Supermolecule—Drug Conjugates Based on Acid-Degradable Polyrotaxanes for pH-Dependent Intracellular Release of Doxorubicin
Doxorubicin (DOX)-conjugated acid-degradable polyrotaxanes (PRXs) were designed as supramolecular drug carriers capable of releasing drugs in acidic cellular environments. Acid-degradable PRXs composed of α-cyclodextrin (α-CD) as a cyclic molecule, poly(ethylene glycol) (PEG) as a polymer axis, and...
| Main Authors: | , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2023-03-01
|
| Series: | Molecules |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1420-3049/28/6/2517 |
| _version_ | 1797609918282334208 |
|---|---|
| author | Atsushi Tamura Mamoru Osawa Nobuhiko Yui |
| author_facet | Atsushi Tamura Mamoru Osawa Nobuhiko Yui |
| author_sort | Atsushi Tamura |
| collection | DOAJ |
| description | Doxorubicin (DOX)-conjugated acid-degradable polyrotaxanes (PRXs) were designed as supramolecular drug carriers capable of releasing drugs in acidic cellular environments. Acid-degradable PRXs composed of α-cyclodextrin (α-CD) as a cyclic molecule, poly(ethylene glycol) (PEG) as a polymer axis, and <i>N</i>-triphenylmethyl (<i>N</i>-Trt) groups as an acid-labile stopper molecules were synthesized and DOX was conjugated with the threaded α-CDs in the PRXs. Because the acid-induced cleavage of <i>N</i>-Trt groups in PRXs leads to PRX dissociation, the DOX-modified α-CDs were released under acidic conditions (pH 5.0). The cytotoxicity of DOX-conjugated PRXs in colon-26 cells revealed significant cell death for DOX-conjugated PRXs after 48 h of treatment. Confocal laser scanning microscopy (CLSM) analysis revealed that the fluorescence signals derived from DOX-conjugated PRXs were observed in cellular nuclei after 48 h, suggesting that the DOX-modified α-CDs were released and accumulated in cellular nuclei. These results confirmed that acid-degradable PRXs can be utilized as drug carriers capable of releasing drug-modified α-CDs in acidic lysosomes and eliciting cytotoxicity. Overall, acid-degradable PRXs represent a promising supramolecular framework for the delivery and intracellular release of drug-modified α-CDs, and PRX–drug conjugates are expected to contribute to the development of pH-responsive drug carriers for cancer therapy. |
| first_indexed | 2024-03-11T06:08:18Z |
| format | Article |
| id | doaj.art-6843ab18650446ef980a508d06e0ecb4 |
| institution | Directory Open Access Journal |
| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-03-11T06:08:18Z |
| publishDate | 2023-03-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Molecules |
| spelling | doaj.art-6843ab18650446ef980a508d06e0ecb42023-11-17T12:51:25ZengMDPI AGMolecules1420-30492023-03-01286251710.3390/molecules28062517Supermolecule—Drug Conjugates Based on Acid-Degradable Polyrotaxanes for pH-Dependent Intracellular Release of DoxorubicinAtsushi Tamura0Mamoru Osawa1Nobuhiko 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, JapanDoxorubicin (DOX)-conjugated acid-degradable polyrotaxanes (PRXs) were designed as supramolecular drug carriers capable of releasing drugs in acidic cellular environments. Acid-degradable PRXs composed of α-cyclodextrin (α-CD) as a cyclic molecule, poly(ethylene glycol) (PEG) as a polymer axis, and <i>N</i>-triphenylmethyl (<i>N</i>-Trt) groups as an acid-labile stopper molecules were synthesized and DOX was conjugated with the threaded α-CDs in the PRXs. Because the acid-induced cleavage of <i>N</i>-Trt groups in PRXs leads to PRX dissociation, the DOX-modified α-CDs were released under acidic conditions (pH 5.0). The cytotoxicity of DOX-conjugated PRXs in colon-26 cells revealed significant cell death for DOX-conjugated PRXs after 48 h of treatment. Confocal laser scanning microscopy (CLSM) analysis revealed that the fluorescence signals derived from DOX-conjugated PRXs were observed in cellular nuclei after 48 h, suggesting that the DOX-modified α-CDs were released and accumulated in cellular nuclei. These results confirmed that acid-degradable PRXs can be utilized as drug carriers capable of releasing drug-modified α-CDs in acidic lysosomes and eliciting cytotoxicity. Overall, acid-degradable PRXs represent a promising supramolecular framework for the delivery and intracellular release of drug-modified α-CDs, and PRX–drug conjugates are expected to contribute to the development of pH-responsive drug carriers for cancer therapy.https://www.mdpi.com/1420-3049/28/6/2517polyrotaxanecyclodextrindoxorubicindrug delivery system |
| spellingShingle | Atsushi Tamura Mamoru Osawa Nobuhiko Yui Supermolecule—Drug Conjugates Based on Acid-Degradable Polyrotaxanes for pH-Dependent Intracellular Release of Doxorubicin Molecules polyrotaxane cyclodextrin doxorubicin drug delivery system |
| title | Supermolecule—Drug Conjugates Based on Acid-Degradable Polyrotaxanes for pH-Dependent Intracellular Release of Doxorubicin |
| title_full | Supermolecule—Drug Conjugates Based on Acid-Degradable Polyrotaxanes for pH-Dependent Intracellular Release of Doxorubicin |
| title_fullStr | Supermolecule—Drug Conjugates Based on Acid-Degradable Polyrotaxanes for pH-Dependent Intracellular Release of Doxorubicin |
| title_full_unstemmed | Supermolecule—Drug Conjugates Based on Acid-Degradable Polyrotaxanes for pH-Dependent Intracellular Release of Doxorubicin |
| title_short | Supermolecule—Drug Conjugates Based on Acid-Degradable Polyrotaxanes for pH-Dependent Intracellular Release of Doxorubicin |
| title_sort | supermolecule drug conjugates based on acid degradable polyrotaxanes for ph dependent intracellular release of doxorubicin |
| topic | polyrotaxane cyclodextrin doxorubicin drug delivery system |
| url | https://www.mdpi.com/1420-3049/28/6/2517 |
| work_keys_str_mv | AT atsushitamura supermoleculedrugconjugatesbasedonaciddegradablepolyrotaxanesforphdependentintracellularreleaseofdoxorubicin AT mamoruosawa supermoleculedrugconjugatesbasedonaciddegradablepolyrotaxanesforphdependentintracellularreleaseofdoxorubicin AT nobuhikoyui supermoleculedrugconjugatesbasedonaciddegradablepolyrotaxanesforphdependentintracellularreleaseofdoxorubicin |