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Angiopep-Conjugated Nanoparticles for Targeted Long-Term Gene Therapy of Parkinson’s Disease

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ABSTRACT

Purpose

To prepare an angiopep-conjugated dendrigraft poly-L-lysine (DGL)-based gene delivery system and evaluate the neuroprotective effects in the rotenone-induced chronic model of Parkinson’s disease (PD).

Methods

Angiopep was applied as a ligand specifically binding to low-density lipoprotein receptor-related protein (LRP) which is overexpressed on blood-brain barrier (BBB), and conjugated to biodegradable DGL via hydrophilic polyethyleneglycol (PEG), yielding DGL-PEG-angiopep (DPA). In vitro characterization was carried out. The neuroprotective effects were evaluated in a chronic parkinsonian model induced by rotenone using a regimen of multiple dosing intravenous administrations.

Results

The successful synthesis of DPA was demonstrated via 1H-NMR. After encapsulating the therapeutic gene encoding human glial cell line-derived neurotrophic factor (hGDNF), DPA/hGDNF NPs showed a sphere-like shape with the size of 119 ± 12 nm and zeta potential of 8.2 ± 0.7 mV. Angiopep-conjugated NPs exhibited higher cellular uptake and gene expression in brain cells compared to unmodified counterpart. The pharmacodynamic results showed that rats in the group with five injections of DPA/hGDNF NPs obtained best improved locomotor activity and apparent recovery of dopaminergic neurons compared to those in other groups.

Conclusion

This work provides a practical non-viral gene vector for long-term gene therapy of chronic neurodegenerative disorders.

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Abbreviations

BBB:

blood-brain barrier

BCECs:

brain capillary endothelial cells

DGL:

dendrigraft poly-L-lysine

DPA:

DGL-PEG-angiopep

GFP:

green fluorenscent protein

hGDNF :

the gene encoding human glial cell line-derived neurotrophic factor

LRP:

low-density lipoprotein receptor-related protein

NMR:

nuclear magnetic resonance

NPs:

nanoparticles

PAMAM:

polyamidoamine

PBS:

phosphate-buffered solution

PD:

Parkinson’s disease

PEG:

polyethylene glycol

PPA:

PAMAM-PEG-angiopep

TH:

tyrosine hydroxylase

REFERENCES

  1. Di Stefano A, Sozio P, Cerasa LS, Iannitelli A. L-Dopa prodrugs: an overview of trends for improving Parkinson’s disease treatment. Curr Pharm Des. 2011;17(32):3482–93.

    Article  PubMed  Google Scholar 

  2. Reichmann H, Emre M. Optimizing levodopa therapy to treat wearing-off symptoms in Parkinson’s disease: focus on levodopa/carbidopa/entacapone. Expert Rev Neurother. 2012;12(2):119–31.

    Article  PubMed  CAS  Google Scholar 

  3. Björklund A, Björklund T, Kirik D. Gene therapy for dopamine replacement in Parkinson’s disease. Sci Transl Med. 2009;1(2):2ps2.

    Article  PubMed  Google Scholar 

  4. Huang RQ, Ke WL, Liu Y, Wu DD, Feng LY, Jiang C, et al. Gene therapy using lactoferrin-modified nanoparticles in a rotenone-induced chronic Parkinson model. J Neurol Sci. 2010;290(1–2):123–30.

    Article  PubMed  CAS  Google Scholar 

  5. Boado RJ, Pardridge WM. The Trojan horse liposome technology for nonviral gene transfer across the blood-brain barrier. J Drug Deliv. 2011;2011:296151.

    Article  PubMed  Google Scholar 

  6. Wagner S, Zensi A, Wien SL, Tschickardt SE, Maier W, Vogel T, et al. Uptake mechanism of ApoE-modified nanoparticles on brain capillary endothelial cells as a blood-brain barrier model. PLoS One. 2012;7(3):e32568.

    Article  PubMed  CAS  Google Scholar 

  7. Demeule M, Currie JC, Bertrand Y, Ché C, Nguyen T, Régina A, et al. Involvement of the low-density lipoprotein receptor-related protein in the transcytosis of the brain delivery vector angiopep-2. J Neurochem. 2008;106(4):1534–44.

    Article  PubMed  CAS  Google Scholar 

  8. Ke WL, Shao K, Huang RQ, Han L, Liu Y, Li JF, et al. Gene delivery targeted to the brain using an Angiopep-conjugated polyethyleneglycol-modified polyamidoamine dendrimer. Biomaterials. 2009;30(36):6976–85.

    Article  PubMed  CAS  Google Scholar 

  9. Huang RQ, Liu SH, Shao K, Han L, Ke WL, Liu Y, et al. Evaluation and mechanism studies of PEGylated dendrigraft poly-L-lysines as novel gene delivery vectors. Nanotechnology. 2010;21(26):265101.

    Article  PubMed  Google Scholar 

  10. Huang RQ, Ke WL, Han L, Li JF, Liu SH, Jiang C. Targeted delivery of chlorotoxin-modified DNA-loaded nanoparticles to glioma via intravenous administration. Biomaterials. 2011;32(9):2399–406.

    Article  PubMed  CAS  Google Scholar 

  11. Xie Y, Ye LY, Zhang XB, Cui W, Lou JN, Nagai T, et al. Transport of nerve growth factor encapsulated into liposomes across the blood-brain barrier: In vitro and in vivo studies. J Control Release. 2005;105(1–2):106–19.

    Article  PubMed  CAS  Google Scholar 

  12. Canzoniero LM, Adornetto A, Secondo A, Magi S, Dell’aversano C, Scorziello A, et al. Involvement of the nitric oxide/protein kinase G pathway in polychlorinated biphenyl-induced cell death in SH-SY 5Y neuroblastoma cells. J Neurosci Res. 2006;84(3):692–7.

    Article  PubMed  CAS  Google Scholar 

  13. Huang RQ, Han L, Li JH, Ren FL, Ke WL, Jiang C, et al. Neuroprotection in a 6-OHDA-lesioned Parkinson model using Lactoferrin-modified Nanoparticles. J Gene Med. 2009;11(9):754–63.

    Article  PubMed  CAS  Google Scholar 

  14. Huang RQ, Ke WL, Liu Y, Jiang C, Pei YY. The use of lactoferrin as a ligand for targeting the polyamidoamine-based gene delivery system to the brain. Biomaterials. 2008;29(2):238–46.

    Article  PubMed  CAS  Google Scholar 

  15. Spuch C, Navarro C. Liposomes for targeted delivery of active agents against neurodegenerative diseases (Alzheimer’s disease and Parkinson’s disease). J Drug Deliv. 2011;2011:469679.

    Article  PubMed  Google Scholar 

  16. Shao K, Huang RQ, Li JF, Han L, Ye LY, Lou JN, et al. Angiopep-2 modified PE-PEG based polymeric micelles for amphotericin B delivery targeted to the brain. J Control Release. 2010;147(1):118–26.

    Article  PubMed  CAS  Google Scholar 

  17. Alam M, Schmidt WJ. Rotenone destroys dopaminergic neurons and induces parkinsonian symptoms in rats. Behav Brain Res. 2002;136(1):317–24.

    Article  PubMed  CAS  Google Scholar 

  18. Samantaray S, Knaryan VH, Guyton MK, Matzelle DD, Ray SK, Banik NL. The parkinsonian neurotoxin rotenone activates calpain and caspase-3 leading to motoneuron degeneration in spinal cord of Lewis rats. Neuroscience. 2007;146(2):741–55.

    Article  PubMed  CAS  Google Scholar 

  19. Hirsch EC, Höglinger G, Rousselet E, Breidert T, Parain K, Feger J, et al. Animal models of Parkinson’s disease in rodents induced by toxins: an update. J Neural Transm Suppl. 2003;65:89–100.

    Article  PubMed  Google Scholar 

  20. Sherer TB, Betarbet R, Kim JH, Greenamyre JT. Selective microglial activation in the rat rotenone model of Parkinson’s disease. Neurosci Lett. 2003;341(2):87–90.

    Article  PubMed  CAS  Google Scholar 

  21. Mercanti G, Bazzu G, Giusti P. A 6-hydroxydopamine in vivo model of Parkinson’s disease. Methods Mol Biol. 2012;846:355–64.

    Article  PubMed  CAS  Google Scholar 

  22. Li JF, Zhou L, Ye DY, Huang SX, Shao K, Huang RQ, et al. Choline-derivate-modified nanoparticles for brain-targeting gene delivery. Adv Mater. 2011;23(39):4516–20.

    Article  PubMed  CAS  Google Scholar 

  23. Liu SH, Guo YB, Huang RQ, Li JF, Huang SX, Kuang YY, et al. Gene and doxorubicin co-delivery system for targeting therapy of glioma. Biomaterials. 2012;33(19):4907–16.

    Article  PubMed  CAS  Google Scholar 

  24. Tsogas I, Theodossiou T, Sideratou Z, Paleos CM, Collet H, Rossi JC, et al. Interaction and transport of poly(L-lysine) dendrigrafts through liposomal and cellular membranes: the role of generation and surface functionalization. Biomacromolecules. 2007;8(10):3263–70.

    Article  PubMed  CAS  Google Scholar 

  25. Duarte EP, Curcio M, Canzoniero LM, Duarte CB. Neuroprotection by GDNF in the ischemic brain. Growth Factors. 2012;30(4):242–57.

    Article  PubMed  CAS  Google Scholar 

  26. Boger HA, Middaugh LD, Huang P, Zaman V, Smith AC, Hoffer BJ, et al. A partial GDNF depletion leads to earlier age-related deterioration of motor function and tyrosine hydroxylase expression in the substantia nigra. Exp Neurol. 2006;202(2):336–47.

    Article  PubMed  CAS  Google Scholar 

  27. Jiang C, Koyabu N, Yonemitsu Y, Shimazoe T, Watanabe S, Naito M, et al. In vivo delivery of glial cell-derived neurotrophic factor across the blood-brain barrier by gene transfer into brain capillary endothelial cells. Hum Gene Ther. 2003;14(12):1181–91.

    Article  PubMed  CAS  Google Scholar 

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ACKNOWLEDGMENTS AND DISCLOSURES

Rongqin Huang and Haojun Ma contributed equally to this work. This work was supported by the grants from Specialized Research Fund for Doctoral Program (20090071120066), “Zhuo Xue” Talent Plan of Fudan University, “Chen Guang” project supported by Shanghai Municipal Education Commission and Shanghai Education Development Foundation, and National Key Basic Research Program (2013CB932502) of China (973 Program).

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Authors and Affiliations

  1. Key Laboratory of Smart Drug Delivery, Ministry of Education & PLA Department of Pharmaceutics, School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai, 201203, China

    Rongqin Huang, Haojun Ma, Yubo Guo, Shuhuan Liu, Yuyang Kuang, Kun Shao, Jianfeng Li, Yang Liu, Liang Han, Shixian Huang, Sai An & Chen Jiang

  2. Institute of Clinical Medical Sciences, China-Japan Friendship Hospital the Ministry of Health, 2 East Yinghua Road, Beijing, 100029, China

    Liya Ye & Jinning Lou

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  1. Rongqin Huang
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  14. Chen Jiang
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Correspondence to Chen Jiang.

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Huang, R., Ma, H., Guo, Y. et al. Angiopep-Conjugated Nanoparticles for Targeted Long-Term Gene Therapy of Parkinson’s Disease. Pharm Res 30, 2549–2559 (2013). https://doi.org/10.1007/s11095-013-1005-8

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  • DOI: https://doi.org/10.1007/s11095-013-1005-8

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