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Chitosan Engineered PAMAM Dendrimers as Nanoconstructs for the Enhanced Anti-Cancer Potential and Improved In vivo Brain Pharmacokinetics of Temozolomide

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Abstract

Purpose

To establish a platform for the possibility of effective and safe delivery of Temozolomide (TMZ) to brain via surface engineered (polyamidoamine) PAMAM dendrimer for the treatment of glioblastoma.

Methods

The present study aims to investigate the efficacy of PAMAM-chitosan conjugate based TMZ nanoformulation (PCT) against gliomas in vitro as well as in vivo. The prepared nanoconjugated formulation was characterized by 1H NMR, FT-IR spectroscopy and for surface morphological parameters. The reported approach was also designed in such a way to ensure toxicity before in vivo delivery through conducting the hemolytic study.

Result

Surface morphology was found as per nanoformulation via size, pdi and zeta potential measurement. PCT was more efficacious in terms of IC50 values compared to pure TMZ against U-251 and T-98G glioma cell lines. The in vivo pharmacokinetic parameters proved sustained release fashion such as half-life (t1/2) of 22.74 h (PCT) rather than15.35 h (TMZ) only. Higher concentration was found in heart than brain in bio-distribution studies. This study exhibits the potential applicability of dendrimer and CS in improving the anticancer activity and delivery of TMZ to brain.

Conclusion

The attractive ex vivo cytotoxicity against two glioma cell lines; U-251 and T-98G and phase solubility studies of TMZ revealed remarkable results. In vivo studies of prepared nanoformulation were significant and promising that explored the double concentration of TMZ in brain due to surface functionality of dendrimer. The reported work is novel and non- obvious as none of such approaches using chitosan anchored dendrimer for TMZ delivery has been reported earlier.

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Abbreviations

AFM:

Atomic force microscopy

BBB:

Bloood brain barrier

CBC:

Complete blood count

CS:

Chitosan

DMSO:

Dimethylsulphoxide

EDC:

1-(3-dimethylaminopropyl)-3-ethyl carbodiimide

MCH:

Mean corpuscular hemoglobin

MCHC:

Mean corpuscular hemoglobin concentration

MCV:

Mean corpuscle volume

PAMAM:

Polyamidoamine

PCS:

PAMAM-chitosan conjugates

PCT:

Temozolamide loaded PAMAM-chitosan conjugates formulation

SEM:

Scanning electron microscopy

TMZ:

Temozolamide

References

  1. World cancer report. In: Stewart BW, Wild CW, editors. World health organization. Geneva: IARC Publications; 2014.

  2. GLOBOCAN. v1.0, Cancer Incidence and Mortality Worldwide: IARC CancerBase No. 11. International Agency for Research on Cancer; 2013. http://globocan.iarc.fr 2012. Accessed 19 Feb 2014.

  3. Hashizume R, Ozawa T, Gryaznov SM, Bollen AM, Lamborn KR, Frey WH, et al. New therapeutic approach for brain tumors: Intranasal delivery of telomerase inhibitor GRN163. Neuro-Oncol. 2008;10:112–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Louis DN, Ohgaki H, Wiestler OD, Cavenee WK, Burger PC, Jouvet A, et al. The WHO classification of tumours of the central nervous system. ActaNeuropathol. 2007;114:97.

    Google Scholar 

  5. Sarin H. Recent progress towards development of effective systemic chemotherapy for the treatment of malignant brain tumors. J Trans Med. 2009;7:77.

    Article  Google Scholar 

  6. Kesharwani P, Jain K, Jain NK. Dendrimer as nanocarrier for drug delivery. ProgPolym Sci. 2014;39:268–307.

    CAS  Google Scholar 

  7. Na M, Yiyun C, Tongwen X, Yang D, Xiaomin W, Zhenwei L, et al. Dendrimers as potential drug carriers Part II. Prolonged delivery of ketoprofen by in vitro and in vivo studies. Euro J Med Chem. 2006;41:670–4.

    Article  Google Scholar 

  8. Swanson SD, Kukowska-Latallo JF, Patri AK, Chen C, Ge S, Cao Z, et al. Baker Jr. Targeted gadolinium-loaded dendrimer nanoparticles for tumor-specific magnetic resonance contrast enhancement. Int J Nanomedicine. 2008;3:201–10.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Trapani A, Denora N, Wang F, Gallo JM, Trapani G. New strategies to deliver anticancer drugs to brain tumors. Expert Opin Drug Deliv. 2009;10:1017–32.

    Google Scholar 

  10. Chiou SH, Immobilization WWT. of Candida rugosa lipase on chitosan with activation of the hydroxyl groups. Biomaterials. 2006;25:197–204.

    Article  Google Scholar 

  11. Katare YK, Daya RP, Gray CS, Luckham RP, Bhandari J, Chauhan AS, et al. Brain targeting of a water insoluble antipsychotic drug haloperidol via the intranasal route using PAMAM dendrimer. Mol Pharm. 2015;12:3380–8.

    Article  CAS  PubMed  Google Scholar 

  12. Bhadra D, Bhadra S, Jain S, Jain NKA. PEGylated dendritic nanoparticulate carrier of fluorouracil. Int J Pharm. 2003;257:111–24.

    Article  CAS  PubMed  Google Scholar 

  13. Costa P, Lobo JMS. Modeling and comparison of dissolution profiles. Euro. J Pharm Sci. 2001;13:123–33.

    CAS  Google Scholar 

  14. Dash S, Murthy PN, Nath L, Chowdhury P. Kinetic modeling on drug release from controlled drug delivery systems. Acta Pol Pharm Drug Res. 2010;67:217–23.

    CAS  Google Scholar 

  15. Kulhari H, Pooja D, Prajapati SK, Chauhan AS. Performance evaluation of PAMAM dendrimer based simvastatin formulations. Int J Pharm. 2011;405:203–9.

    Article  CAS  PubMed  Google Scholar 

  16. Singhai AK, Jain S, Jain NK. Evaluation of an aqueous injection of Ketoprofen. Pharmazie. 1997;52:149–51.

    CAS  PubMed  Google Scholar 

  17. Agarwal P, Gupta U, Jain NK. Glycoconjugated peptide dendrimers-based nanoparticulate system for the delivery of chloroquine phosphate. Biomaterials. 2007;28:3349–59.

    Article  Google Scholar 

  18. Song H, Geng H, Ruan J, Wang K, Bao C, Wang J, et al. Development of Polysorbate 80/Phospholipid mixed micellar formation for docetaxel and assessment of its in vivo distribution in animal models. Nanoscale Res Lett. 2011;6:1–12.

  19. Yoshino A, Ogino A, Yachi K, Ohta T, Fukushima T, Watanabe T, et al. Gene expression profiling predicts response to temozolomide in malignant gliomas. Int J Oncol. 2010;36:1367–77.

    Article  CAS  PubMed  Google Scholar 

  20. Agrawal U, Gupta U, Jain NK. Glycoconjugated peptide dendrimers-based nanoparticulate system for the delivery of chloroquine phosphate. Biomaterials. 2007;28:3349–59.

    Article  CAS  PubMed  Google Scholar 

  21. Chauhan AS, Jain NK, Diwan PV. Pre-clinical and behavioural toxicity profile of PAMAM dendrimers in mice. Proc R Soc A. 2010;466:1535–50.

    Article  CAS  Google Scholar 

  22. Miura H, Onishi H, Sasatsu M, Machida Y. Antitumor characteristics of methoxypolyethylene glycol-poly(DL-lactic acid) nanoparticles containing camptothecin. J Control Release. 2004;97:101–13.

    Article  CAS  PubMed  Google Scholar 

  23. Straub JA, Chickering DE, Lovely JC, Zhang H, Shah B, Waud WR, et al. Intravenous hydrophobic drug delivery: a porous particle formulation of paclitaxel (AI-850). Pharm Res. 2005;22:347–55.

    Article  CAS  PubMed  Google Scholar 

  24. Jain D, Bajaj A, Athawale R, Shrikhande S, Goel PN, Nikam Y, Gude R, Patil S, Raut PR. Surface-coated PLA nanoparticles loaded with temozolomide for improved brain deposition and potential treatment of gliomas: development, characterization and in vivo studies. Drug Deliv. 2016;23:1–18.

  25. Khan A, Imam SS, Aqil M, Ahad A, Sultana Y, Ali A, et al. Brain Targeting of Temozolomide via the intranasal route using lipid-based nanoparticles: Brain pharmacokinetic and scintigraphic analyses. Mol Pharm. 2016;13:3773–82.

    Article  CAS  PubMed  Google Scholar 

  26. Kasaai MR. Determination of the degree of N-acetylation for chitin and chitosan by various NMR spectroscopy techniques: A review. Carbohydrate Polym. 2010;79:801–10.

    Article  CAS  Google Scholar 

  27. Dongen M, Dougherty C, Holl M. Multivalent polymers for drug delivery and imaging: The challenges of conjugation. Biomacromolecules. 2014;15:3215–34.

    Article  PubMed  PubMed Central  Google Scholar 

  28. Zhang S, Zhao Y, Zhao B, Wang B. Hybrids of Nonviral Vectors for Gene Delivery. Bioconjug Chem. 2010;21:1003–9.

    Article  CAS  PubMed  Google Scholar 

  29. Wolinsky JB, Grinstaff MW. Therapeutic and diagnostic applications of dendrimers for cancer treatment. Adv Drug Deliv Rev. 2008;60:1037–55.

    Article  CAS  PubMed  Google Scholar 

  30. Wang H, Zhao Y, Wu Y, YL H, Nan K, Nie G, et al. Enhanced anti-tumor efficacy by co-delivery of doxorubicin and paclitaxel with amphiphilicmethoxy PEG-PLGA copolymer nanoparticles. Biomaterials. 2011;32:8281–90.

    Article  CAS  PubMed  Google Scholar 

  31. Singh P, Gupta U, Asthana A, Jain NK. Folate and folate-PEG-PAMAM dendrimers: synthesis, characterization and targeted anticancer drug delivery potential in tumor induced mice. Bioconjug Chem. 2008;19:2239–52.

    Article  CAS  PubMed  Google Scholar 

  32. Gupta M, Chashoo G, Sharma PR, Saxena AK, Gupta PN, Agarwal GP, et al. Dual targeted polymeric nanoparticles based on tumor endothelium and tumor cells for enhanced antitumor drug deliver. Mol Pharm. 2014;11:697–715.

    Article  CAS  PubMed  Google Scholar 

  33. Jain A, Singhai P, Gurnany E, Updhayay S, Mody N. Transferrin-tailored solid lipid nanoparticles as vectors for site-specific delivery of temozolomide to brain. J Nanopart Res. 2013;15:1–9.

    Google Scholar 

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ACKNOWLEDGMENTS AND DISCLOSURES

The authors would like to acknowledge the financial support received from University Grants Commission, New Delhi, India to Dr. Umesh Gupta as UGC-Start up Research Grant and Mr. Ashok Kumar Sharma as UGC-National Research Fellowship. Authors also acknowledge Rungta College of Pharmaceutical Science and Research, Bhilai, Chhattisgarh, India for supporting necessary facilities to conduct animal studies.

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Authors and Affiliations

  1. Department of Pharmacy, School of Chemical Sciences and Pharmacy, Central University of Rajasthan,, Bandarsindri, Ajmer, Rajasthan, 305817, India

    Ashok Kumar Sharma, Lokesh Gupta, Hitesh Sahu & Umesh Gupta

  2. Cancer Pharmacology Division,, CSIR-Indian Institute of Integrative Medicine,, Jammu, 180001, India

    Arem Qayum & Shashank K. Singh

  3. Rungta College of Pharmaceutical Science and Research, Kohka, Bhilai, Chhattisgarh, India

    Kartik T. Nakhate &  Ajazuddin

Authors
  1. Ashok Kumar Sharma
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  2. Lokesh Gupta
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Correspondence to Umesh Gupta.

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Sharma, A.K., Gupta, L., Sahu, H. et al. Chitosan Engineered PAMAM Dendrimers as Nanoconstructs for the Enhanced Anti-Cancer Potential and Improved In vivo Brain Pharmacokinetics of Temozolomide. Pharm Res 35, 9 (2018). https://doi.org/10.1007/s11095-017-2324-y

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  • DOI: https://doi.org/10.1007/s11095-017-2324-y

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