2. Academic Validation
  3. A novel peptide-drug conjugate for glioma-targeted drug delivery

A novel peptide-drug conjugate for glioma-targeted drug delivery

  • J Control Release. 2024 Apr 13:369:722-733. doi: 10.1016/j.jconrel.2024.04.011.
Jianfen Zhou 1,  Nana Meng 1,  Linwei Lu 2,  Jiasheng Lu 1,  Sunyi Wu 1,  Yuan Ding 1,  Shuai Wu 3,  Yanning Bao 1,  Qianzhu Xu 1,  Ruohan Chen 1,  Jun Wang 1,  Cao Xie 1,  Jinsong Wu 3,  Weiyue Lu 4
Affiliations

Affiliations

  • 1 Department of Pharmaceutics, School of Pharmacy, Fudan University & Key Laboratory of Smart Drug Delivery (Fudan University), Ministry of Education and PLA, Shanghai 201203, China.
  • 2 Department of Integrative Medicine, Huashan Hospital, Fudan University, and Institutes of Integrative Medicine of Fudan University, Shanghai 200040, China.
  • 3 Glioma Surgery Division, Department of Neurosurgery, Huashan Hospital, Fudan University, Shanghai 200040, China.
  • 4 Department of Pharmaceutics, School of Pharmacy, Fudan University & Key Laboratory of Smart Drug Delivery (Fudan University), Ministry of Education and PLA, Shanghai 201203, China; Shanghai Engineering Technology Research Center for Pharmaceutical Intelligent Equipment, and Shanghai Frontiers Science Center for Druggability of Cardiovascular non-coding RNA, Institute for Frontier Medical Technology, Shanghai University of Engineering Science, Shanghai 201620, China. Electronic address: [email protected].
PMID: 38583575 DOI: 10.1016/j.jconrel.2024.04.011
Abstract

The existence of the blood-brain barrier (BBB) and blood-brain tumor barrier (BBTB) greatly limits the application of chemotherapy in glioma. To address this challenge, an optimal drug delivery system must efficiently cross the BBB/BBTB and specifically deliver therapeutic drugs into glioma cells while minimizing systemic toxicity. Here we demonstrated that glucose-regulated protein 78 (GRP78) and Dopamine Receptor D2 were highly expressed in patient-derived glioma tissues, and dopamine receptors were highly expressed on the BBB. Subsequently, we synthesized a novel "Y"-shaped peptide and compared the effects of different linkers on the receptor affinity and targeting ability of the peptide. A peptide-drug conjugate (pHA-AOHX-VAP-doxorubicin conjugate, pHA-AOHX-VAP-DOX) with a better affinity for glioma cells and higher solubility was derived for glioma treatment. pHA-AOHX-VAP-DOX could cross both BBB and BBTB via Dopamine Receptor and GRP78 receptor, and finally target glioma cells, significantly prolonging the survival time of nude mice bearing intracranial glioma. Furthermore, pHA-AOHX-VAP-DOX significantly reduced the toxicity of DOX and increased the maximum tolerated dose (MTD). Collectively, this work paves a new avenue for overcoming multiple barriers and effectively delivering chemotherapeutic agents to glioma cells while providing key evidence to identify potential receptors for glioma-targeted drug delivery.

Keywords

Dopamine receptor; Doxorubicin; GRP78; Glioma; Peptide-drug conjugate; Targeted drug delivery.

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