Bone metastasis secondary to breast cancer negatively impacts patient quality of life and survival.The treatment of bone metastases is challenging since many anticancer drugs are not effectively delivered to the bone ...Bone metastasis secondary to breast cancer negatively impacts patient quality of life and survival.The treatment of bone metastases is challenging since many anticancer drugs are not effectively delivered to the bone to exert a therapeutic effect.To improve the treatment efficacy,we developed Pluronic P123(P123)-based polymeric micelles dually decorated with alendronate(ALN)and cancer-specific phage protein DMPGTVLP(DP-8)for targeted drug delivery to breast cancer bone metastases.Doxorubicin(DOX)was selected as the anticancer drug and was encapsulated into the hydrophobic core of the micelles with a high drug loading capacity(3.44%).The DOX-loaded polymeric micelles were spherical,123 nm in diameter on average,and exhibited a narrow size distribution.The in vitro experiments demonstrated that a pH decrease from 7.4 to 5.0 markedly accelerated DOX release.The micelles were well internalized by cultured breast cancer cells and the cell death rate of micelle-treated breast cancer cells was increased compared to that of free DOX-treated cells.Rapid binding of the micelles to hydroxyapatite(HA)microparticles indicated their high affinity for bone.P123-ALN/DP-8@DOX inhibited tumor growth and reduced bone resorption in a 3D cancer bone metastasis model.In vivo experiments using a breast cancer bone metastasis nude model demonstrated increased accumulation of the micelles in the tumor region and considerable antitumor activity with no organ-specific histological damage and minimal systemic toxicity.In conclusion,our study provided strong evidence that these pH-sensitive dual ligand-targeted polymeric micelles may be a successful treatment strategy for breast cancer bone metastasis.展开更多
Malignant melanoma(MM)is a kind of highly-invasive and highly-metastatic tumor,which is insensitive to radiochemotherapy.It is also one of the most invasive tumors in skin cancer with limited treatment options.Due to ...Malignant melanoma(MM)is a kind of highly-invasive and highly-metastatic tumor,which is insensitive to radiochemotherapy.It is also one of the most invasive tumors in skin cancer with limited treatment options.Due to its rapid increase in incidence in recent years and the limitations of monotherapy,it is necessary to use combination therapy.The combination therapy can not only enhance the treatment effect,but also avoid the development of drug resistance as much as possible.This paper focused on the combined therapy of targeted traditional therapies,immunotherapy with radiotherapy and chemotherapy or other traditional therapies,as well as the research status and new developments of these combined therapies.展开更多
Dbait is a small double-stranded DNA molecule that has been utilized as a radiosensitizer to enhance the sensitivity of glioma to radiotherapy(RT). However, there is no effective drug delivery system to effectively ov...Dbait is a small double-stranded DNA molecule that has been utilized as a radiosensitizer to enhance the sensitivity of glioma to radiotherapy(RT). However, there is no effective drug delivery system to effectively overcome the blood–brain barrier(BBB). The aim of this study was to develop a gene delivery system by using the BBB and glioma dual-targeting and microenvironment-responsive micelles(ch-Kn(s-s)R8-An) to deliver Dbait into glioma for RT. Angiopep-2 can target the low-density lipoprotein receptor-related protein-1(LRP1) that is overexpressed on brain capillary endothelial cells(BCECs) and glioma cells. In particular, due to upregulated matrix metalloproteinase 2(MMP-2) in the tumor microenvironment, we utilized MMP-2-responsive peptides as the enzymatically degradable linkers to conjugate angiopep-2. The results showed that ch-Kn(s-s)R8-An micelles maintained a reasonable size(80–160 nm) with a moderate distribution and a decreased mean diameter from the cross-linking as well as exhibited low critical micelle concentration(CMC) with positive surface charge, ranging from 15 to40 mV. The ch-K5(s-s)R8-An/pEGFP showed high gene transfection efficiency in vitro, improved uptake in glioma cells and good biocompatibility in vitro and in vivo. In addition, the combination of ch-K5(s-s)R8-An/Dbait with RT significantly inhibited the growth of U251 cells in vitro. Thus, ch-K5(s-s)R8-An/Dbait may prove to be a promising gene delivery system to target glioma and enhance the efficacy of RT on U251 cells.展开更多
Photoimmunotherapy(PIT)is an emerging therapeutic approach that integrates phototherapy and immunotherapy to eliminate primary tumors under an appropriate dosage of local light irradiation,while simultaneously prevent...Photoimmunotherapy(PIT)is an emerging therapeutic approach that integrates phototherapy and immunotherapy to eliminate primary tumors under an appropriate dosage of local light irradiation,while simultaneously preventing tumor metastasis and recurrence by activating the host antitumor immune response.Tumor-responsive dynamic nanoassemblies(TDNs)have evolved from being a mere curiosity to a promising platform for high-performance PIT.However,the dynamic nano-bio interaction between TDNs and tumor microenvironment remains poorly understood,which shall be critical for precise control of TDNs assembling/disassembling behavior and superior PIT efficacy.To deepen the understanding of the structure–function relationship of TDNs,this review introduces the rational design,nano-bio interactions,and controllable functionalities of cutting-edge TDNs for enhanced PIT.Moreover,the synergetic mechanism between TDNs-based PIT and immunomodulatory agents-mediated immunomodulation is particularly emphasized.Finally,the challenges and future perspectives in this emerging field are assessed.展开更多
基金supported by the National Natural Science Foundation of China(#81872220 and#81703437)Xinjiang Uygur Autonomous Region Science and Technology Support Project(#2020E0290)+4 种基金Basic Public Welfare Research Project of Zhejiang Province(#LGF18H160034,LGC21B050011 and#LGF20H300012),Science and Technology Bureau of Jiaxing(2020AY10021)Key Research and Development and Transformation project of Qinghai Province(2021-SF-C20)Dutch Cancer Foundation(KWF project#10666)a Zhejiang Provincial Foreign Expert Program Grant,Zhejiang Provincial Key Natural Science Foundation of China(#Z20H160031)and Jiaxing Key Laboratory of Oncological Photodynamic Therapy and Targeted Drug Research,and“Innovative Jiaxing·Excellent Talent Support Program”-Top Talents in Technological Innovation.
文摘Bone metastasis secondary to breast cancer negatively impacts patient quality of life and survival.The treatment of bone metastases is challenging since many anticancer drugs are not effectively delivered to the bone to exert a therapeutic effect.To improve the treatment efficacy,we developed Pluronic P123(P123)-based polymeric micelles dually decorated with alendronate(ALN)and cancer-specific phage protein DMPGTVLP(DP-8)for targeted drug delivery to breast cancer bone metastases.Doxorubicin(DOX)was selected as the anticancer drug and was encapsulated into the hydrophobic core of the micelles with a high drug loading capacity(3.44%).The DOX-loaded polymeric micelles were spherical,123 nm in diameter on average,and exhibited a narrow size distribution.The in vitro experiments demonstrated that a pH decrease from 7.4 to 5.0 markedly accelerated DOX release.The micelles were well internalized by cultured breast cancer cells and the cell death rate of micelle-treated breast cancer cells was increased compared to that of free DOX-treated cells.Rapid binding of the micelles to hydroxyapatite(HA)microparticles indicated their high affinity for bone.P123-ALN/DP-8@DOX inhibited tumor growth and reduced bone resorption in a 3D cancer bone metastasis model.In vivo experiments using a breast cancer bone metastasis nude model demonstrated increased accumulation of the micelles in the tumor region and considerable antitumor activity with no organ-specific histological damage and minimal systemic toxicity.In conclusion,our study provided strong evidence that these pH-sensitive dual ligand-targeted polymeric micelles may be a successful treatment strategy for breast cancer bone metastasis.
基金Public Welfare Technology Application Research Program of Zhejiang Province(LGF18H160034,LGD20H300001,2015C37125)2019 National Undergraduate Innovation Training Program(20190354034)+2 种基金2018 Zhejiang Science and Technology Innovation Activity Program(Emerging talent Program)(2018R417029)2018 Jiaxing Key Technology Innovation Team2018 SRT Key Project of Jiaxing University(85178428)。
文摘Malignant melanoma(MM)is a kind of highly-invasive and highly-metastatic tumor,which is insensitive to radiochemotherapy.It is also one of the most invasive tumors in skin cancer with limited treatment options.Due to its rapid increase in incidence in recent years and the limitations of monotherapy,it is necessary to use combination therapy.The combination therapy can not only enhance the treatment effect,but also avoid the development of drug resistance as much as possible.This paper focused on the combined therapy of targeted traditional therapies,immunotherapy with radiotherapy and chemotherapy or other traditional therapies,as well as the research status and new developments of these combined therapies.
基金the financial support received from the National Natural Science Foundation of China(No.81472349,81302714and 81201809,China)the Natural Science Foundation of Shanghai(No.14ZR1433300,China)+3 种基金the Interdisciplinary Program of Shanghai Jiao Tong University(No.0507N17014,China)the Innovation Program of Shanghai Municipal Education Commission(No.15ZZ041,China)Natural Science Foundation of Zhejiang Province(No.LQ12H30005,China)the Public Welfare Technology Application Research Project(No.LGF18H160034,China)
文摘Dbait is a small double-stranded DNA molecule that has been utilized as a radiosensitizer to enhance the sensitivity of glioma to radiotherapy(RT). However, there is no effective drug delivery system to effectively overcome the blood–brain barrier(BBB). The aim of this study was to develop a gene delivery system by using the BBB and glioma dual-targeting and microenvironment-responsive micelles(ch-Kn(s-s)R8-An) to deliver Dbait into glioma for RT. Angiopep-2 can target the low-density lipoprotein receptor-related protein-1(LRP1) that is overexpressed on brain capillary endothelial cells(BCECs) and glioma cells. In particular, due to upregulated matrix metalloproteinase 2(MMP-2) in the tumor microenvironment, we utilized MMP-2-responsive peptides as the enzymatically degradable linkers to conjugate angiopep-2. The results showed that ch-Kn(s-s)R8-An micelles maintained a reasonable size(80–160 nm) with a moderate distribution and a decreased mean diameter from the cross-linking as well as exhibited low critical micelle concentration(CMC) with positive surface charge, ranging from 15 to40 mV. The ch-K5(s-s)R8-An/pEGFP showed high gene transfection efficiency in vitro, improved uptake in glioma cells and good biocompatibility in vitro and in vivo. In addition, the combination of ch-K5(s-s)R8-An/Dbait with RT significantly inhibited the growth of U251 cells in vitro. Thus, ch-K5(s-s)R8-An/Dbait may prove to be a promising gene delivery system to target glioma and enhance the efficacy of RT on U251 cells.
基金This work was funded by the National Key Research and Development Program of China(Nos.2022YFB3203804,2022YFB3203801,and 2022YFB3203800)the Leading Talent of“Ten Thousand Plan”-National High-Level Talents Special Support Plan,National Natural Science Foundation of China(Nos.32071374 and 32000985)+4 种基金Program of Shanghai Academic Research Leader under the Science and Technology Innovation Action Plan(No.21XD1422100)Program of Shanghai Science and Technology Development(No.22TS1400700)Zhejiang Provincial Natural Science Foundation of China(Nos.LR22C100001 and LQ21H300003)Innovative Research Team of High-Level Local Universities in Shanghai(No.SHSMUZDCX20210900)CAS Interdisciplinary Innovation Team(No.JCTD-2020-08)。
文摘Photoimmunotherapy(PIT)is an emerging therapeutic approach that integrates phototherapy and immunotherapy to eliminate primary tumors under an appropriate dosage of local light irradiation,while simultaneously preventing tumor metastasis and recurrence by activating the host antitumor immune response.Tumor-responsive dynamic nanoassemblies(TDNs)have evolved from being a mere curiosity to a promising platform for high-performance PIT.However,the dynamic nano-bio interaction between TDNs and tumor microenvironment remains poorly understood,which shall be critical for precise control of TDNs assembling/disassembling behavior and superior PIT efficacy.To deepen the understanding of the structure–function relationship of TDNs,this review introduces the rational design,nano-bio interactions,and controllable functionalities of cutting-edge TDNs for enhanced PIT.Moreover,the synergetic mechanism between TDNs-based PIT and immunomodulatory agents-mediated immunomodulation is particularly emphasized.Finally,the challenges and future perspectives in this emerging field are assessed.
