Photocontrolled Release of Doxorubicin Conjugated through a Thioacetal Photocage in Folate-Targeted Nanodelivery Systems

Pamela T. Wong, Shengzhuang Tang, Jayme Cannon, Dexin Chen, Rachel Sun, Jennifer Lee, James Phan, Ke Tao*, Kang Sun, Biqiong Chen, James R. Baker, Seok Ki Choi

*Corresponding author for this work

Research output: Contribution to journalArticle

17 Citations (Scopus)
267 Downloads (Pure)

Abstract

Despite their proven ability for precise and targeted release, nanoplatform systems for photocontrolled delivery often face formidable synthetic challenges, in part due to the paucity of advanced linker strategies. Here, we report on a novel linker strategy using a thioacetal ortho-nitrobenzaldehyde (TNB) cage, demonstrating its application for delivery of doxorubicin (Dox) in two nanoscale systems. This photocleavable linker, TNB(OH), which presents two identical arms, each terminated with a hydroxyl functionality, was prepared in a single step from 6-nitroveratraldehyde. TNB(OH) was used to cross-link Dox to a folate receptor (FAR)-targeting poly(amidoamine) dendrimer conjugate G5(FA)n=5.4(Dox)m=5.1, and also used to prepare an upconversion nanocrystal (UCN) conjugate, UCN-PPIX@Dox)(G5FA), a larger core/shell nanostructure. In this core/shell nanostructure, the UCN core emits UV and visible light luminescence upon near-infrared (NIR) excitation, allowing for the photocleavage of the TNB linker as well as the photostimulation of protoporphyrin IX (PPIX) coupled as a cytotoxic photosensitizer. Drug-release experiments performed in aqueous solutions with long-wavelength ultraviolet A (UVA) light showed that Dox release occurred rapidly from its TNB linked form or from its dendrimer conjugated form with comparable decay kinetics. Cellular toxicity studies in FAR-overexpressing KB carcinoma cells demonstrated that each nanoconjugate lacked intrinsic cytotoxicity until exposed to UVA or NIR (980 nm) (for the UCN nanoconjugate), which resulted in induction of potent cytotoxicity. In summary, this new TNB strategy offers synthetic convenience in drug conjugation chemistry with the ability for the temporal control of drug activation at the delivery site.

Original languageEnglish
Pages (from-to)3016-3028
Number of pages13
JournalBioconjugate Chemistry
Volume28
Issue number12
Early online date17 Nov 2017
DOIs
Publication statusPublished - 20 Dec 2017

ASJC Scopus subject areas

  • Biotechnology
  • Bioengineering
  • Biomedical Engineering
  • Pharmacology
  • Pharmaceutical Science
  • Organic Chemistry

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  • Cite this

    Wong, P. T., Tang, S., Cannon, J., Chen, D., Sun, R., Lee, J., Phan, J., Tao, K., Sun, K., Chen, B., Baker, J. R., & Choi, S. K. (2017). Photocontrolled Release of Doxorubicin Conjugated through a Thioacetal Photocage in Folate-Targeted Nanodelivery Systems. Bioconjugate Chemistry, 28(12), 3016-3028. https://doi.org/10.1021/acs.bioconjchem.7b00614