Dimeric Prodrug Self-Delivery Nanoparticles with Enhanced Drug Loading and Bioreduction Responsiveness for Targeted Cancer Therapy

Xi He, Kaimin Cai, Yu Zhang, Yifei Lu, Qin Guo, Yujie Zhang, Lisha Liu, Chunhui Ruan, Qinjun Chen, Xinli Chen, Chao Li, Tao Sun, Jianjun Cheng, Chen Jiang

Research output: Contribution to journalArticle

Abstract

Efficient drug accumulation in tumor cells is essential for cancer therapy. Herein, we developed dimeric prodrug self-delivery nanoparticles (NPs) with enhanced drug loading and bioreduction responsiveness for triple negative breast cancer (TNBC) therapy. Specially designed camptothecin dimeric prodrug (CPTD) containing a disulfide bond was constructed to realize intracellular redox potential controlled drug release. Direct conjugation of hydrophobic CPTD to poly(ethylene glycol) PEG 5000 , a prodrug-based amphiphilic CPTD-PEG 5000 co-polymer was synthesized, which could encapsulate parental CPTD prodrug spontaneously and form ultrastable NPs due to the highly analogous structure. Such dimeric prodrug self-delivery nanoparticles showed ultrahigh stability with critical micelle concentration as low as 0.75 μg/mL and remained intact during endocytosis. In addition, neurotensin (NT), a 13 amino acid ligand, was further modified on the nanoparticles for triple negative breast cancer (TNBC) targeting. Optimized NT-CPTD NPs showed improved pharmacokinetics profile and increased drug accumulation in TNBC lesions than free CPT, which largely reduced the systemic toxicity and presented an improved anticancer efficacy in vivo. In summary, with advantages of extremely high drug loading capacity, tumor microenvironmental redox responsiveness, and targeted TNBC accumulation, NT-CPTD NPs showed their potential for effective triple negative breast cancer therapy.

Original languageEnglish (US)
Pages (from-to)39455-39467
Number of pages13
JournalACS Applied Materials and Interfaces
Volume10
Issue number46
DOIs
StatePublished - Nov 21 2018

Keywords

  • camptothecin
  • neurotensin
  • prodrug
  • redox responsiveness
  • triple negative breast cancer

ASJC Scopus subject areas

  • Materials Science(all)

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  • Cite this

    He, X., Cai, K., Zhang, Y., Lu, Y., Guo, Q., Zhang, Y., Liu, L., Ruan, C., Chen, Q., Chen, X., Li, C., Sun, T., Cheng, J., & Jiang, C. (2018). Dimeric Prodrug Self-Delivery Nanoparticles with Enhanced Drug Loading and Bioreduction Responsiveness for Targeted Cancer Therapy. ACS Applied Materials and Interfaces, 10(46), 39455-39467. https://doi.org/10.1021/acsami.8b09730