Multifunctional TPP-PEG-biotin self-assembled nanoparticle drug delivery-based combination therapeutic approach for co-targeting of GRP78 and lysosome

Purushothaman, Baskaran; Lee, Jeongmin; Hong, Sera; Song, Joon Myong

doi:10.1186/s12951-020-00661-y

Cited by 25 publications

(17 citation statements)

References 43 publications

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“…Because both normative and non-normative autophagies depend on lysosomal degradation, lysosomes provide ideal targets for autophagy inhibition [ 9 , 10 ]. Preclinical studies showing that targeting lysosomes can improve anticancer therapies have led to more than 20 phase I/II clinical trials combining anticancer agents with the lysosomal inhibitor hydroxychloroquine (HCQ) [ 11 ].…”

Section: Introductionmentioning

confidence: 99%

High PPT1 expression predicts poor clinical outcome and PPT1 inhibitor DC661 enhances sorafenib sensitivity in hepatocellular carcinoma

Cheng

et al. 2022

Cancer Cell Int

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Background Adaptive resistance and side effects of sorafenib treatment result in unsatisfied survival of patients with hepatocellular carcinoma (HCC). Palmitoyl-protein thioesterase 1 (PPT1) plays a critical role in progression of various cancers. However, its role on prognosis and immune infiltrates in HCC remains unclarified. Methods By data mining in the Cancer Genome Atlas databases, the role of PPT1 in HCC were initially investigated. Furthermore, HCC cell lines Hep 3B and Hep 1-6 were treated with DC661 or siRNA against PPT1. The biological function of PPT1 was determined by CCK-8 test, colony formation assay, TUNEL staining, immunofluorescence staining, Western blot test, and PI-Annexin V apoptosis assays in vitro. Animal models of subcutaneous injection were applied to investigate the therapeutic role of targeting PPT1. Results We found that PPT1 levels were significantly upregulated in HCC tissues compared with normal tissues and were significantly associated with a poor prognosis. Multivariate analysis further confirmed that high expression of PPT1 was an independent risk factor for poor overall survival of HCC patients. We initially found that PPT1 was significantly upregulated in sorafenib-resistant cell lines established in this study. Upon sorafenib treatment, HCC cells acquired adaptive resistance by inducing autophagy. We found that DC661, a selective and potent small-molecule PPT1-inhibitor, induced lysosomal membrane permeability, caused lysosomal deacidification, inhibited autophagy and enhanced sorafenib sensitivity in HCC cells. Interestingly, this sensitization effect was also mediated by the induction mitochondrial pathway apoptosis. In addition, the expression level of PPT1 was associated with the immune infiltration in the HCC tumor microenvironment, and PPT1 inhibitor DC661 significantly enhanced the anti-tumor immune response by promoting dendritic cell maturation and further promoting CD8+ T cell activation. Moreover, DC661 combined with sorafenib was also very effective at treating tumor models in immunized mice. Conclusions Our findings suggest that targeting PPT1 with DC661 in combination with sorafenib might be a novel and effective alternative therapeutic strategy for HCC.

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Section: Introductionmentioning

confidence: 99%

High PPT1 expression predicts poor clinical outcome and PPT1 inhibitor DC661 enhances sorafenib sensitivity in hepatocellular carcinoma

Cheng

et al. 2022

Cancer Cell Int

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“…Lysosomes are emerging as a central regulator of the autophagic process, and play a critical role in tumor growth [ 20 ]. Lysosome-mediated autophagy has been considered as an effective mechanism for cancer cell survival, and degradation of lysosomes is regarded as a new targeted cancer treatment [ 21 ]. Lysosome trafficking is a key event in the process of metastasis and plays a significant role in tumor invasion.…”

Section: Discussionmentioning

confidence: 99%

Overexpression of Apolipoprotein C1 (APOC1) in Clear Cell Renal Cell Carcinoma and Its Prognostic Significance

Xiao

2020

Med Sci Monit

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Background The aims of this study included 3 aspects: 1) assessing the expression of Apolipoprotein C1 (APOC1) in clear cell renal cell carcinoma (ccRCC) and normal groups; 2) evaluating the prognostic significance of APOC1 expression in the overall survival (OS) of ccRCC patients; and 3) exploring APOC1-related signaling pathways. Material/Methods The APOC1 expression value and clinical data of ccRCC patients were obtained from the cBioPortal database. We then evaluated the association of APOC1 expression with clinical characteristics of ccRCC patients. We also assessed the correlation between APOC1 expression and clinical outcome using Kaplan-Meier method. Our work then verified the independent prognostic factors of ccRCC by Cox regression analysis. Finally, the potential role of genes co-expressed with APOC1 was revealed via functional enrichment analysis. Results Bioinformatic data revealed that APOC1 was expressed at higher levels in ccRCC tissue than in the normal group (all P <0.05). The high expression of APOC1 was associated with unfavorable prognosis of female patients ( P <0.01), but not of male patients. APOC1 high expression also shortened the survival time of ccRCC patients age ≥60 years old ( P <0.05). Cox regression analysis further indicated that APOC1 expression was an independent prognostic factor for OS of ccRCC patients. Additionally, we found that APOC1 expression was significantly associated with sex, grade, clinical stage, and T stage. Finally, enrichment analysis suggested that APOC1-associated pathways were involved in tumor growth and metastasis. Conclusions The current study indicated that APOC1 was highly expressed in ccRCC and was significantly associated with key clinical features. APOC1 appears to be an independent prognostic factor in patients with ccRCC. Importantly, APOC1 might be a potential therapeutic target for ccRCC via regulating pathways involved in cell growth and metastasis.

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“…3b). The "brushlike" PEG shell of SNM@DOX prevented protein adsorption that was favorable to prolong blood circulation time, facilitating the accumulation of SNM@DOX in tumor sites [36][37][38][39][40]. In contrast, the tumor accumulation of DOX•HCl was much lower, the highest amount in tumor was 2.33 ± 0.42%ID/g occurred at 12 h post injection, and the drug eliminated from body quickly (Fig.…”

Section: In Vivo Anti-tumor Performancesmentioning

confidence: 99%

Evaluation of the stability of cucurbit[8]uril-based ternary host−guest complexation in physiological environment and the fabrication of a supramolecular theranostic nanomedicine

Chen

et al. 2021

J Nanobiotechnol

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Background Supramolecular theranostics have exhibited promising potentials in disease diagnosis and therapy by taking advantages of the dynamic and reversible nature of non-covalent interactions. It is extremely important to figure out the stability of the driving forces in physiological environment for the preparation of theranostic systems. Methods The host−guest complexation between cucurbit[8]uril (CB[8]), 4,4′-bipyridinium, and napththyl guest was fully studied using various characterizations, including nuclear magnetic resonance spectroscopy, ultraviolet–visible (UV–vis) spectroscopy, isothermal titration calorimetry (ITC). The association constants of this ternary complex were determined using isothermal titration calorimetry. The stability of the non-covalent interactions and self-assemblies form from this molecular recognition was confirmed by UV–vis spectroscopy and dynamic light scattering (DLS). A supramolecular nanomedicine was constructed on the basis of this 1:1:1 ternary recognition, and its in vitro and in vivo anticancer efficacy were thoroughly evaluated. Positron emission tomography (PET) imaging was used to monitor the delivery and biodistribution of the supramolecular nanomedicine. Results Various experiments confirmed that the ternary complexation between 4,4′-bipyridinium, and napththyl derivative and CB[8] was stable in physiological environment, including phosphate buffered solution and cell culture medium. Supramolecular nanomedicine (SNM@DOX) encapsulating a neutral anticancer drug (doxrubincin, DOX) was prepared based on this molecular recognition that linked the hydrophobic poly(ε-caprolactone) chain and hydrophilic polyethylene glycol segment. The non-covalent interactions guaranteed the stability of SNM@DOX during blood circulation and promoted its tumor accumulation by taking advantage of the enhanced permeability and retention effect, thus greatly improving the anti-tumor efficacy as compared with the free drug. Conclusion Arising from the host-enhanced charge-transfer interactions, the CB[8]-based ternary recognition was stable enough in physiological environment, which was suitable for the fabrication of supramolecular nanotheranostics showing promising potentials in precise cancer diagnosis and therapy. Graphic Abstract

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Multifunctional TPP-PEG-biotin self-assembled nanoparticle drug delivery-based combination therapeutic approach for co-targeting of GRP78 and lysosome

Cited by 25 publications

References 43 publications

High PPT1 expression predicts poor clinical outcome and PPT1 inhibitor DC661 enhances sorafenib sensitivity in hepatocellular carcinoma

High PPT1 expression predicts poor clinical outcome and PPT1 inhibitor DC661 enhances sorafenib sensitivity in hepatocellular carcinoma

Overexpression of Apolipoprotein C1 (APOC1) in Clear Cell Renal Cell Carcinoma and Its Prognostic Significance

Evaluation of the stability of cucurbit[8]uril-based ternary host−guest complexation in physiological environment and the fabrication of a supramolecular theranostic nanomedicine

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