BIOTECHNOLOGY AND APPLIED BIOCHEMISTRY
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2024
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IF 3.2
Jiajie Zhang,Ming Qu,Zhanhao Mo,He Sui,Lin Liu,Deliang Fu
In prior research, both miRNA-125b and BLZ945 have shown potential in effectively inhibiting M2 macrophage polarization and producing antitumor effects. Nevertheless, their physicochemical characteristics present significant challenges for efficient in vivo delivery. Ionizable cationic lipid nanoparticles (LNPs), recognized for their superior biocompatibility and drug-loading capacity, serve as a novel carrier for nucleic acid-based therapeutics. In our study, we successfully encapsulated both agents within LNPs and conducted a thorough characterization. Subsequently, we investigated their potential to repolarize M2 macrophages in vitro and evaluated their in vivo distribution, biosafety, and antitumor efficacy. The findings revealed that the LNPs maintained excellent drug-loading efficiency, consistent particle size, and stable zeta potential. All formulations effectively inhibited M2 macrophage polarization in vitro. Upon administration in vivo, the LNPs not only demonstrated favorable biosafety profiles but also accumulated efficiently in tumor tissues, substantially reducing tumor burden, particularly notable in co-loaded LNPs. Our results affirm that LNPs are an effective carrier for miRNA-125b and BLZ945, highlighting this encapsulation approach as promising for the treatment of solid tumors and meriting further investigation. Practitioner points : (i) Ionizable cationic nanoparticles provide high and stable encapsulation rates to efficiently load nucleic acid polymers into the LNP, avoiding the rapid accumulation of circulating macrophages, which can lead to reduced penetration of the LNP into target tissues. Therefore, it can be used as a novel drug delivery method to benefit clinical patients. (ii) miRNA-125b LNP/BLZ945 LNP attenuated the depleting effect of BLZ945 on macrophages and significantly inhibited macrophage M2 polarization. It could be effectively distributed in tumors and showed good biosafety while exerting antitumor effects, bringing hope to clinical pancreatic tumor patients.
研究领域:
药学
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肿瘤学
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分子生物学
✓ 已验证
DOI
高影响因子
Biomaterials Science
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2020
·Vol. 8
·期 20
·5666-5676
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IF 6.183
Qi Wei,Na Shen,Haiyang Yu,Yue Wang,Zhaohui Tang,Xuesi Chen
Combretastatin A4 nanoparticles (CA4-NPs), which notably inhibit tumor growth, were found to cause tumor regrowth due to the intratumoral enrichment of M2-type macrophages after treatment. Since BLZ945, an inhibitor of CSF-1 receptor (CSF-1R), depletes and inhibits the proliferation of M2-type macrophages, it has the potential to relieve the immunosuppressive microenvironment and improve anti-tumor therapy of CA4-NPs. However, CSF-1R exists widely, not only in macrophages, and BLZ945 could cause potential hepatotoxicity. It is necessary to establish a tumor-targeting drug delivery system to reduce the off-target and side effects of BLZ945. In this study, FXIIIa substrate peptide A15 decorated BLZ945 nanoparticles (A15-BLZ-NPs) were developed, in which, BLZ945-poly(D,L-lactide) (BLZ945-PLA), produced by ring-opening polymerization, was encapsulated in poly(ethylene glycol)-poly(D,L-lactide) (PEG5k-PLA5k), and A15 was decorated on the surface PEG segment. A15-BLZ-NPs could crosslink with fibrin through elevated FXIIIa and specifically target intratumoral coagulation spots induced by CA4-NPs. In vivo studies showed that CA4-NPs induced enhanced distribution of BLZ945 in tumors, as the BLZ945 content was 3.75-fold in the CA4-NP + A15-BLZ-NP group compared to that of A15-BLZ-NP single treatment. Meanwhile, compared to the CA4-NP group, the combination treatment significantly reduced the proportion of M2-type macrophages (from 64.4% to 24.5%) and enriched cytotoxic T lymphocytes (from 1.5% to 18.9%) in tumors, suggesting that A15-BLZ-NPs remodeled and activated tumor immunity after CA4-NP treatment. Furthermore, the combined treatment effectively improved the tumor inhibition rate to 73.4%, which was significantly higher than that of CA4-NP (15.5%) or A15-BLZ-NP (23.9%) single treatment. This work established a novel combination strategy for anti-tumor therapy.
研究领域:
肿瘤学
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药理学
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免疫学
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纳米技术
✓ 已验证
产品关联
DOI
PubMed
高影响因子
International Journal of Nanomedicine
·
2023
·
IF 8
Dongmei Guo,Yue Huang,Kun Wang,Chenguang Yang,Lili Ma,Yu Zhang,Haiyang Yu,Manhua Cui,Zhaohui Tang
Purpose Cervical cancer (CC) is a highly vascularized tumor with abundant abnormal blood vessel, which could be targeted by therapeutic strategies. Poly(L-glutamic acid)-g-methoxy poly(ethylene glycol)/combretastatin A4 (CA4)/BLZ945 nanoparticles (CB-NPs) have shown great potential as nano vascular disrupting agents (VDAs) in the realm of synergistic cancer therapy.Methods In this study, we investigated the nanocharacteristics of CB-NPs, focusing on active pharmaceutical ingredients (API), as well as lyophilized samples combining API with protective agents (PAs). The in vivo efficacy of final sample (API + PAs) was evaluated.Results The assembled sphere of API with complex core and thin-shell structure was confirmed. PAs were found to significantly influence in vivo efficacy. Collaborative efforts between API and PAs, namely mannitol and lactose, resulted in the most promising lyophilized sample, ie, the final sample (FS2) for CC therapy. Impressively, FS2 demonstrated an exceptional 100% cure rate on the CC U14-bearing mice model.Conclusion FS2 has provided significant insights for cervical cancer therapy. It is also crucial to develop a comprehensive evaluation strategy for the formulation of nanomedicine, which has the potential to serve as a guideline for future clinical trials.
研究领域:
药剂学
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肿瘤学
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纳米医学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF PHARMACEUTICS
·
2023
·
IF 5.8
Yue Huang,Chenguang Yang,Jianlin lv,Yu Zhang,Kun Wang,Lili Ma,Zhilin Liu,Haiyang Yu,Mingqiang Li,Zhaohui Tang
Poly(L-glutamic acid)- g -methoxy poly(ethylene glycol)/Combretastatin A4 (CA4)/BLZ945 nanoparticles (CB-NPs) have shown great potential in synergistic cancer therapy. However, it is still unclear how the nanoparticles’ formula, such as injection dose, active agent ratio, and drug loading content, affects the side effects and in vivo efficacy of CB-NPs. In this study, a series of CB-NPs with different BLZ945/CA4 (B/C) ratios and drug loading contents were synthesized and evaluated on a hepatoma (H22) tumor-bearing mice model. The injection dose and B/C ratio were found to have a significant influence on the in vivo anticancer efficacy. The CB-NPs 20 with B/C weight ratio of 0.45/1, and total drug loading content (B + C) of 20.7 wt%, showed the highest potential for clinical application. Systematic pharmacokinetics , biodistribution , and in vivo efficacy evaluation for CB-NPs 20 have been finished, which may provide significant instruction for medicine screening and clinical application.
研究领域:
肿瘤学
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药剂学
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生物医学工程
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Frontiers in Bioengineering and Biotechnology
·
2024
·
IF 4.3
Chen Jiaqi,Yin Min,Yang Chenguang,Wang Kun,Ma Lili,Yu Haiyang,Huang Yue,Liu Feng,Tang Zhaohui
Introduction: The prognosis of advanced renal carcinoma is not ideal, necessitating the exploration of novel treatment strategies. Poly(L-glutamic acid)-g-methoxy poly(ethylene glycol)/Combretastatin A4 (CA4)/BLZ945 nanoparticles (CB-NPs) possess the dual capability of CA4 (targeting blood vessels to induce tumor necrosis) and BLZ945 (inducing M2 macrophage apoptosis), thereby inhibiting tumor growth.Methods: Here, the therapeutic effects and underlying mechanism was explored by CCK-8 cytotoxicity experiment, transwell cell invasion and migration experiment, H&E, western blot analysis, immunohistochemistry, flow cytometry, and other techniques.Results: These results demonstrated that CB-NPs could inhibit the growth of Renca cells and subcutaneous tumors in mice, with an impressive tumor inhibition rate of 88.0%. Results suggested that CB-NPs can induce necrosis in renal carcinoma cells and tissues, downregulate VEGFA expression, promote renal carcinoma cell apoptosis, and reduce the polarization of M2 macrophages.Discussion: These findings offer innovative perspectives for the treatment of advanced renal carcinoma.
研究领域:
肿瘤学
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药学
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纳米技术
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）