Rationale Design of a Zn(II)-Coordinated, Cell Penetrating, and Functionalized Tetrapeptide Self-Assembly for Delivery of Chemotherapeutic Drugs to Folic Acid Receptor-Expressing Cancer Cells

Nanjundan Raghul; Anushree Lye; Bhagwat Giri Goswami; Suman Nayak; Adele Stewart; Rabindranath Lo; Biswanath Maity; Priyadip Das

doi:10.1021/acsabm.5c00965

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Rationale Design of a Zn(II)-Coordinated, Cell Penetrating, and Functionalized Tetrapeptide Self-Assembly for Delivery of Chemotherapeutic Drugs to Folic Acid Receptor-Expressing Cancer Cells

Journal article

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Rationale Design of a Zn(II)-Coordinated, Cell Penetrating, and Functionalized Tetrapeptide Self-Assembly for Delivery of Chemotherapeutic Drugs to Folic Acid Receptor-Expressing Cancer Cells

Nanjundan Raghul, Anushree Lye, Bhagwat Giri Goswami, Suman Nayak, Adele Stewart, Rabindranath Lo, Biswanath Maity and Priyadip Das

ACS applied bio materials, Vol.8(8), pp.7270-7283

08/18/2025

DOI: 10.1021/acsabm.5c00965

PMID: 40734540

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Abstract

Design and development of functionalized and biocompatible drug delivery systems (DDS) for site-specific release of small molecules is emerging as a means to target disease sites while sparing healthy tissue. Cell penetrating short peptides capable of self-assembly and drug encapsulation represent one scaffold with which selective DDSs can be rationally designed due to their chemical diversity, biocompatibility, tunable bioactivity, ease of functionality, and high loading capacity. Herein, we designed and synthesized two tetra peptides, BOC-YWWD (PB1 with Trp-Trp-Sequence) and BOC-WYWD (PB2 without Trp-Trp sequence). Structural rigidification of these two peptides with Zn(II) in the self-assembled state were characterized by the density functional theory (DFT) method and demonstrated to shift self-assembly of their characteristic emission from the ultraviolet to visible range allowing for visualization of cellular entry. PB1-Zn, unlike PB2-Zn, exhibits cell penetrating capabilities and is photo and thermally stable and biocompatible. Self-assembled PB1-Zn effectively encapsulated the chemotherapeutic drug Doxorubicin (Dox) and facilitated intracellular drug delivery. To test the utility of PB1-Zn as a DDS, we chemically modified PB1-Zn with folic acid to target folate receptor α (FLOR1), commonly overexpressed on the surface of cancer cells. In HeLa cervical cancer cells, this chemical conjugation with folic acid significantly improved the ability of Dox to activate the pro-apoptotic DNA damage response and trigger oxidative stress and mitochondrial dysfunction critical for the cancer cell killing actions of the drug. However, PB1-Zn failed to facilitate Dox delivery into the lung cancer epithelial cell line, A549, which does not express high levels of FLOR1. Our results represent an important proof of concept describing the fabrication of fluorescent Zn(II) coordinated, self-assembled short peptides containing the sequential Trp-Trp unit that may be used to develop superior imaging reagents and site-specific DDSs.

Apoptosis

Cellular imaging

Folate receptor

Cell penetrating peptide

Site-specific drug delivery

Details

Title: Subtitle: Rationale Design of a Zn(II)-Coordinated, Cell Penetrating, and Functionalized Tetrapeptide Self-Assembly for Delivery of Chemotherapeutic Drugs to Folic Acid Receptor-Expressing Cancer Cells
Creators: Nanjundan Raghul - SRM Institute of Science and Technology
Anushree Lye - Bose Institute
Bhagwat Giri Goswami - Department of Chemistry, SSSTSR Govt. Degree College Nainidanda, Pauri Garhwal, Uttarakhand 246277, India
Suman Nayak - SRM Institute of Science and Technology
Adele Stewart - University of Iowa
Rabindranath Lo - Czech Academy of Sciences, Institute of Organic Chemistry and Biochemistry
Biswanath Maity - Bose Institute
Priyadip Das - SRM Institute of Science and Technology
Resource Type: Journal article
Publication Details: ACS applied bio materials, Vol.8(8), pp.7270-7283
DOI: 10.1021/acsabm.5c00965
PMID: 40734540
NLM abbreviation: ACS Appl Bio Mater
ISSN: 2576-6422
eISSN: 2576-6422
Publisher: American Chemical Society; WASHINGTON
Grant note: SRM Institute of Science and Technology: CRG/2023/001681 Anusandhan National Research Foundation (ANRF), Government of IndiaSRM Institute of Science and Technology for the Junior Research Fellowship: EMDR/SG/14/2023-0061 Indian Council of Medical ResearchInstitute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences: :90254 Ministry of Education, Youth and Sports of the Czech Republic
P.D. extends gratitude to the Anusandhan National Research Foundation (ANRF), Government of India, for Core Research Grant (File no. CRG/2023/001681) as well as to the Department of Chemistry, Department of Biotechnology, Interdisciplinary Institute of Indian System of Medicine (IIISM) and Nano Research Centre (NRC) at SRM Institute of Science & Technology and Department of Chemistry, for several characterization studies. N.R., S.N., and B.G.G. thank the SRM Institute of Science and Technology for the Junior Research Fellowship. B.M. expresses appreciation to the Indian Council of Medical Research for financial support (Grant no.: EMDR/SG/14/2023-0061). We also extend our thanks to SRMIST, CBMR, and Bose Institute for providing the necessary instruments and laboratory facilities to carry out this research. R.L. thanks Prof. Pavel Hobza from the Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences (IOCB Prague) for computational facilities, and this work was supported by the Ministry of Education, Youth and Sports of the Czech Republic through the e-INFRA CZ (ID:90254).
Language: English
Electronic publication date: 07/30/2025
Date published: 08/18/2025
Academic Unit: Iowa Neuroscience Institute; Neuroscience and Pharmacology
Record Identifier: 9984927090502771

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