Chloroquine-Modified Hydroxyethyl Starch as a Polymeric Drug for Cancer Therapy

Chen

Molecular Carcinogenesis

et al. 2020

Postoperative radiotherapy combined with chemotherapy is a commonly used treatment for glioblastoma (GBM) but radiotherapy often fails to achieve the expected results mainly due to tumor radioresistance. In this study, we established a radioresistant subline from human glioma cell line U251 and found that Cathepsin D (CTSD), a gene closely related to the clinical malignancy and prognosis in glioma, had higher expression level in radioresistant clones than that in parental cells, and knocking down CTSD by small interfering RNA (siRNA) or its inhibitor Pepstatin-A increased the radiosensitivity. The level of autophagy was enhanced in the radioresistant GBM cells compared with its parent cells, and silencing autophagy by light chain 3 (LC3) siRNA significantly sensitized GBM cells to ionizing radiation (IR). Moreover, the protein expression level of CTSD was positively correlated with the autophagy marker LC3 II/I and negatively correlated with P62 after IR in radioresistant cells. As expected, through the combination of Western blot and immunofluorescence assays, inhibition of CTSD increased the formation of autophagosomes, while decreased the formation of autolysosomes, which indicating an attenuated autophagy level, leading to radiosensitization ultimately. Our results revealed for the first time that CTSD regulated the radiosensitivity of glioblastoma by affecting the fusion of autophagosomes and lysosomes. In significance, CTSD might be a potential molecular biomarker and a new therapeutic target in glioblastoma. K E Y W O R D Sautophagy, CTSD, glioblastoma, radioresistance

Section: Discussionmentioning

confidence: 99%

Inhibition of Cathepsin D (CTSD) enhances radiosensitivity of glioblastoma cells by attenuating autophagy

Chen

Molecular Carcinogenesis

et al. 2020

“…To retain the branched structure of amylopectin, hydrodynamic diameters around dozens of nanometers have been frequently measured in HES solutions with DLS. 28,34,58,59,76 TEM and AFM imaging has revealed that HES exhibits a colloidal structure in self-assembled nanoparticles 67,77 and conjugates. 60 Nonetheless, the conformation and structure of a single HES particle remains an enigma.…”

Section: Resultsmentioning

confidence: 99%

“…The size distributions of HES in an aqueous solution have been reported in previous studies. 34,76,77 However, the morphology of HES is largely unknown, particularly that of a single HES particle. TEM and AFM have been widely employed to directly characterize the morphology of macromolecules.…”

Section: Hes Morphologymentioning

confidence: 99%

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Colloidal hydroxyethyl starch for tumor-targeted platinum delivery

Xiao

Yang

et al. 2019

Nanoscale Adv.

“…Besides HPMA‐based PCQ, our group reported another PCQ drug, chloroquine‐modified hydroxyethyl starch (CQ‐HES) which was synthesized by conjugation of HES with HCQ by a carbonyldiimidazole coupling. CQ‐HES was able to target CXCR4 signaling and improve inhibition of migration and invasion of PC cells when compared with HCQ (Sleightholm, Yang, Yu, Xie, & Oupický, ). Overall, PCQ represents a new generation of safe and effective CXCR4 inhibitors for metastatic cancer therapy.…”

Section: Chloroquine‐based Cxcr4 Antagonists (Pcq)mentioning

confidence: 99%

Promise of chemokine network‐targeted nanoparticles in combination nucleic acid therapies of metastatic cancer

Xie

WIREs Nanomed Nanobiotechnol

et al. 2018

Self Cite

Chemokines and chemokine receptors play key roles in cancer progression and metastasis. Although multiple chemokines and chemokine receptors have been investigated, inhibition of CXCR4 emerged as one of the most promising approaches in combination cancer therapy, especially when focused on the metastatic disease. Small RNA molecules, such as small interfering RNA (siRNA) and microRNA (miRNA), represent new class of therapeutics for cancer treatment through RNA interference-mediated gene silencing. However, the clinical applicability of siRNA and miRNA is severely limited by the lack of effective delivery systems. There is a significant therapeutic potential for CXCR4-targeted nanomedicines in combination with the delivery of siRNA and miRNA in cancer. Recently developed CXCR4-targeted polymeric drugs and nanomedicines, including cyclam- and chloroquine-based polymeric CXCR4 antagonists are introduced here and their ability to deliver functional siRNA and miRNA is discussed. This article is categorized under: Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease Nanotechnology Approaches to Biology > Nanoscale Systems in Biology.