Inhibition of CD73 using folate targeted nanoparticles carrying anti-CD73 siRNA potentiates anticancer efficacy of Dinaciclib.

Conventional therapeutic methods against cancer, including chemotherapy, radiotherapy, surgery, and combination therapy, have exhibited different toxicity levels due to their unspecific mechanism of action. To overcome the challenges facing conventional cancer therapies, newly developed methods are being investigated. Significant levels of specificity, remarkable accumulation at the tumor site, limited side effects, and minimal off-target effects enable the newly synthesized nanoparticles (NPs) to become the preferred drug delivery method in anticancer therapeutic approaches. According to the literature, CD73 has a pivotal role in cancer progression and resistance to chemotherapy and radiotherapy. Therefore, CD73 has attracted considerable attention among scientists to target this molecule. Accordingly, FDA approved CDK inhibitors such as Dinaciclib that blocks CDK1, 2, 5, and 9, and exhibits significant anticancer activity. So in this study, we intended to simultaneously suppress CD73 and CDKs in cancer cells by using the folic acid (FA)-conjugated chitosan-lactate (CL) NPs loaded with anti-CD73 siRNA and Dinaciclib to control tumor progression and metastasis. The results showed that NPs could effectively transfect cancer cells in a FA receptor-dependent manner leading to suppression of proliferation, survival, migration, and metastatic potential. Moreover, the treatment of tumor-bearing mice with this combination strategy robustly inhibited tumor growth and enhanced survival time in mice. These findings imply the high potential of FA-CL NPs loaded with anti-CD73 siRNA and Dinaciclib for use in cancer treatment shortly.

Hallaj S ，Heydarzadeh Asl S ，Alian F ，Farshid S ，Eshaghi FS ，Namdar A ，Atyabi F ，Masjedi A ，Hallaj T ，Ghorbani A ，Ghalamfarsa G ，Sojoodi M ，Jadidi-Niaragh F ... -  《-》

Codelivery of HIF-1α siRNA and Dinaciclib by Carboxylated Graphene Oxide-Trimethyl Chitosan-Hyaluronate Nanoparticles Significantly Suppresses Cancer Cell Progression.

Izadi S ，Moslehi A ，Kheiry H ，Karoon Kiani F ，Ahmadi A ，Masjedi A ，Ghani S ，Rafiee B ，Karpisheh V ，Hajizadeh F ，Atyabi F ，Assali A ，Mirzazadeh Tekie FS ，Namdar A ，Ghalamfarsa G ，Sojoodi M ，Jadidi-Niaragh F ... -  《-》

Anti-Tumor and Chemosensitizing Effects of the CDK Inhibitor Dinaciclib on Cholangiocarcinoma In Vitro and In Vivo.

Cholangiocarcinoma (CCA) is a highly aggressive disease. Most of CCA patients are diagnosed in an advanced stage of the disease, when it is unresectable and there is chemoresistance, resulting in poor prognosis. However, effective therapeutic regimens and molecular targets for CCA remain poor. Cyclin-dependent kinases (CDKs) are key regulatory enzymes in cell cycle progression. Aberrant CDK activation is a hallmark of cancer. Dinaciclib is a small molecule inhibitor of multiple CDKs, currently under clinical evaluation for treating advanced malignancies. The efficacy of anti-tumor activity of dinaciclib against chemotherapy resistant CCA cells was examined in vitro and in vivo. In this study, the effect of dinaciclib on growth and cell cycle in CCA cell lines were determined using the MTT assay and cell cycle analysis. The anti-tumor activity of dinaciclib was investigated in CCA-inoculated mice. In addition, the chemosensitizing effect of dinaciclib was investigated in gemcitabine-treated CCA cell lines. Dinaciclib significantly suppressed cell proliferation, induced G1/S phase cell cycle arrest and apoptosis of CCA cell lines. It significantly suppressed the growth of CCA cells in xenograft mouse models. We also found that dinaciclib significantly inhibited the growth of gemcitabine-resistant CCA cell lines (KKU-213A-GemR and KKU-100-GemR). Furthermore, dinaciclib significantly enhanced the anti-tumor activity of gemcitabine in CCA cell lines. Dinaciclib has the potential to be an effective therapeutic agent to control tumor cell growth of both parental and gemcitabine-resistant CCA cells.

Sungwan P ，Kidoikhammouan S ，Thonsri U ，Saengboonmee C ，Wongkham S ，Okada S ，Seubwai W ... -  《-》

Blockade of CD73 using siRNA loaded chitosan lactate nanoparticles functionalized with TAT-hyaluronate enhances doxorubicin mediated cytotoxicity in cancer cells both in vitro and in vivo.

Chemotherapy drugs are still one of the first treatment options used in many cancers; however, problems such as cytotoxic side effects on normal cells after systemic administration and resistance to treatment have reduced the use of chemotherapeutics day by day. Targeted delivery of these drugs to the tumor site and sensitization of cancer cells to death induced by chemotherapy drugs are ways that can overcome the limitations of the use of these drugs. In this study, we designed and generated a novel nanocarrier composed of chitosan lactate nanoparticles (NPs) functionalized by HIV-1 derived TAT peptide (Transactivating transcriptional activator) and hyaluronate (HA) to deliver CD73 siRNA and doxorubicin to 4T1 and CT26 cancer cells, both in vivo and in vitro, as a novel combinatorial treatment strategy. The CD73 molecule plays a key role in many cancer cell behaviors such as proliferation, angiogenesis, metastasis, imunosuppression, and resistance to chemotherapy. Therefore, we decided to reduce the side effects of DOX by simultaneously transmitting CD73 siRNA and DOX by CL-TAT-HA NPs, increase the susceptibility of cancer cells to DOX-induced cell death, and stimulate anti-tumor immune responses, for the first time. These results indicated that simultaneous transfer of CD73 siRNA and DOX to cancer cells (4 T1 and CT26) increased cell death and inhibited the prolifration and spread of cancer cells. Also, the preferential aggregation of NPs in the tumor microenvironment reduced tumor growh, promoted the survival of tumor-bearing mice, and induced anti-tumor immune responses. These findings indicate that CL-TAT-HA NPs are a good candidate for targeted siRNA/drug delivery to cancer cells and the simultaneous transfer of CD73 siRNA and DOX to cancer cells using this nanocarrier can be used to treat cancer.

Salehi Khesht AM ，Karpisheh V ，Sahami Gilan P ，Melnikova LA ，Olegovna Zekiy A ，Mohammadi M ，Hojjat-Farsangi M ，Majidi Zolbanin N ，Mahmoodpoor A ，Hassannia H ，Aghebati-Maleki L ，Jafari R ，Jadidi-Niaragh F ... -  《-》

Inhibition of cyclin dependent kinase 9 by dinaciclib suppresses cyclin B1 expression and tumor growth in triple negative breast cancer.

Rajput S ，Khera N ，Guo Z ，Hoog J ，Li S ，Ma CX ... -  《Oncotarget》