FAP-targeting biomimetic nanosystem to restore the activated cancer-associated fibroblasts to quiescent state for breast cancer radiotherapy
FAP-C NPs, consisting of PLGA-C NPs encapsulated with the vitamin D analog calcipotriol as the core and 4T1 cell membrane chimeric with FAP single-chain fragment variable as the shell, can accumulate in tumor and restore the activated CAFs to a quiescent state to remodel the tumor microenvironment a...
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| Veröffentlicht in: | International journal of pharmaceutics 2025-02, Vol.670, p.125190, Article 125190 |
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| creator | Gao, Chen Jian, Chen Wang, Lulu Liu, Yajing Xiong, Yiquan Wu, Tingting Shi, Chen |
| description | FAP-C NPs, consisting of PLGA-C NPs encapsulated with the vitamin D analog calcipotriol as the core and 4T1 cell membrane chimeric with FAP single-chain fragment variable as the shell, can accumulate in tumor and restore the activated CAFs to a quiescent state to remodel the tumor microenvironment and improve the sensitivity to radiotherapy.
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Cancer associated fibroblasts (CAFs) are one of the most important stromal cells in the tumor microenvironment, playing a pivotal role in the development, recurrence, metastasis, and immunosuppression of cancer and treatment resistance. Here, we developed a core–shell biomimetic nanosystem termed as FAP-C NPs. This system was comprised of 4T1 extracellular vesicles fused with a FAP single-chain antibody fragment to form the biomimetic shell, and PLGA nanoparticles loaded with calcipotriol as the core. The FAP-modified shell endowed this nanosystem with active targeting ability to CAFs. Calcipotriol, a vitamin D analog, can activate the vitamin D receptor expressed on CAFs, promoting their transition from an activated to quiescent state. This process would help to reduce the pro-tumorigenic signals generated by CAFs, inhibit the stemness of cancer cells, and attenuate the inhibitory effect of CAFs on immune cells. The hydrated particle size of FAP-C NPs was approximately 206 nm, with a narrow distribution (polydispersity index |
| doi_str_mv | 10.1016/j.ijpharm.2025.125190 |
| format | Article |
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[Display omitted]
Cancer associated fibroblasts (CAFs) are one of the most important stromal cells in the tumor microenvironment, playing a pivotal role in the development, recurrence, metastasis, and immunosuppression of cancer and treatment resistance. Here, we developed a core–shell biomimetic nanosystem termed as FAP-C NPs. This system was comprised of 4T1 extracellular vesicles fused with a FAP single-chain antibody fragment to form the biomimetic shell, and PLGA nanoparticles loaded with calcipotriol as the core. The FAP-modified shell endowed this nanosystem with active targeting ability to CAFs. Calcipotriol, a vitamin D analog, can activate the vitamin D receptor expressed on CAFs, promoting their transition from an activated to quiescent state. This process would help to reduce the pro-tumorigenic signals generated by CAFs, inhibit the stemness of cancer cells, and attenuate the inhibitory effect of CAFs on immune cells. The hydrated particle size of FAP-C NPs was approximately 206 nm, with a narrow distribution (polydispersity index < 0.2). The zeta potential of FAP-C NPs was −12.63 ± 0.61 mV. FAP-C NPs can restore CAFs to a quiescent state to shield the function of activated CAFs, inhibit tumor cell stemness, facilitate the maturation of dendritic cell, and relieve the inhibition of CAFs on lymphocytes. Besides, when combined with radiotherapy, this biomimetic nanosystem could inhibit the activation of CAFs, improve the sensitivity to radiation, and stimulate potent anti-tumor immune response with a 2-fold increase in the infiltration of cytotoxic T cells in tumor microenvironment, thereby effectively suppressing tumor growth with the tumor inhibitory rate as 78.3 %. Therefore, FAP-C NPs hold great potential for targeted breast cancer therapy.</description><identifier>ISSN: 0378-5173</identifier><identifier>ISSN: 1873-3476</identifier><identifier>EISSN: 1873-3476</identifier><identifier>DOI: 10.1016/j.ijpharm.2025.125190</identifier><identifier>PMID: 39788396</identifier><language>eng</language><publisher>Netherlands: Elsevier B.V</publisher><subject>Animals ; Biomimetic Materials - administration & dosage ; Biomimetic Materials - chemistry ; Biomimetic Materials - pharmacology ; Biomimetic nanoplatform ; Breast cancer ; Breast Neoplasms - drug therapy ; Breast Neoplasms - pathology ; Calcipotriol ; Cancer-associated fibroblasts ; Cancer-Associated Fibroblasts - drug effects ; Cell Line, Tumor ; Endopeptidases ; Extracellular Vesicles ; Female ; Gelatinases ; Humans ; Membrane Proteins ; Mice ; Mice, Inbred BALB C ; Nanoparticles - administration & dosage ; Nanoparticles - chemistry ; Polylactic Acid-Polyglycolic Acid Copolymer - chemistry ; Serine Endopeptidases ; Tumor Microenvironment - drug effects ; Vitamin D receptor</subject><ispartof>International journal of pharmaceutics, 2025-02, Vol.670, p.125190, Article 125190</ispartof><rights>2025 Elsevier B.V.</rights><rights>Copyright © 2025 Elsevier B.V. All rights reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><cites>FETCH-LOGICAL-c243t-add5a733c55a621ebf6a4e729e663ffefa33a9e366189951b3b4e04c95f36c893</cites><orcidid>0009-0007-3368-4508</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S0378517325000262$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,776,780,3537,27901,27902,65306</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/39788396$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Gao, Chen</creatorcontrib><creatorcontrib>Jian, Chen</creatorcontrib><creatorcontrib>Wang, Lulu</creatorcontrib><creatorcontrib>Liu, Yajing</creatorcontrib><creatorcontrib>Xiong, Yiquan</creatorcontrib><creatorcontrib>Wu, Tingting</creatorcontrib><creatorcontrib>Shi, Chen</creatorcontrib><title>FAP-targeting biomimetic nanosystem to restore the activated cancer-associated fibroblasts to quiescent state for breast cancer radiotherapy</title><title>International journal of pharmaceutics</title><addtitle>Int J Pharm</addtitle><description>FAP-C NPs, consisting of PLGA-C NPs encapsulated with the vitamin D analog calcipotriol as the core and 4T1 cell membrane chimeric with FAP single-chain fragment variable as the shell, can accumulate in tumor and restore the activated CAFs to a quiescent state to remodel the tumor microenvironment and improve the sensitivity to radiotherapy.
[Display omitted]
Cancer associated fibroblasts (CAFs) are one of the most important stromal cells in the tumor microenvironment, playing a pivotal role in the development, recurrence, metastasis, and immunosuppression of cancer and treatment resistance. Here, we developed a core–shell biomimetic nanosystem termed as FAP-C NPs. This system was comprised of 4T1 extracellular vesicles fused with a FAP single-chain antibody fragment to form the biomimetic shell, and PLGA nanoparticles loaded with calcipotriol as the core. The FAP-modified shell endowed this nanosystem with active targeting ability to CAFs. Calcipotriol, a vitamin D analog, can activate the vitamin D receptor expressed on CAFs, promoting their transition from an activated to quiescent state. This process would help to reduce the pro-tumorigenic signals generated by CAFs, inhibit the stemness of cancer cells, and attenuate the inhibitory effect of CAFs on immune cells. The hydrated particle size of FAP-C NPs was approximately 206 nm, with a narrow distribution (polydispersity index < 0.2). The zeta potential of FAP-C NPs was −12.63 ± 0.61 mV. FAP-C NPs can restore CAFs to a quiescent state to shield the function of activated CAFs, inhibit tumor cell stemness, facilitate the maturation of dendritic cell, and relieve the inhibition of CAFs on lymphocytes. Besides, when combined with radiotherapy, this biomimetic nanosystem could inhibit the activation of CAFs, improve the sensitivity to radiation, and stimulate potent anti-tumor immune response with a 2-fold increase in the infiltration of cytotoxic T cells in tumor microenvironment, thereby effectively suppressing tumor growth with the tumor inhibitory rate as 78.3 %. Therefore, FAP-C NPs hold great potential for targeted breast cancer therapy.</description><subject>Animals</subject><subject>Biomimetic Materials - administration & dosage</subject><subject>Biomimetic Materials - chemistry</subject><subject>Biomimetic Materials - pharmacology</subject><subject>Biomimetic nanoplatform</subject><subject>Breast cancer</subject><subject>Breast Neoplasms - drug therapy</subject><subject>Breast Neoplasms - pathology</subject><subject>Calcipotriol</subject><subject>Cancer-associated fibroblasts</subject><subject>Cancer-Associated Fibroblasts - drug effects</subject><subject>Cell Line, Tumor</subject><subject>Endopeptidases</subject><subject>Extracellular Vesicles</subject><subject>Female</subject><subject>Gelatinases</subject><subject>Humans</subject><subject>Membrane Proteins</subject><subject>Mice</subject><subject>Mice, Inbred BALB C</subject><subject>Nanoparticles - administration & dosage</subject><subject>Nanoparticles - chemistry</subject><subject>Polylactic Acid-Polyglycolic Acid Copolymer - chemistry</subject><subject>Serine Endopeptidases</subject><subject>Tumor Microenvironment - drug effects</subject><subject>Vitamin D receptor</subject><issn>0378-5173</issn><issn>1873-3476</issn><issn>1873-3476</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2025</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFUcFuFDEMjRCIbgufAMqRyyzJeJKZnFBVUahUCQ5wjjwZp81qZ7JNspX2H_hosuzClZMt-z3bz4-xd1KspZD642YdNrtHTPO6Fa1ay1ZJI16wlRx6aKDr9Uu2EtAPjZI9XLDLnDdCCN1KeM0uwPTDAEav2K_b6-9NwfRAJSwPfAxxDnPNHV9wifmQC828RJ4ol5iIl0fi6Ep4xkITd7g4Sg3mHF34U_FhTHHcYi75SHvaB8qOlsJzqX3uY-Jjoto-c3nCKcQ6NeHu8Ia98rjN9PYcr9jP288_br4299--3N1c3zeu7aA0OE0KewCnFFZBNHqNHfWtIa3Be_IIgIZAazkYo-QIY0eic0Z50G4wcMU-nObuUnzaV2V2DvXK7RYXivtsQSowclAtVKg6QV2KOSfydpfCjOlgpbBHI-zGno2wRyPsyYjKe39esR9nmv6x_n6-Aj6dAFSFPgdKNrtA9SVTSOSKnWL4z4rfNymgQg</recordid><startdate>20250210</startdate><enddate>20250210</enddate><creator>Gao, Chen</creator><creator>Jian, Chen</creator><creator>Wang, Lulu</creator><creator>Liu, Yajing</creator><creator>Xiong, Yiquan</creator><creator>Wu, Tingting</creator><creator>Shi, Chen</creator><general>Elsevier B.V</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><orcidid>https://orcid.org/0009-0007-3368-4508</orcidid></search><sort><creationdate>20250210</creationdate><title>FAP-targeting biomimetic nanosystem to restore the activated cancer-associated fibroblasts to quiescent state for breast cancer radiotherapy</title><author>Gao, Chen ; Jian, Chen ; Wang, Lulu ; Liu, Yajing ; Xiong, Yiquan ; Wu, Tingting ; Shi, Chen</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c243t-add5a733c55a621ebf6a4e729e663ffefa33a9e366189951b3b4e04c95f36c893</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2025</creationdate><topic>Animals</topic><topic>Biomimetic Materials - administration & dosage</topic><topic>Biomimetic Materials - chemistry</topic><topic>Biomimetic Materials - pharmacology</topic><topic>Biomimetic nanoplatform</topic><topic>Breast cancer</topic><topic>Breast Neoplasms - drug therapy</topic><topic>Breast Neoplasms - pathology</topic><topic>Calcipotriol</topic><topic>Cancer-associated fibroblasts</topic><topic>Cancer-Associated Fibroblasts - drug effects</topic><topic>Cell Line, Tumor</topic><topic>Endopeptidases</topic><topic>Extracellular Vesicles</topic><topic>Female</topic><topic>Gelatinases</topic><topic>Humans</topic><topic>Membrane Proteins</topic><topic>Mice</topic><topic>Mice, Inbred BALB C</topic><topic>Nanoparticles - administration & dosage</topic><topic>Nanoparticles - chemistry</topic><topic>Polylactic Acid-Polyglycolic Acid Copolymer - chemistry</topic><topic>Serine Endopeptidases</topic><topic>Tumor Microenvironment - drug effects</topic><topic>Vitamin D receptor</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Gao, Chen</creatorcontrib><creatorcontrib>Jian, Chen</creatorcontrib><creatorcontrib>Wang, Lulu</creatorcontrib><creatorcontrib>Liu, Yajing</creatorcontrib><creatorcontrib>Xiong, Yiquan</creatorcontrib><creatorcontrib>Wu, Tingting</creatorcontrib><creatorcontrib>Shi, Chen</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>International journal of pharmaceutics</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Gao, Chen</au><au>Jian, Chen</au><au>Wang, Lulu</au><au>Liu, Yajing</au><au>Xiong, Yiquan</au><au>Wu, Tingting</au><au>Shi, Chen</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>FAP-targeting biomimetic nanosystem to restore the activated cancer-associated fibroblasts to quiescent state for breast cancer radiotherapy</atitle><jtitle>International journal of pharmaceutics</jtitle><addtitle>Int J Pharm</addtitle><date>2025-02-10</date><risdate>2025</risdate><volume>670</volume><spage>125190</spage><pages>125190-</pages><artnum>125190</artnum><issn>0378-5173</issn><issn>1873-3476</issn><eissn>1873-3476</eissn><abstract>FAP-C NPs, consisting of PLGA-C NPs encapsulated with the vitamin D analog calcipotriol as the core and 4T1 cell membrane chimeric with FAP single-chain fragment variable as the shell, can accumulate in tumor and restore the activated CAFs to a quiescent state to remodel the tumor microenvironment and improve the sensitivity to radiotherapy.
[Display omitted]
Cancer associated fibroblasts (CAFs) are one of the most important stromal cells in the tumor microenvironment, playing a pivotal role in the development, recurrence, metastasis, and immunosuppression of cancer and treatment resistance. Here, we developed a core–shell biomimetic nanosystem termed as FAP-C NPs. This system was comprised of 4T1 extracellular vesicles fused with a FAP single-chain antibody fragment to form the biomimetic shell, and PLGA nanoparticles loaded with calcipotriol as the core. The FAP-modified shell endowed this nanosystem with active targeting ability to CAFs. Calcipotriol, a vitamin D analog, can activate the vitamin D receptor expressed on CAFs, promoting their transition from an activated to quiescent state. This process would help to reduce the pro-tumorigenic signals generated by CAFs, inhibit the stemness of cancer cells, and attenuate the inhibitory effect of CAFs on immune cells. The hydrated particle size of FAP-C NPs was approximately 206 nm, with a narrow distribution (polydispersity index < 0.2). The zeta potential of FAP-C NPs was −12.63 ± 0.61 mV. FAP-C NPs can restore CAFs to a quiescent state to shield the function of activated CAFs, inhibit tumor cell stemness, facilitate the maturation of dendritic cell, and relieve the inhibition of CAFs on lymphocytes. Besides, when combined with radiotherapy, this biomimetic nanosystem could inhibit the activation of CAFs, improve the sensitivity to radiation, and stimulate potent anti-tumor immune response with a 2-fold increase in the infiltration of cytotoxic T cells in tumor microenvironment, thereby effectively suppressing tumor growth with the tumor inhibitory rate as 78.3 %. Therefore, FAP-C NPs hold great potential for targeted breast cancer therapy.</abstract><cop>Netherlands</cop><pub>Elsevier B.V</pub><pmid>39788396</pmid><doi>10.1016/j.ijpharm.2025.125190</doi><orcidid>https://orcid.org/0009-0007-3368-4508</orcidid></addata></record> |
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| subjects | Animals Biomimetic Materials - administration & dosage Biomimetic Materials - chemistry Biomimetic Materials - pharmacology Biomimetic nanoplatform Breast cancer Breast Neoplasms - drug therapy Breast Neoplasms - pathology Calcipotriol Cancer-associated fibroblasts Cancer-Associated Fibroblasts - drug effects Cell Line, Tumor Endopeptidases Extracellular Vesicles Female Gelatinases Humans Membrane Proteins Mice Mice, Inbred BALB C Nanoparticles - administration & dosage Nanoparticles - chemistry Polylactic Acid-Polyglycolic Acid Copolymer - chemistry Serine Endopeptidases Tumor Microenvironment - drug effects Vitamin D receptor |
| title | FAP-targeting biomimetic nanosystem to restore the activated cancer-associated fibroblasts to quiescent state for breast cancer radiotherapy |
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