Enhanced Tumor Targeting and Antitumor Activity of Methylated β-Cyclodextrin-Threaded Polyrotaxanes by Conjugating Cyclic RGD Peptides
We previously reported that acid-degradable methylated β-cyclodextrins (Me-β-CDs)-threaded polyrotaxanes (Me-PRXs) can induce autophagic cell death through endoplasmic reticulum (ER) stress-related autophagy, even in apoptosis-resistant cells. Hence, Me-PRXs show great potential as anticancer therap...
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| Format: | Article |
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MDPI AG
2024-02-01
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| Series: | Biomolecules |
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| Online Access: | https://www.mdpi.com/2218-273X/14/2/223 |
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| author | Shunyao Zhang Atsushi Tamura Nobuhiko Yui |
| author_facet | Shunyao Zhang Atsushi Tamura Nobuhiko Yui |
| author_sort | Shunyao Zhang |
| collection | DOAJ |
| description | We previously reported that acid-degradable methylated β-cyclodextrins (Me-β-CDs)-threaded polyrotaxanes (Me-PRXs) can induce autophagic cell death through endoplasmic reticulum (ER) stress-related autophagy, even in apoptosis-resistant cells. Hence, Me-PRXs show great potential as anticancer therapeutics. In this study, peptide-supermolecule conjugates were designed to achieve the targeted delivery of Me-PRX to malignant tumors. Arg-Gly-Asp peptides are well-known binding motifs of integrin α<sub>v</sub>β<sub>3</sub>, which is overexpressed on angiogenic sites and many malignant tumors. The tumor-targeted cyclic Arg-Gly-Asp (cRGD) peptide was orthogonally post-modified to Me-PRX via click chemistry. Surface plasmon resonance (SPR) results indicated that cRGD-Me-PRX strongly binds to integrin α<sub>v</sub>β<sub>3</sub>, whereas non-targeted cyclic Arg-Ala-Glu (cRGE) peptide conjugated to Me-PRX (cRGE-Me-PRX) failed to interact with integrins α<sub>v</sub>β<sub>3</sub>. In vitro, cRGD-Me-PRX demonstrated enhanced cellular internalization and antitumor activity in 4T1 cells than that of unmodified Me-PRX and non-targeted cRGE-Me-PRX, due to its ability to recognize integrin α<sub>v</sub>β<sub>3</sub>. Furthermore, cRGD-Me-PRX accumulated effectively in tumors, leading to antitumor effects, and exhibited excellent biocompatibility and safety in vivo. Therefore, cRGD conjugation to enhance selectivity for integrin α<sub>v</sub>β<sub>3</sub>-positive cancer cells is a promising design strategy for Me-PRXs in antitumor therapy. |
| first_indexed | 2024-03-07T22:40:59Z |
| format | Article |
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| issn | 2218-273X |
| language | English |
| last_indexed | 2024-03-07T22:40:59Z |
| publishDate | 2024-02-01 |
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| record_format | Article |
| series | Biomolecules |
| spelling | doaj.art-bc3f57241a38435087610485a4102c342024-02-23T15:09:25ZengMDPI AGBiomolecules2218-273X2024-02-0114222310.3390/biom14020223Enhanced Tumor Targeting and Antitumor Activity of Methylated β-Cyclodextrin-Threaded Polyrotaxanes by Conjugating Cyclic RGD PeptidesShunyao Zhang0Atsushi Tamura1Nobuhiko Yui2Department of Organic Biomaterials, Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University (TMDU), 2-3-10 Kanda-Surugadai, Chiyoda, Tokyo 101-0062, JapanDepartment of Organic Biomaterials, Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University (TMDU), 2-3-10 Kanda-Surugadai, Chiyoda, Tokyo 101-0062, JapanDepartment of Organic Biomaterials, Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University (TMDU), 2-3-10 Kanda-Surugadai, Chiyoda, Tokyo 101-0062, JapanWe previously reported that acid-degradable methylated β-cyclodextrins (Me-β-CDs)-threaded polyrotaxanes (Me-PRXs) can induce autophagic cell death through endoplasmic reticulum (ER) stress-related autophagy, even in apoptosis-resistant cells. Hence, Me-PRXs show great potential as anticancer therapeutics. In this study, peptide-supermolecule conjugates were designed to achieve the targeted delivery of Me-PRX to malignant tumors. Arg-Gly-Asp peptides are well-known binding motifs of integrin α<sub>v</sub>β<sub>3</sub>, which is overexpressed on angiogenic sites and many malignant tumors. The tumor-targeted cyclic Arg-Gly-Asp (cRGD) peptide was orthogonally post-modified to Me-PRX via click chemistry. Surface plasmon resonance (SPR) results indicated that cRGD-Me-PRX strongly binds to integrin α<sub>v</sub>β<sub>3</sub>, whereas non-targeted cyclic Arg-Ala-Glu (cRGE) peptide conjugated to Me-PRX (cRGE-Me-PRX) failed to interact with integrins α<sub>v</sub>β<sub>3</sub>. In vitro, cRGD-Me-PRX demonstrated enhanced cellular internalization and antitumor activity in 4T1 cells than that of unmodified Me-PRX and non-targeted cRGE-Me-PRX, due to its ability to recognize integrin α<sub>v</sub>β<sub>3</sub>. Furthermore, cRGD-Me-PRX accumulated effectively in tumors, leading to antitumor effects, and exhibited excellent biocompatibility and safety in vivo. Therefore, cRGD conjugation to enhance selectivity for integrin α<sub>v</sub>β<sub>3</sub>-positive cancer cells is a promising design strategy for Me-PRXs in antitumor therapy.https://www.mdpi.com/2218-273X/14/2/223polyrotaxanemethylated β-cyclodextrincyclic RGD peptideantitumor activitytumor targeting |
| spellingShingle | Shunyao Zhang Atsushi Tamura Nobuhiko Yui Enhanced Tumor Targeting and Antitumor Activity of Methylated β-Cyclodextrin-Threaded Polyrotaxanes by Conjugating Cyclic RGD Peptides Biomolecules polyrotaxane methylated β-cyclodextrin cyclic RGD peptide antitumor activity tumor targeting |
| title | Enhanced Tumor Targeting and Antitumor Activity of Methylated β-Cyclodextrin-Threaded Polyrotaxanes by Conjugating Cyclic RGD Peptides |
| title_full | Enhanced Tumor Targeting and Antitumor Activity of Methylated β-Cyclodextrin-Threaded Polyrotaxanes by Conjugating Cyclic RGD Peptides |
| title_fullStr | Enhanced Tumor Targeting and Antitumor Activity of Methylated β-Cyclodextrin-Threaded Polyrotaxanes by Conjugating Cyclic RGD Peptides |
| title_full_unstemmed | Enhanced Tumor Targeting and Antitumor Activity of Methylated β-Cyclodextrin-Threaded Polyrotaxanes by Conjugating Cyclic RGD Peptides |
| title_short | Enhanced Tumor Targeting and Antitumor Activity of Methylated β-Cyclodextrin-Threaded Polyrotaxanes by Conjugating Cyclic RGD Peptides |
| title_sort | enhanced tumor targeting and antitumor activity of methylated β cyclodextrin threaded polyrotaxanes by conjugating cyclic rgd peptides |
| topic | polyrotaxane methylated β-cyclodextrin cyclic RGD peptide antitumor activity tumor targeting |
| url | https://www.mdpi.com/2218-273X/14/2/223 |
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