The irregular defects and residual tumor tissue after surgery are challenges for effective breast cancer treatment.Herein,a smart hydrogel with self-adaptable size and dual responsive cargos release was fabricated to ...The irregular defects and residual tumor tissue after surgery are challenges for effective breast cancer treatment.Herein,a smart hydrogel with self-adaptable size and dual responsive cargos release was fabricated to treat breast cancer via accurate tumor elimination,on-demand adipose tissue regeneration and effective infection inhibition.The hydrogel consisted of thiol groups ended polyethylene glycol(SH-PEG-SH)and doxorubicin encapsulated mesoporous silica nanocarriers(DOX@MSNs)double crosslinked hyaluronic acid(HA)after loading of antibacterial peptides(AP)and adipose-derived stem cells(ADSCs).A pH-cleavable unsaturated amide bond was pre-introduced between MSNs and HA frame to perform the tumor-specific acidic environment dependent DOX@MSNs release,meanwhile an esterase degradable glyceryl dimethacrylate cap was grafted on MSNs,which contributed to the selective chemotherapy in tumor cells with over-expressed esterase.The bond cleavage between MSNs and HA would also cause the swelling of the hydrogel,which not only provide sufficient space for the growth of ADSCs,but allows the hydrogel to fully fill the irregular defects generated by surgery and residual tumor atrophy,resulting in the on-demand regeneration of adipose tissue.Moreover,the sustained release of AP could be simultaneously triggered along with the size change of hydrogel,which further avoided bacterial infection to promote tissue regeneration.展开更多
Peptide-drug conjugates have achieved considerable development and application as a novel strategy for targeted delivery of anticancer drugs. Bioactive peptides induced calcium deposition can irreversibly assist inhib...Peptide-drug conjugates have achieved considerable development and application as a novel strategy for targeted delivery of anticancer drugs. Bioactive peptides induced calcium deposition can irreversibly assist inhibition of tumors. However, active regulation of calcium level through signal transduction of bioactive substances has not been reported yet. In this study, novel neuropeptide-doxorubicin conjugates(NP-DOX) with lysosome-specific acid response were described for neuropeptide Y_1 receptor(Y_1R)-overexpressed triple-negative breast cancer. The delivery mechanism of NP-DOX was clarified that diverse pathways were involved, including intracellular and intercellular transport. Importantly, up-regulation of Y_1 R-mediated intracellular calcium level via second messenger inositol triphosphate was presented in NP-DOX treated MDA-MB-231 cells. In vivo antitumor efficacy demonstrated that NP-DOX showed less organ toxicity and enhanced tumor inhibition benefited from its controlled release and Y_1R-mediated calcium deposition, compared with free DOX. This bioconjugate is a proof-of-concept confirming that neuropeptide-mediated control of signaling responses in neuropeptide-drug conjugates enables great potential for further applications in tumor chemotherapy.展开更多
目的:探究复方半边莲口服液对乳腺癌荷瘤小鼠的肿瘤抑制和改善肿瘤免疫的作用。方法:将24只BALB/C雌鼠原位接种4T1乳腺癌细胞,待瘤体体积超过40 mm 3时,随机分成对照组、复方半边莲口服液低、中、高剂量组,连续给药。每天测量荷瘤小鼠...目的:探究复方半边莲口服液对乳腺癌荷瘤小鼠的肿瘤抑制和改善肿瘤免疫的作用。方法:将24只BALB/C雌鼠原位接种4T1乳腺癌细胞,待瘤体体积超过40 mm 3时,随机分成对照组、复方半边莲口服液低、中、高剂量组,连续给药。每天测量荷瘤小鼠肿瘤大小,观察复方半边莲口服液对小鼠瘤体体积的影响;连续给药30 d后,处死荷瘤小鼠,通过测量不同组处理后荷瘤小鼠肿瘤重量,计算复方半边莲口服液各剂量组的抑瘤率;将肿瘤组织剪碎,经胶原酶处理成单细胞,并分离其中的淋巴细胞,使用流式分析仪检测肿瘤微环境中淋巴细胞的比例。结果:与对照组相比,复方半边莲口服液中、高剂量组于给药第10天、20天瘤体体积均降低(P<0.05),给药30 d,低、中、高剂量组瘤体体积均明显降低(P<0.01);低、中、高剂量组肿瘤重量明显降低(P<0.01),抑瘤率分别为17.95%、28.77%、49.43%;低、中、高剂量组CD3+T细胞、CD4+T细胞比例明显升高(P<0.01),中、高剂量组CD8+T细胞比例明显升高(P<0.01),而低、中、高剂量组调节性T细胞比例明显降低(P<0.01)。结论:复方半边莲口服液能够抑制乳腺癌荷瘤小鼠肿瘤的生长,增强荷瘤小鼠抗肿瘤免疫功能,值得临床推广应用。展开更多
基金the National High Level Talents Special Support Plan(X.C.)the“Young Talent Support Plan”of Xi'an Jiaotong University(X.C.)+2 种基金the Natural Science Foundation of Shaanxi Province(No.2022JZ-48 to X.C.)the National Natural Science Foundation of China(No.82272141 to X.C.)the Shaanxi Provincial Key Research and Development Plan Project(No.2023-JC-QN-0260 to X.Q.).
文摘The irregular defects and residual tumor tissue after surgery are challenges for effective breast cancer treatment.Herein,a smart hydrogel with self-adaptable size and dual responsive cargos release was fabricated to treat breast cancer via accurate tumor elimination,on-demand adipose tissue regeneration and effective infection inhibition.The hydrogel consisted of thiol groups ended polyethylene glycol(SH-PEG-SH)and doxorubicin encapsulated mesoporous silica nanocarriers(DOX@MSNs)double crosslinked hyaluronic acid(HA)after loading of antibacterial peptides(AP)and adipose-derived stem cells(ADSCs).A pH-cleavable unsaturated amide bond was pre-introduced between MSNs and HA frame to perform the tumor-specific acidic environment dependent DOX@MSNs release,meanwhile an esterase degradable glyceryl dimethacrylate cap was grafted on MSNs,which contributed to the selective chemotherapy in tumor cells with over-expressed esterase.The bond cleavage between MSNs and HA would also cause the swelling of the hydrogel,which not only provide sufficient space for the growth of ADSCs,but allows the hydrogel to fully fill the irregular defects generated by surgery and residual tumor atrophy,resulting in the on-demand regeneration of adipose tissue.Moreover,the sustained release of AP could be simultaneously triggered along with the size change of hydrogel,which further avoided bacterial infection to promote tissue regeneration.
基金financially supported by the Key R&D Program of Zhejiang Province (No.2020C03110)the National Natural Science Foundation of China (Nos.T2222021, 32011530115,32025021)+1 种基金the Science&Technology Bureau of Ningbo City (Nos.2020Z094, 2021Z072)Excellent Member of Youth Innovation Promotion Association Foundation of CAS (No.Y2021079)。
文摘Peptide-drug conjugates have achieved considerable development and application as a novel strategy for targeted delivery of anticancer drugs. Bioactive peptides induced calcium deposition can irreversibly assist inhibition of tumors. However, active regulation of calcium level through signal transduction of bioactive substances has not been reported yet. In this study, novel neuropeptide-doxorubicin conjugates(NP-DOX) with lysosome-specific acid response were described for neuropeptide Y_1 receptor(Y_1R)-overexpressed triple-negative breast cancer. The delivery mechanism of NP-DOX was clarified that diverse pathways were involved, including intracellular and intercellular transport. Importantly, up-regulation of Y_1 R-mediated intracellular calcium level via second messenger inositol triphosphate was presented in NP-DOX treated MDA-MB-231 cells. In vivo antitumor efficacy demonstrated that NP-DOX showed less organ toxicity and enhanced tumor inhibition benefited from its controlled release and Y_1R-mediated calcium deposition, compared with free DOX. This bioconjugate is a proof-of-concept confirming that neuropeptide-mediated control of signaling responses in neuropeptide-drug conjugates enables great potential for further applications in tumor chemotherapy.
文摘目的:探究复方半边莲口服液对乳腺癌荷瘤小鼠的肿瘤抑制和改善肿瘤免疫的作用。方法:将24只BALB/C雌鼠原位接种4T1乳腺癌细胞,待瘤体体积超过40 mm 3时,随机分成对照组、复方半边莲口服液低、中、高剂量组,连续给药。每天测量荷瘤小鼠肿瘤大小,观察复方半边莲口服液对小鼠瘤体体积的影响;连续给药30 d后,处死荷瘤小鼠,通过测量不同组处理后荷瘤小鼠肿瘤重量,计算复方半边莲口服液各剂量组的抑瘤率;将肿瘤组织剪碎,经胶原酶处理成单细胞,并分离其中的淋巴细胞,使用流式分析仪检测肿瘤微环境中淋巴细胞的比例。结果:与对照组相比,复方半边莲口服液中、高剂量组于给药第10天、20天瘤体体积均降低(P<0.05),给药30 d,低、中、高剂量组瘤体体积均明显降低(P<0.01);低、中、高剂量组肿瘤重量明显降低(P<0.01),抑瘤率分别为17.95%、28.77%、49.43%;低、中、高剂量组CD3+T细胞、CD4+T细胞比例明显升高(P<0.01),中、高剂量组CD8+T细胞比例明显升高(P<0.01),而低、中、高剂量组调节性T细胞比例明显降低(P<0.01)。结论:复方半边莲口服液能够抑制乳腺癌荷瘤小鼠肿瘤的生长,增强荷瘤小鼠抗肿瘤免疫功能,值得临床推广应用。
