Applied Microbiology and Biotechnology

, Volume 102, Issue 7, pp 3229–3241 | Cite as

Development and optimization of a tumor targeting system based on microbial synthesized PHA biopolymers and PhaP mediated functional modification

  • Fan Fan
  • Leilei Wang
  • Zhenlin Ouyang
  • Yurong Wen
  • Xiaoyun LuEmail author
Biotechnologically relevant enzymes and proteins


Polyhydroxyalkanoate (PHA) is a class of microbial synthesized biodegradable and biocompatible aliphatic polymer which has been developed into nanoparticles (NPs) for sustained release of hydrophobic compounds. Taking advantage of the natural PHA binding protein PhaP which could be steadily adsorbed onto PHA NPs through hydrophobic interaction, a tumor targeting system was developed in this study by presenting an epidermal growth factor receptor (EGFR)-targeting peptide (ETP) on the surface of PHA NPs, via PhaP mediated adsorption. To reveal the effects of residual emulsifiers on PhaP mediated ETP modification and optimize the tumor targeting capacity of the system, a novel emulsifier-free PHA NPs (EF-NPs) was fabricated together with other two kinds of conventional emulsifier-required PHA NPs (PVA-NPs and P68-NPs, which were prepared with poly(vinyl alcohol) (PVA) and Pluronic F68 as emulsifiers, respectively). By analyzing the surface hydrophobicity, the amount of adsorbed fusion protein, and the cellular uptake of all kinds of PHA NPs, our results demonstrated that EF-NPs with stronger surface hydrophobicity were the most proper formulation for further PhaP mediated ETP functionalization. The residual PVA and Pluronic F68 affected the modification efficiency and secondary structure of ETP-PhaP fusion protein, and finally obstructed the targeting effect of ETP-PhaP modified PVA-NPs and P68-NPs to EGFR over-expressed tumor cells. The animal experiment further confirmed the effectiveness and feasibility of in vivo application of ETP-PhaP functionalized EF-NPs, indicating that it could be served as a promising tumor targeting system with satisfactory EGFR targeting ability. This PhaP mediated bio-modification process also opens a wide way for developing various PHA-based targeting systems by presenting different tumor or other tissue-specific targeting peptides.


PHA PhaP Nanoparticles Residual emulsifiers Tumor targeting 



This work was financially supported by the National Natural Science Foundation of China (Nos. 81172170 and 81371288) and the Fundamental Research Funds for the Central Universities from Xi’an Jiaotong University. Prof. Guoqiang Chen (Lab of Microbiology, Department of Biological Science and Biotechnology, Tsinghua University) was acknowledged for providing the PHBHHx materials. The authors would also like to express thanks to Prof. Daocheng Wu (School of Life Science and Technology, Xi’an Jiaotong University) for the assistance with the characterization of nanoparticles.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no competing interest.

Ethical approval

All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. This article does not contain any studies with human participants performed by any of the authors.

Supplementary material

253_2018_8790_MOESM1_ESM.pdf (250 kb)
ESM 1 (PDF 249 kb)


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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of Biological Science and Bioengineering, Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and TechnologyXi’an Jiaotong UniversityXi’anPeople’s Republic of China

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