Interleukin 2 (IL-2) is widely used as an active immunotherapeutic agent in clinical metastatic cancers. However, its therapeutic concentrations do not last long due to its short half-life. Thus, only a transient prol...Interleukin 2 (IL-2) is widely used as an active immunotherapeutic agent in clinical metastatic cancers. However, its therapeutic concentrations do not last long due to its short half-life. Thus, only a transient proliferation of the anti-cancer CD8+ T cells can be achieved, resulting in poor efficacy. Therefore, the aim of this work was to create a system that promotes CD8+ T cell proliferation at the tumor site using IL-2 persistently present and activates an anti-cancer immune response. This goal was achieved by the design of the IL-2-loaded polypeptide nanoparticles (P-IL-2) where methoxy poly(ethylene glycol) block poly-[(N-2-hydroxyethyl)-aspartamide] phenylboronic acid was used to encapsulate IL-2 through boron-nitrogen coordination with poly(L-lysine). P-IL-2 significantly prolonged the circulation time of IL-2 and achieved a selective drug release at the tumor site in the presence of high levels of reactive oxygen species, thus activating an anti-cancer immune response and exerting a better anti-cancer effect. The half-life of P-IL-2 was 3.15-fold higher than that of IL-2, and the quantity of CD8+ T cells after using P-IL-2 was 1.89-fold higher than that after using IL-2. In addition, the combination of P-IL-2 and anti-CTLA-4 monoclonal antibody resulted in an enhanced immune activation. Hence, this work provides a new approach to improve the efficacy of IL-2 in anti-cancer immunotherapy.展开更多
Combretastatin A4 phosphate(CA4P)is a potent vascular disrupting agent with good water solubility.However,it is only effective at high doses,which decreases clinical applicability.Herein,we designed stable CA4P polyme...Combretastatin A4 phosphate(CA4P)is a potent vascular disrupting agent with good water solubility.However,it is only effective at high doses,which decreases clinical applicability.Herein,we designed stable CA4P polymeric nanoparticles(CA4P NPs)consisting of various cholesterol derivatives,and with a drug loading efficacy of 93%.The nanoparticles released CA4P in a sustained manner and achieved a 72%inhibition rate in the murine H22 liver tumor model,which was about 2.9-fold higher than that of free CA4P(24.6%).Furthermore,the carrier components of CA4P NPs were metabolized to arginine,cholesterol,ethanol and poly(ethylene glycol)in vivo;therefore,the CA4P NPs are safe and have significant potential for clinical translation.展开更多
基金supported by the National Natural Science Foundation of China(Nos.52025035,51873206 and 52203198)the Project of Health research talents Project of Jilin Province(No.2020SCZ06)+1 种基金the Project of Jilin Province Development and Reform Commission(No.2021C043-6)the Jilin Provincial International Cooperation Key Laboratory of Biomedical Polymers(No.20210504001GH).
文摘Interleukin 2 (IL-2) is widely used as an active immunotherapeutic agent in clinical metastatic cancers. However, its therapeutic concentrations do not last long due to its short half-life. Thus, only a transient proliferation of the anti-cancer CD8+ T cells can be achieved, resulting in poor efficacy. Therefore, the aim of this work was to create a system that promotes CD8+ T cell proliferation at the tumor site using IL-2 persistently present and activates an anti-cancer immune response. This goal was achieved by the design of the IL-2-loaded polypeptide nanoparticles (P-IL-2) where methoxy poly(ethylene glycol) block poly-[(N-2-hydroxyethyl)-aspartamide] phenylboronic acid was used to encapsulate IL-2 through boron-nitrogen coordination with poly(L-lysine). P-IL-2 significantly prolonged the circulation time of IL-2 and achieved a selective drug release at the tumor site in the presence of high levels of reactive oxygen species, thus activating an anti-cancer immune response and exerting a better anti-cancer effect. The half-life of P-IL-2 was 3.15-fold higher than that of IL-2, and the quantity of CD8+ T cells after using P-IL-2 was 1.89-fold higher than that after using IL-2. In addition, the combination of P-IL-2 and anti-CTLA-4 monoclonal antibody resulted in an enhanced immune activation. Hence, this work provides a new approach to improve the efficacy of IL-2 in anti-cancer immunotherapy.
基金financially supported by the Ministry of Science and Technology of China(No.2022YFE0110200)the Natural Science Foundation of Hunan Province of China(No.2021JJ30680)the National Natural Science Foundation of China(Nos.52203198,52025035 and 52103195)。
文摘Combretastatin A4 phosphate(CA4P)is a potent vascular disrupting agent with good water solubility.However,it is only effective at high doses,which decreases clinical applicability.Herein,we designed stable CA4P polymeric nanoparticles(CA4P NPs)consisting of various cholesterol derivatives,and with a drug loading efficacy of 93%.The nanoparticles released CA4P in a sustained manner and achieved a 72%inhibition rate in the murine H22 liver tumor model,which was about 2.9-fold higher than that of free CA4P(24.6%).Furthermore,the carrier components of CA4P NPs were metabolized to arginine,cholesterol,ethanol and poly(ethylene glycol)in vivo;therefore,the CA4P NPs are safe and have significant potential for clinical translation.
