Preclinical development of carrier-free prodrug nanoparticles for enhanced antitumor therapeutic potential with less toxicity

Man Kyu Shim, Suah Yang, Jooho Park, Jun Sik Yoon, Jinseong Kim, Yujeong Moon, Nayeon Shim, Mihee Jo, Yongwhan Choi, Kwangmeyung Kim

Research output: Contribution to journalArticlepeer-review

7 Scopus citations


Background: Nanomedicine has emerged as a promising strategy for cancer treatment. The most representative nanomedicine used in clinic is PEGylated liposomal doxorubicin DOXIL®, which is first FDA-approved nanomedicine. However, several shortcomings, such as low drug loading capacity, low tumor targeting, difficulty in mass production and potential toxicity of carrier materials, have hindered the successful clinical translation of nanomedicines. In this study, we report a preclinical development process of the carrier-free prodrug nanoparticles designed as an alternative formulation to overcome limitations of conventional nanomedicines in the terms of technical- and industrial-aspects. Results: The carrier-free prodrug nanoparticles (F68-FDOX) are prepared by self-assembly of cathepsin B-specific cleavable peptide (FRRG) and doxorubicin (DOX) conjugates without any additional carrier materials, and further stabilized with Pluronic F68, resulting in high drug loading (> 50%). The precise and concise structure allow mass production with easily controllable quality control (QC), and its lyophilized powder form has a great long-term storage stability at different temperatures (− 4, 37 and 60 °C). With high cathepsin B-specificity, F68-FDOX induce a potent cytotoxicity preferentially in cancer cells, whereas their cytotoxicity is greatly minimized in normal cells with innately low cathepsin B expression. In tumor models, F68-FDOX efficiently accumulates within tumor tissues owing to enhanced permeability and retention (EPR) effect and subsequently release toxic DOX molecules by cathepsin B-specific cleavage mechanism, showing a broad therapeutic spectrum with significant antitumor activity in three types of colon, breast and pancreatic cancers. Finally, the safety of F68-FDOX treatment is investigated after single-/multi-dosage into mice, showing greatly minimized DOX-related toxicity, compared to free DOX in normal mice. Conclusions: Collectively, these results provide potential preclinical development process of an alternative approach, new formulation of carrier-free prodrug nanoparticles, for clinical translation of nanomedicines.

Original languageEnglish
Article number436
JournalJournal of Nanobiotechnology
Issue number1
StatePublished - Dec 2022

Bibliographical note

Funding Information:
This work was supported by the National Research Foundation of Korea (NRF) Grant funded by the Korea government (NRF-2019R1A2C3006283 and NRF-2021R1C1C2005460), National Research Council of Science & Technology (NST), and Seoul Business Agency (SBA).

Publisher Copyright:
© 2022, The Author(s).


  • Cathepsin B
  • Doxorubicin
  • Nanoparticles
  • Preclinical study
  • Prodrug
  • Targeted therapy


Dive into the research topics of 'Preclinical development of carrier-free prodrug nanoparticles for enhanced antitumor therapeutic potential with less toxicity'. Together they form a unique fingerprint.

Cite this