Journal of Nanomaterials
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2019
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IF 2.233
Yun Zhou,Ke Li,Fan Li,Shuang Han,Yang Wang,Xueping Li,Yonghua Zhan
For the patients with hepatocellular carcinoma (HCC), conventional chemotherapy is insufficient or has no benefit. Although combination chemotherapy has been proven as an efficient strategy to enhance anti-HCC efficacy, some barriers, such as low bioavailability and side effects, are limiting clinical development. In order to overcome disadvantages of combination chemotherapy in HCC, targeted nanoparticles (NPs) simultaneously loaded with doxorubicin (DOX) and ABT-199 in an optimal synergistic ratio were developed. First, the most synergistic combination with DOX was screened from ABT-199, ABT-263, and ABT-737. Among them, ABT-199 showed optimal synergy with DOX in a ratio of 10 : 1. Then, cationic amphipathic starch (CSaSt) and hyaluronic acid (HA) were used in coencapsulations of those two drugs. Dual-drug synergistic nanoparticles (DDS NPs) were constructed by absorption of DOX NPs around ABT-199 micelles with an optimal ratio via electrostatic interaction. The shape of DDS NPs was similar to a raspberry, and the size was . The encapsulation efficiencies of DOX and ABT-199 in DDS NPs were and , respectively; meanwhile, the drug loadings were and , respectively. After 72 h of dialysis, 95% of ABT-199 remained and less than 50% of DOX was released. In vitro investigation showed that the drugs in DDS NPs maintained the treated effect in three HCC cell lines; moreover, DDS NPs could perform intracellular delivery of dual drugs and exhibited continuous release of the drugs into different targets. Low in vivo toxicity was found after the acute toxicity test. In vivo fluorescent imaging revealed that DDS NPs could efficiently target and accumulate in the tumor tissues and be maintained more than 72 h after intravenous injection. Compared with free drugs, DDS NPs with the same dosages exhibited a more significant antitumor effect in the HCC xenograft mouse model. The results indicated that DDS NPs have great potential in HCC chemotherapy.
研究领域:
药学
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肿瘤学
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纳米技术
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药物递送系统
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产品关联
DOI
高影响因子
Acta Biomaterialia
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2022
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IF 10.633
Bin Liang,Dawei Jiang,Luqi Pan,Fang Xiong,Shuya Feng,Shenghao Wu,Haige Ye,Zhijie Yu,Changcan Shi,Shenmeng Gao
Selective BCL2 inhibitor ABT-199 has been approved to treat hematological malignancies including acute myeloid leukemia (AML). However, acquired drug resistance and severe side effects occur after extended treatment limiting the clinical usage of ABT-199. Here, we successfully encapsulated pure ABT-199 in amphiphilic mPEG- b -PTMC 169 block copolymer , forming mPEG-b-PTMC 169 @ABT-199 nanoparticles (abbreviated as PEG-ABT-199), which presented better aqueous dispersion and higher efficiency of loading and encapsulation than pure ABT-199. We then compared the anti-leukemic ability of pure ABT-199 and PEG-ABT-199 in vitro and in vivo . PEG-ABT-199 had a lower IC50 value compared with pure ABT-199 in MV4-11 and MOLM-13 cell lines. In addition, PEG-ABT-199 significantly induced apoptosis and decreased colony number than pure ABT-199. Most importantly, PEG-ABT-199 markedly reduced leukemic burden, inhibited the infiltration of leukemic blasts in the spleen, and extended the overall survival (OS) in MLL-AF9-transduced murine AML compared with free ABT-199. Meanwhile, the blank PEG169 NP was non-toxic to normal hematopoiesis in vitro and in vivo , suggesting that PEG169 NP is a safe carrier. Mechanistically, PEG-ABT-199 enhanced mitochondria-targeted delivery of ABT-199 to trigger the collapse of mitochondrial membrane potential (MMP), the release of cytochrome c (cyt-c), and mitochondria-based apoptosis. In conclusion, our results suggest that PEG-ABT-199 has more vital anti-leukemic ability than pure ABT-199. PEG-ABT-199 has potential application in clinical trials to alleviate side effects and improve anti-leukemia ability. Statement of significance ATB-199, an orally selective inhibitor for BCL2 protein, presents marked activity in relapsed or refractory AML, T-ALL, and CLL patients. However, ABT-199 resistance severely limits the further clinical usage because of off-target effects, non-specific toxicities, and low delivery of drugs. To reduce the side-effects and improve the solubility and bioavailability, ABT-199 was encapsulated into the amphiphilic mPEG- b -PTMC block copolymer by co-assembly method to obtain mPEG- b [email protected] nanoparticles (PEG-ABT-199). PEG-ABT-199 has several advantages compared with pure ABT-199. 1.PEG-ABT-199 presents better aqueous dispersion and higher efficiencies of loading and encapsulation than pure ABT-199. 2. PEG-ABT-199 substantially enhances the anti-leukemic ability in vitro and in vivo compared with pure ABT-199. 3. PEG-ABT-199 has little effects on normal cells. 4. PEG-ABT-199 can reduce treatment cost.
研究领域:
药理学
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肿瘤学
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纳米技术
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血液学
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产品关联
DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF PHARMACEUTICS
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2026
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IF 6
Zhidi He,Yulin Xu,Zhipeng Tian,Dong Chen,Ziyan Dong,Shiyu Zhu,Man Li,Rong Guo,Bing Xiang,Qin He
Despite its clinical utility, the therapeutic potential of Venetoclax (ABT-199) in acute myeloid leukemia (AML) remains limited by the heterogeneous nature of the disease, which often leads to reduced efficacy of monotherapy. Herein, we demonstrate that ABT-199-induced apoptosis can be potentiated by all-trans retinoic acid (ATRA) to suppress the DNA damage response. To address the lack of targeted drug delivery against AML and facilitate enhanced therapeutic efficacy, we engineered a biomimetic micelle, HPAA, by co-assembling an amphiphilic mPEG-ATRA conjugate with ABT-199 into micelles, followed by cloaking with P-selectin-rich membranes from activated human umbilical vein endothelial cells to target CD44 overexpressed on AML cells. The resulting HPAA micelles exhibited enhanced cellular uptake in MOLM13 cells, achieving approximately 2-fold higher uptake efficiency than non-targeted PAA micelles. Consequently, HPAA induced robust apoptosis and superior anti-leukemic effects, significantly suppressing MOLM13 cell proliferation in vitro. In an orthotopic AML model, HPAA preferentially accumulated in the bone marrow resident AML cells. Accordingly, treatment substantially reduced the MOLM13 cell burden in the peripheral blood, bone marrow and liver. This work establishes HPAA as a promising biomimetic nanoplatform for AML therapy by integrating active targeting with the novel drug repurposing of ATRA as a Chk1 suppressor to potentiate ABT-199 efficacy. HPAA potentiates ABT-199 efficacy in acute myeloid leukemia by repurposing ATRA to suppress Chk1, thereby inducing significant apoptosis. Download: Download high-res image (110KB) Download: Download full-size image
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DOI
高影响因子
BIOMATERIALS
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2023
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IF 14
Fengying Shao,Jianyu Han,Zhaoyan Tian,Zhi Wang,Songqin Liu,Yafeng Wu
Taking advantage of endogenous Ca 2+ to upregulate intramitochondrial Ca 2+ level has become a powerful mean for mitochondrial dysfunction-mediated tumor therapy. However, the Ca 2+ entered into mitochondria is limited ascribing to the uncontrollability and non-selectivity of endogenous Ca 2+ transport. It remains a great challenge to make the maximum use of endogenous Ca 2+ to ensure sufficient Ca 2+ overloading in mitochondria. Herein, we smartly fabricate an intracellular Ca 2+ directional transport channel to selectively transport endogenous Ca 2+ from endoplasmic reticulum (ER) to mitochondria based on cascade release nanoplatform ABT-199@liposomes/doxorubicin@Fe III -tannic acid (ABT@Lip/DOX@Fe-TA). In tumor acidic microenvironment , Fe 3+ ions are firstly released and reduced by tannic acid (TA) to Fe 2+ for ROS generation. Subsequently, under the NIR light irradiation, the released ABT-199 molecules combine with ROS contribute to the formation of IP3R-Grp75-VDAC1 channel between ER and mitochondria, thus Ca 2+ ions are directionally delivered and intramitochondrial Ca 2+ level is significantly upregulated. The synergetic ROS generation and mitochondrial Ca 2+ overloading effectively intensifies mitochondrial dysfunction, thereby achieving efficient tumor inhibition. This work presents a new insight and promising avenue for endogenous Ca 2+ -involved tumor therapies.
研究领域:
肿瘤学
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药学
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生物医学工程
✓ 已验证
产品关联
DOI
PubMed
高影响因子
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