A Small Molecule Nanodrug by Self-Assembly of Dual Anticancer Drugs and Photosensitizer for Synergistic near-Infrared Cancer Theranostics

Guo, Yan; Jiang, Kai; Shen, Zhichun; Zheng, Guirong; Fan, Lulu; Zhao, Rui; Shao, Jingwei

doi:10.1021/acsami.7b14755

Cited by 114 publications

(67 citation statements)

References 53 publications

(70 reference statements)

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“…Subsequently, UA was released from UA-PMs with a slow rate. This result is consistent with the previous report [42][43][44].…”

Section: In Vitro Release Characteristic Of Ua-pmssupporting

confidence: 94%

“…In recent years, various formulations of UA such as carrier-based and carrier-free nanoparticles [8,12,13], pH-sensitive prodrug [14,15] and oral formulation [16] have been developed. As we known, polymer micelles (PMs) are constructed from amphiphilic block copolymers that tend to self-assemble and form the unique core-shell structure consisting of a hydrophobic inner core and a hydrophilic corona outside in an aqueous medium.…”

Section: Ivyspringmentioning

confidence: 99%

“…It is known that tumor is associated with the faintly acidic microenvironment [42][43][44]. The in vitro release behavior of UA-PMs was evaluated at 37 °C using PBS as releasing medium at pH 7.4 and pH 5.5 conditions (Figure 3).…”

Section: In Vitro Release Characteristic Of Ua-pmsmentioning

confidence: 99%

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Polymeric micelles loading with ursolic acid enhancing anti-tumor effect on hepatocellular carcinoma

Zhou

Liu

et al. 2019

J. Cancer

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Ursolic acid (UA) is widely found in many dietary plants, which has been proved to be effective in cancer therapy. But unfortunately its hydrophobic property limits its clinical application. Polymer micelles (PMs) are constructed from amphiphilic block copolymers that tend to self-assemble and form the unique core-shell structure consisting of a hydrophilic corona outside and a hydrophobic inner core. PMs could entrap the hydrophobic substance into its hydrophobic inner core for solubilizing these poorly water-soluble drugs and it is widely applied as a novel nano-sized drug delivery system. This study aimed to develop the drug delivery system of UA-loaded polymer micelles (UA-PMs) to overcome the disadvantages of UA in clinical application thus enhancing antitumor effect on hepatocellular carcinoma. UA-PMs was prepared and characterized for the physicochemical properties. It was investigated the cell-growth inhibition effect of UA-PMs against the human hepatocellular carcinoma cell line HepG2 and human normal liver cell line L-02. UA-PMs was evaluated about the in vivo toxicity and the antitumor activity. We took a diblock copolymer of methoxy poly (ethylene glycol)-poly(L-lactic acid) (mPEG-PLA) as carrier material to prepare UA-PMs by the thin-film dispersion method. MTT assay and wound-healing assay were investigated to assess the inhibition effect of UA-PMs against HepG2 cells on cell-growth and cell-migration. Further, we chose KM mice for the acute toxicity experiment and assessed the antitumor effect of UA-PMs on the H22 tumor xenograft. UA-PMs could markedly inhibit the proliferation and migration of HepG2 cells. In vivo study showed that UA-PMs could significantly inhibit the growth of H22 xenograft and prolong the survival time of tumor-bearing mice. It demonstrated that UA-PMs possess great potential in liver cancer therapy and may enlarge the application of UA in clinical therapy.

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“…Subsequently, UA was released from UA-PMs with a slow rate. This result is consistent with the previous report [42][43][44].…”

Section: In Vitro Release Characteristic Of Ua-pmssupporting

confidence: 94%

Section: Ivyspringmentioning

confidence: 99%

See 1 more Smart Citation

Polymeric micelles loading with ursolic acid enhancing anti-tumor effect on hepatocellular carcinoma

Zhou

Liu

et al. 2019

J. Cancer

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“…Unlike free bilirubin, the introduction of hydrophilic poly (ethylene glycol) (PEG) is seized upon as a solution to make hydrophobic one well‐dispersed in water and dramatically prolong the blood circulation . Besides, the intermolecular aromatic planar rings help to facilitate the packing between bilirubin itself and drugs with similar structure through the π–π stacking and hydrophobic interactions, thus leading to superb loading efficiency and capacity …”

Section: Introductionmentioning

confidence: 99%

“…Furthermore, the dimeric prodrugs could respond to the high glutathione (GSH) level of the tumor, to produce active monomeric drugs. SN38 is an active metabolite of camptothecin in vivo, and works on DNA topoisomerase for cancer cells killing . LND, a hexokinase inhibitor, exhibits antitumor activity by impacting energy metabolism .…”

Section: Introductionmentioning

confidence: 99%

Tumor Microenvironment‐Responsive Dual Drug Dimer‐Loaded PEGylated Bilirubin Nanoparticles for Improved Drug Delivery and Enhanced Immune‐Chemotherapy of Breast Cancer

Yang

Tong

et al. 2019

Adv Funct Materials

101

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The application of combinational therapy makes up for the limitation of monotherapy and achieves superior treatment against cancer. However, the combinational therapy remains restricted by the poor tumor-specific delivery and the abscopal effect. Herein, reactive oxygen species (ROS)responsive PEGylated bilirubin nanoparticles (BRNPs) are developed to encapsulate two glutathione-activatable drugs, including dimer-7ethyl-10-hydroxycamptothecin (d-SN38) and dimer-lonidamine (d-LND). Dimerization of the drugs significantly increases the drug loading capacity and the encapsulation efficiency of nanoparticles. With the assistance of iRGD peptide (cRGDKGPDC), the cellular uptake of BRNPs is more than double when compared with the control. In response to high levels of intracellular ROS, d-SN38 and d-LND are rapidly released from nanoparticles (SL@BRNPs). Furthermore, the pharmacodynamic experiments verify combining SL@BRNPs with anti-PD-L1 antibody greatly inhibits the primary tumor of breast cancer, improves CD8+ T cells levels, and CD8+ T cells/Tregs ratios in the tumor. Additionally, it shows high immune memory effect and can prevent the growth of lung metastasis. Taken together, the strategy pioneers a new way for the rational design of nanoassemblies through the combination of activatable drug dimers and stimuli-responsive drug release, and a successful application of novel drug delivery systems in combination with the immune checkpoint blockade antibody.

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Mitochondria‐ and Lysosomes‐Targeted Synergistic Chemo‐Photodynamic Therapy Associated with Self‐Monitoring by Dual Light‐Up Fluorescence

Chen

et al. 2018

Adv Funct Materials

108

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The current cancer therapy faces great challenges on improving the treatment efficiency and overcoming the drug resistance. To tackle these challenges, herein dual-organelle-targeted nanoparticles (NPs) are developed with synergistic chemo-photodynamic therapy functions through self-assembly of mitochondria-targeted chemotherapeutic agent AIE-Mito-TPP and lysosomes-targeted photosensitizer AlPcSNa 4 . The dual-organelle-targeted NPs can be quickly taken up by cancer cells through endocytosis and gradually decompose to release AIE-Mito-TPP and AlPcSNa 4 , which, respectively, accumulate in mitochondria and lysosomes. The AIE-Mito-TPP can efficiently destroy mitochondrial functions, while the AlPcSNa 4 can efficiently destroy lysosomes via reactive oxygen species generation under NIR light irradiation. The dual-organelle-targeted drug delivery process can also be self-monitored by the dual light-up fluorescence of green-emissive AIE-Mito-TPP and red-emissive AlPcSNa 4 . With A375 cells and A375-bearing nude mice as a model, the theranostic potential of the AIE-Mito-TPP/AlPcSNa 4 NPs is systematically investigated both in vitro and in vivo. Under NIR light irradiation, the AIE-Mito-TPP/AlPcSNa 4 NPs show a remarkable cytotoxicity against A375 cells and efficiently inhibit the in vivo tumor growth. Therefore, the theranostic NPs with dual-organelle-targeted and synergistic chemo-photodynamic therapy functions associated with self-monitoring ability are expected to have promising applications in imaging-guided precise cancer therapy. Synthesis of AIE-Mito-TPP/AlPcSNa 4 NPs:The DMSO solutions of AlPcSNa 4 (75 µL, 4 × 10 −3 m) and AIE-Mito-TPP (600 µL, 1.0 × 10 −3 m) were first mixed at room temperature, and then 67.5 µL of the mixture solution was added into water solution (2.9325 mL) under stirring for 2 h to yield the stock solution of AIE-Mito-TPP/AlPcSNa 4 NPs (20 × 10 −6 m of AIE-Mito-TPP and 10 × 10 −6 m of AlPcSNa 4 ).Intracellular Release Monitoring: The A375 cells were seeded in glass-bottom cell culture dishes (10 × 10 4 per dish). After incubation for 24 h, the cells were rinsed with PBS and further treatment with AIE-Mito-TPP (2.5 × 10 −6 m), AlPcSNa 4 (1.25 × 10 −6 m), or AIE-Mito-TPP/AlPcSNa 4 NPs (2.5 × 10 −6 m of AIE-Mito-TPP and 1.25 × 10 −6 m of AlPcSNa 4 ) for 0.5 h. The cells were then rinsed three times with PBS and fresh culture media was added. After further incubation at 37 °C for 0, 2, 4, and 6 h, the fluorescence images were taken under confocal laser scanning microscope (CLSM). For AIE-Mito-TPP, λ ex = 405 nm, λ em = 450-600 nm. For AlPcSNa 4 , λ ex = 633 nm, λ em = 640-750 nm.Colocalization Experiment with LysoTracker Red: The A375 cells were seeded in glass-bottom cell culture dishes (10 × 10 4 per dish). After incubation for 24 h, the cells were rinsed with PBS and 1.0 mL of DMEM containing LysoTracker Red (100 × 10 −9 m) was added. After further incubation at 37 °C for 45 min, the cells were rinsed with PBS and then treated with AIE-Mito-TPP/AlPcSNa 4 NPs (2.5 × 10 −6 m of AIE-Mito-TPP an...

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A Small Molecule Nanodrug by Self-Assembly of Dual Anticancer Drugs and Photosensitizer for Synergistic near-Infrared Cancer Theranostics

Cited by 114 publications

References 53 publications

Polymeric micelles loading with ursolic acid enhancing anti-tumor effect on hepatocellular carcinoma

Polymeric micelles loading with ursolic acid enhancing anti-tumor effect on hepatocellular carcinoma

Tumor Microenvironment‐Responsive Dual Drug Dimer‐Loaded PEGylated Bilirubin Nanoparticles for Improved Drug Delivery and Enhanced Immune‐Chemotherapy of Breast Cancer

Mitochondria‐ and Lysosomes‐Targeted Synergistic Chemo‐Photodynamic Therapy Associated with Self‐Monitoring by Dual Light‐Up Fluorescence

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