity index

DLS:

Dynamic light scattering

TEM:

Transmission electron microscopy

CMC:

Critical micelle concentration

CI:

Combination index

RBC:

Red blood cell

HR:

Hemolysis ratio

HE:

Hematoxylin and eosin

CLSM:

Confocal laser scanning microscopy

AUC:

Area under the concentration–time curve

TIR:

Tumor inhibition rate

mPEG-PLG:

Poly (L-glutamic acid)-g-methoxy poly(ethylene glycol)

mPEG-PLG-GEM:

Prodrug of gemcitabine

mPEG-PLG-GEM@CDDP:

Gemcitabine and cisplatin co-loaded mPEG-PLG micelles

GEM@CDDP-Sol:

Gemcitabine hydrochloride and cisplatin solutions

RR:

Ribonucleotide reductase

DMF:

N,N-Dimethylformamide

1H-NMR:

Nuclear Magnetic Resonance

FTIR:

Fourier Transform infrared spectroscopy

RP-HPLC:

Reversed phase high performance liquid chromatography

DMEM:

Dulbecco's modified Eagle's medium

mPEG-PLG-FITC:

FITC loaded mPEG-PLG micelles

PBS:

Phosphate buffered solution

DAPI:

4',6-Diamidino-2-phenylindol, 2-(4-amidinophenyl)-1H -indole-6-carboxamidine

LC–MS/MS:

Liquid chromatograph-mass spectrometer

WBC:

White blood cell

HGB:

Hemoglobin

PLT:

Platelet

AST:

Aspartate Transaminase

ALT:

Alanine transaminase

BUN:

Blood urea nitrogen

CR:

Creatinine

GEM-Sol:

Gemcitabine hydrochloride solutions

CDDP-Sol:

Cisplatin solutions

FITC-Sol:

Fluorescein isothiocyanate isomer solutions

PEG:

Polyethylene glycol

Vz :

Apparent volume of distribution

CLz :

Clearance

PK:

Pharmacokinetics

t1/2z :

Half life

Cmax :

Peak Concentration

References

  1. Bray F, Ferlay J, Soerjomataram I, et al. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA: A Cancer Journal for Clinicians 2018;68(6): 394–424.

  2. Cronin K A, Lake A J, Scott S, et al. Annual report to the nation on the status of cancer, part I: National cancer statistics. Cancer 2018;124(13): 2785–800.

  3. Feng R M, Zong Y N, Cao S M, et al. Current cancer situation in China: good or bad news from the 2018 Global Cancer Statistics? Cancer Communications 2019;39(1):1–12.

  4. Chen Q, Luo L, Xue Y, Han J, Tang X. Cisplatin-loaded polymeric complex micelles with a modulated drug/copolymer ratio for improved in vivo performance. Acta Biomater. 2019;94:205–18.

    Article  Google Scholar 

  5. Zou L, Wang D, Hu Y, Fu C, Zhang J. Drug resistance reversal in ovarian cancer cells of paclitaxel and borneol combination therapy mediated by PEG-PAMAM nanoparticles. Oncotarget. 2017;8(36):60453–68.

    Article  Google Scholar 

  6. Mengyi H, Zhenglan H, Sicheng C, Hao W, Tianyu F, Shujuan Y, et al. Synergistic antitumor effect of suberoylanilide hydroxamic acid and cisplatin in osteosarcoma cells. Oncology Letters. 2018;16(4):4663–70.

  7. Zhou M, Li L, Li L, et al. Overcoming chemotherapy resistance via simultaneous drug-efflux circumvention and mitochondrial targeting. Acta Pharmaceutica Sinica B 2019;9(3):615–25.

  8. Sottile R, Pangigadde PN, Tan T, Anichini A, Sabbatino F, Trecroci F, et al. HLA class I downregulation is associated with enhanced NK-cell killing of melanoma cells with acquired drug resistance to BRAF inhibitors. Eur J Immunol. 2016;46(2):409–19.

    Article  CAS  Google Scholar 

  9. Yuan YG, Peng QL, Sangiliyandi G. Silver nanoparticles enhance the apoptotic potential of gemcitabine in human ovarian cancer cells: combination therapy for effective cancer treatment. Int J Nanomedicine. 2017;12:6487–502.

    Article  CAS  Google Scholar 

  10. Chandran S, Praveen G, Snima KS, Nair SV, Pavithran K, Chennazhi K, et al. Potential use of drug loaded nano composite pectin scaffolds for the treatment of ovarian cancer. Curr Drug Deliv. 2013;10(3):326–35.

    Article  CAS  Google Scholar 

  11. Şenyiğit ZA, Karavana SY, Ozdemir DI, Caliskan C, Baloglu E. Design and evaluation of an intravesical delivery system for superficial bladder cancer: preparation of gemcitabine HCl-loaded chitosan–thioglycolic acid nanoparticles and comparison of chitosan/poloxamer gels as carriers. International Journal of Nanomedicine. 2015;10(default):6493.

    Article  Google Scholar 

  12. Jing L, Shu W, Zeng-Feng S, Yuan Y. Synergistic effects of sorafenib in combination with gemcitabine or pemetrexed in lung cancer cell lines with K-ras mutations. Contemp Oncol. 2016;20(1):33–8.

    Google Scholar 

  13. Dora CP, Kushwah V, Katiyar SS, Kumar P, Jain S. Improved metabolic stability and therapeutic efficacy of a novel molecular gemcitabine phospholipid complex. Int J Pharm. 2017;530(1):113–27.

    Article  CAS  Google Scholar 

  14. Parsian M, Unsoy G, Mutlu P, et al. Loading of Gemcitabine on chitosan magnetic nanoparticles increases the anti-cancer efficacy of the drug. European Journal of Pharmacology. 2016;784:121–8.

  15. Schelhaas S, Held A, Wachsmuth L, et al. Gemcitabine mechanism of action confounds early assessment of treatment response by 3′-deoxy-3′-[18F] fluorothymidine in preclinical models of lung cancer. Cancer research, 2016;76(24):7096–105.

  16. Sloat BR, Sandoval MA, Li D, Chung WG, Lansakara PD, Proteau PJ, et al. In vitro and in vivo anti-tumor activities of a gemcitabine derivative carried by nanoparticles. Int J Pharm. 2011;409(1–2):278–88.

    Article  CAS  Google Scholar 

  17. de Sousa CL, Monteiro G. Gemcitabine: metabolism and molecular mechanisms of action, sensitivity and chemoresistance in pancreatic cancer. Eur J Pharmacol. 2014;741:8–16.

    Article  Google Scholar 

  18. Johnstone T C, Suntharalingam K, Lippard S J. The next generation of platinum drugs: targeted Pt (II) agents, nanoparticle delivery, and Pt (IV) prodrugs. Chemical Reviews 2016;116(5): 3436–86.

  19. Zhang X, Li L, Li C, et al. Cisplatin-crosslinked glutathione-sensitive micelles loaded with doxorubicin for combination and targeted therapy of tumors. Carbohydrate polymers 2017;155: 407–15.

  20. Miao L, Guo S, Zhang J, Kim WY, Huang L. Nanoparticles with Precise Ratiometric Co-Loading and Co-Delivery of Gemcitabine Monophosphate and Cisplatin for Treatment of Bladder Cancer. Adv Funct Mater. 2014;24(42):6601–11.

    Article  CAS  Google Scholar 

  21. Chen T Y, Tsai M J, Chang L C, et al. Co-Delivery of cisplatin and gemcitabine via viscous nanoemulsion for potential synergistic intravesical chemotherapy. Pharmaceutics 2020;12(10):949.

  22. Yu H, Song H, Xiao J, Chen H, Jin X, Lin X, et al. The effects of novel chitosan-targeted gemcitabine nanomedicine mediating cisplatin on epithelial mesenchymal transition, invasion and metastasis of pancreatic cancer cells. Biomed Pharmacother. 2017;96:650–8.

    Article  CAS  Google Scholar 

  23. Emamzadeh M, Emamzadeh M, Pasparakis G. Dual controlled delivery of gemcitabine and cisplatin using polymer-modified thermosensitive liposomes for pancreatic cancer. ACS Applied Bio Materials 2019;2(3):1298–309.

  24. Zhang R, Ru Y, Gao Y, Li J, Mao S. Layer-by-layer nanoparticles co-loading gemcitabine and platinum (IV) prodrugs for synergistic combination therapy of lung cancer. Drug Des Devel Ther. 2017;11:2631–42.

    Article  CAS  Google Scholar 

  25. Liu Z, Chu W, Sun Q, et al. Micelle-contained and PEGylated hybrid liposomes of combined gemcitabine and cisplatin delivery for enhancing antitumor activity. International Journal of Pharmaceutics 2021;602:120619.

  26. Junjie L, Xingming G, Zhong L, Jixi Z, Menghuan L, Kaiyong C. Hierarchically stimuli-responsive nanovectors for improved tumor penetration and programed tumor therapy. Nanoscale. 2018;10: https://doi.org/10.1039.C8NR02971G

  27. Wang Y, Qian J, Yang M, Xu W, Wang J, Hou G, et al. Doxorubicin/cisplatin co-loaded hyaluronic acid/chitosan-based nanoparticles for in vitro synergistic combination chemotherapy of breast cancer. Carbohydr Polym. 2019;225:115206.

    Article  CAS  Google Scholar 

  28. Gonzalez-Urias A, Zapata-Gonzalez I, Licea-Claverie A, Licea-Navarro AF, Bernaldez-Sarabia J, Cervantes-Luevano K. Cationic versus anionic core-shell nanogels for transport of cisplatin to lung cancer cells. Colloids Surf B Biointerfaces. 2019;182:110365.

    Article  CAS  Google Scholar 

  29. Li Y, Lu H, Liang S, et al. Dual stable nanomedicines prepared by cisplatin-crosslinked camptothecin prodrug micelles for effective drug delivery. ACS Applied Materials & Interfaces 2019:11(23): 20649–59.

  30. Kuijpers AJ, Engbers GH, Krijgsveld J, Zaat SA, Dankert J, Feijen J. Cross-linking and characterisation of gelatin matrices for biomedical applications. J Biomater Sci Polym Ed. 2000;11(3):225–43.

    Article  CAS  Google Scholar 

  31. Li Q, Lv S, Tang Z, Liu M, Zhang D, Yang Y, et al. A co-delivery system based on paclitaxel grafted mPEG-b-PLG loaded with doxorubicin: preparation, in vitro and in vivo evaluation. Int J Pharm. 2014;471(1–2):412–20.

    Article  CAS  Google Scholar 

  32. Khare V, Al Shakarchi W, Gupta P, Curtis A, Hoskins C. Synthesis and characterization of TPGS–gemcitabine prodrug micelles for pancreatic cancer therapy. Rsc Advances. 2016: https://doi.org/10.1039.C6RA09347G

  33. Ding N, Wang Y, Wang X, et al. Improving plasma stability and antitumor effect of gemcitabine via PEGylated liposome prepared by active drug loading. Journal of Drug Delivery Science and Technology 2020;57:101538.

  34. Chou TC. Drug combination studies and their synergy quantification using the Chou-Talalay method. Cancer Res. 2010;70(2):440–6.

    Article  CAS  Google Scholar 

  35. Ashton JC. Drug combination studies and their synergy quantification using the chou-talalay method-letter. Cancer Res. 2015;75(11):2400.

    Article  CAS  Google Scholar 

  36. McKeon A M, Egan A, Chandanshive J, et al. Novel improved synthesis of HSP70 inhibitor, pifithrin-μ. in vitro synergy quantification of pifithrin-μ combined with Pt drugs in prostate and colorectal cancer cells. Molecules 2016;21(7):949.

  37. Lv S, Tang Z, Li M, Lin J, Song W, Liu H, et al. Co-delivery of doxorubicin and paclitaxel by PEG-polypeptide nanovehicle for the treatment of non-small cell lung cancer. Biomaterials. 2014;35(23):6118–29.

    Article  CAS  Google Scholar 

  38. Li M, Song W, Tang Z, et al. Nanoscaled poly (L-glutamic acid)/doxorubicin-amphiphile complex as pH-responsive drug delivery system for effective treatment of nonsmall cell lung cancer. ACS Applied Materials & Interfaces 2013;5(5):1781–92.

  39. Qu Y, An F, Luo Y, et al. A nephron model for study of drug-induced acute kidney injury and assessment of drug induced nephrotoxicity. Biomaterials 2018;155:41–53.

  40. Sakolish C, Chen Z, Dalaijamts C, et al. Predicting tubular reabsorption with a human kidney proximal tubule tissue-on-a-chip and physiologically-based modeling. Toxicology in Vitro 2020;63:104752

  41. Li M, Tang Z, Lv S, Song W, Hong H, Jing X, et al. Cisplatin crosslinked pH-sensitive nanoparticles for efficient delivery of doxorubicin. Biomaterials. 2014;35(12):3851–64.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We sincerely thank Amanda Pearce for the linguistic assistance during the revision of this manuscript.

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Author information

Authors and Affiliations

  1. Department of Pharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University, Shenyang, 110016, Liaoning, People’s Republic of China

    Ning Ding, Zhiqing Zhao, Na Yin, Ying Xu, Jingxin Gou, Haibing He, Yanjiao Wang, Yu Zhang & Xing Tang

  2. School of Functional Food and Wine, Shenyang Pharmaceutical University, Shenyang, 110016, Liaoning, People’s Republic of China

    Tian Yin

Authors
  1. Ning Ding
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Zhiqing Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Na Yin
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ying Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Tian Yin
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Jingxin Gou
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Haibing He
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Yanjiao Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Yu Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Xing Tang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Haibing He.

Ethics declarations

Conflict of interest

The authors declare no competing financial interest.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (DOCX 820 KB)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Ding, N., Zhao, Z., Yin, N. et al. Co-delivery of gemcitabine and cisplatin via Poly (L-glutamic acid)-g-methoxy poly (ethylene glycol) micelle to improve the in vivo stability and antitumor effect. Pharm Res 38, 2091–2108 (2021). https://doi.org/10.1007/s11095-021-03139-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11095-021-03139-0

Keywords

Search

Navigation