Retinal-conjugated pH-sensitive micelles induce tumor senescence for boosting breast cancer chemotherapy
Abstract
Evoking tumor cellular senescence, an irreversible status of cell growth quiescence, has been recently proposed as a potential strategy to improve the efficacy of cancer treatment. In the current study, all-trans retinal, the precursor of all-trans retinoic acid, was conjugated to dextran via hydrazone bond to generate amphiphilic dextran-retinal (DR) conjugates, which self-assembled into pH-sensitive DR micelles. Our results showed that DR micelles moderately inhibited MCF-7 breast cancer cell growth through inducing p21-associated cellular senescence, which relied on retinoic acid receptors (RARs) and was accompanied by significant G0/G1 cell cycle arrest. Moreover, DR micelles were capable of encapsulating doxorubicin (DOX) to generate DOX-loaded DD micelles, facilitating the uptake and release of DOX in cancer cells. Compared with free DOX, DD micelles more effectively suppressed tumor growth and prolonged survival time of mouse xenograft model through inducing tumor apoptosis and cellular senescence. However, blocking cellular senescence diminished DD-caused apoptosis in MCF-7 cells by 40-50%. Therefore, pH-sensitive DR micelles not only served as a potent platform for DOX delivery, but also enhanced the anti-tumor effect of DOX by inducing tumor cellular senescence. These data reveal a great potential of evoking tumor senescence with retinal-conjugated micelles for boosting breast cancer chemotherapy.
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Compared with free DOX, DOX-loaded micelles improved cancer inhibition efficiency and reduced toxicity.
“Compared with free DOX, DOX-loaded micelles improved cancer inhibition efficiency and reduced toxicity.”
From Recent Advances in Nanomicelles Delivery Systems. (2020) · cites this paper as [140]
The pH-sensitive linkers on these copolymers are commonly stable at pH 7.4, but are hydrolyzed in acidic environment, whereby the micelles are disaggregated to provide fast drug release.
“The pH-sensitive linkers on these copolymers are commonly stable at pH 7.4, but are hydrolyzed in acidic environment, whereby the micelles are disaggregated to provide fast drug release.”
From Recent Advances in Nanomicelles Delivery Systems. (2020) · cites this paper as [140]
The in vitro release of DOX from DOX-loaded DR micelles showed that less than 10% of DOX was released in PBS at pH 7.4, but remarkably high at pH 5.0 with about 100% of DOX release within 24 h.
“The in vitro release of DOX showed that less than 10% of DOX was released in PBS at pH 7.4, but remarkably high at pH 5.0 with about 100% of DOX release within 24 h.”
From Recent Advances in Nanomicelles Delivery Systems. (2020) · cites this paper as [140]
Compared to free drugs, the nanoparticle formulation increased the accumulation of all-trans-retinal and doxorubicin at the tumor site and induced higher levels of cell senescence and antitumoral activity.
“Compared to free drugs, the nanoparticle formulation increased the accumulation of the all-trans-retinal and doxorubicin at the tumor site and induced higher levels of cell senescence and antitumoral activity.”
From Advances and challenges in retinoid delivery systems in regenerative and therapeutic medicine (2020) · cites this paper as [112]
Some progress has been made in the last 5 years regarding formulations with the ability to release RA in combination with other agents.
“Although some progress has been made in the last 5 years regarding formulations with the ability to release RA in combination with other agents54,112”
From Advances and challenges in retinoid delivery systems in regenerative and therapeutic medicine (2020) · cites this paper as [112]
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- Authors
- Zhang, Y., Li, P., Pan, H., Liu, L., Ji, M., Sheng, N., Wang, C., Cai, L., & Ma, Y.
- Affiliations
- Chinese Academy of Sciences (CN)
- Corresponding author
- Ma, Yifan
- Venue
- Biomaterials
- Publisher
- Elsevier BV
- Published
- 2016-03
- Volume
- 83
- Pages
- 219-232
- ISSN
- 0142-9612 (ISSN-L)
- OpenAlex
- W2224801830
- Cited by
- 56
- References
- 61
- Citations by year
- 2026: 4 · 2025: 7 · 2024: 1 · 2023: 4 · 2022: 3 · 2021: 5 · 2020: 8 · 2019: 6 · 2018: 7 · 2017: 9 · 2016: 2
- FWCI
- 3.27
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Biomaterials (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Physical Sciences › Materials Science › Biomaterials › Nanoparticle-Based Drug Delivery
- Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmaceutical Science › Advanced Drug Delivery Systems
- Keywords
- pH-responsive micelles, breast cancer chemotherapy, doxorubicin delivery, all-trans-retinal, retinoic acid receptor, p21, G0/G1 cell cycle arrest, apoptosis, MCF-7 cells, drug delivery nanocarriers
- MeSH terms
- Animals, Antineoplastic Agents, Breast Neoplasms, Cell Survival, Dextrans, Doxorubicin, Endocytosis, Female, Humans, Hydrogen-Ion Concentration, Mice, Inbred BALB C, Mice, Nude, Micelles, Retinaldehyde, Tissue Distribution, Cellular Senescence, Apoptosis, Receptors, Retinoic Acid, Cell Proliferation, MCF-7 Cells
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