Blockade of HIF-1α and STAT3 by hyaluronate-conjugated TAT-chitosan-SPION nanoparticles loaded with siRNA molecules prevents tumor growth.

HIF-1α and STAT3 are two of the critical factors in the growth, proliferation, and metastasis of cancer cells and play a crucial role in inhibiting anti-cancer immune responses. Therefore, we used superparamagnetic iron oxide (SPION) nanoparticles (NPs) coated with thiolated chitosan (ChT) and trimethyl chitosan (TMC) and functionalized with hyaluronate (H) and TAT peptide for delivery of siRNA molecules against STAT3 and HIF-1α to cancer cells both in vivo and in vitro. The results indicated that tumor cell transfection with siRNA-encapsulated NPs robustly inhibited proliferation and migration and induced apoptosis in tumor cells. Furthermore, simultaneous silencing of HIF-1α and STAT3 significantly repressed cancer development in two different tumor types (4T1 breast cancer and CT26 colon cancer) which were associated with upregulation of cytotoxic T lymphocytes and IFN-γ secretion. The findings suggest inhibiting the HIF-1α/STAT3 axis by SPION-TMC-ChT-TAT-H NPs as an effective way to treat cancer.

Budi HS ，Izadi S ，Timoshin A ，Asl SH ，Beyzai B ，Ghaderpour A ，Alian F ，Eshaghi FS ，Mousavi SM ，Rafiee B ，Nikkhoo A ，Ahmadi A ，Hassannia H ，Ahmadi M ，Sojoodi M ，Jadidi-Niaragh F ... -  《-》

Silencing of HIF-1α/CD73 axis by siRNA-loaded TAT-chitosan-spion nanoparticles robustly blocks cancer cell progression.

Induction of Hypoxia Inducible Factor (HIF) as a direct consequence of oxygen deficiency in tumor tissues is a potent stimulus of CD73 (ecto-5'-nucleotidase) expression. Hypoxic environment and CD73 overexpression are associated with altered metabolism, elevated cancer cell proliferation, and tumor vascularization. Herein, a delivery system was developed for silencing CD73 and HIF-1α gene using siRNA-loaded Superparamagnetic iron oxide (SPION) nanocarriers for cancer treatment. SPIONs were encapsulated with thiolated chitosan (TC) and trimethyl chitosan (TMC) for improving their stabilization and functionalization. The nanoparticles (NPs) were about 133 nm in size, spherical, and non-toxic, and the addition of TAT peptide (derived from HIV-1 TAT protein) to TMC-TC-SPIONs significantly increased their cellular uptake by cancer cells. The produced NPs could efficiently accumulate in the tumor site, indicating their stability and targeting ability in reaching the tumor region. TAT-conjugated TMC-TC-SPIONs containing siRNAs could significantly reduce the HIF-1α and CD73 expression levels in cancer cells. Following transfection, cancer cells showed a significant reduction in migration and proliferation. Moreover, siRNA-loaded NPs could effectively reduce tumor growth and angiogenesis, as investigated by the chick chorioallantoic membrane (CAM) assay. This study suggested that TAT-TMC-TC-SPIONs can be potential nanocarrier for gene transfection in cancer therapy. Moreover, the co-silencing of CD73 and HIF-1α can be assumed as a novel anti-cancer treatment strategy with high tumor suppression potential.

Hajizadeh F ，Moghadaszadeh Ardebili S ，Baghi Moornani M ，Masjedi A ，Atyabi F ，Kiani M ，Namdar A ，Karpisheh V ，Izadi S ，Baradaran B ，Azizi G ，Ghalamfarsa G ，Sabz G ，Yousefi M ，Jadidi-Niaragh F ... -  《-》

Inhibition of HIF-1α/EP4 axis by hyaluronate-trimethyl chitosan-SPION nanoparticles markedly suppresses the growth and development of cancer cells.

Increased expression of Hypoxia-inducible factor-1α (HIF-1α) in the tumor microenvironment, mainly due to tumor growth, plays a major role in the growth of cancer. Tumor cells induce the expression of cyclooxygenase 2 (COX2) and its product, prostaglandin E2 (PGE2), through overexpression of HIF-1α. It has been shown that ligation of PGE2 with its receptor, EP4, robustly promotes cancer progression. HIF-1α/COX2/PGE2/EP4 signaling pathways appear to play an important role in tumor growth. Therefore, we decided to block the expansion of cancer cells by blocking the initiator (HIF-1α) and end (EP4) of this pathway. In this study, we used hyaluronate (HA), and trimethyl chitosan (TMC) recoated superparamagnetic iron oxide nanoparticles (SPIONs) loaded with HIF-1α-silencing siRNA and the EP4 antagonist (E7046) to treat cancer cells and assessed the effect of combination therapy on cancer progression. The results showed that optimum physicochemical characteristics of NPs (size 126.9 nm, zeta potential 27 mV, PDI < 0.2) and linkage of HA with CD44 molecules overexpressed on cancer cells could deliver siRNAs to cancer cells and significantly suppress the HIF-1α in them. Combination therapy of cancer cells by using HIF-1α siRNA-loaded SPION-TMC-HA NPs and E7046 also prevent proliferation, migration, invasion, angiogenesis, and colony formation of the cancer cells, remarkably.

Karpisheh V ，Fakkari Afjadi J ，Nabi Afjadi M ，Haeri MS ，Abdpoor Sough TS ，Heydarzadeh Asl S ，Edalati M ，Atyabi F ，Masjedi A ，Hajizadeh F ，Izadi S ，Mirzazadeh Tekie FS ，Hajiramezanali M ，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 ... -  《-》

Codelivery of STAT3 and PD-L1 siRNA by hyaluronate-TAT trimethyl/thiolated chitosan nanoparticles suppresses cancer progression in tumor-bearing mice.

Immunotherapy methods using potential tumor microenvironment modulators have elicited durable therapeutic responses in cancer treatment. Immune checkpoint molecule programmed cell death-ligand 1 (PD-L1) and oncogenic transcription factor STAT3 (signal transducer and activator of transcription-3) assigned as inhibitory targets of our study and particular delivery system designed to deliver small interfering RNAs (siRNAs) to silence the targeted genes. Generated trimethyl chitosan (TMC) and thiolated chitosan (TC) nanoparticles (NPs) conjugated with HIV-1-derived TAT peptide and HA (hyaluronic acid) exhibited eligible physicochemical characteristics, notable siRNA encapsulation, serum stability, non-toxicity, controlled siRNA release, and extensive cellular uptake by cancer cells. Dual inhibition with STAT3/PD-L1 siRNA-loaded HA-TAT-TMC-TC NPs led to promising results, including significant downregulation of PD-L1 and STAT3 genes, striking suppressive effects on proliferation, migration, and angiogenesis of breast and melanoma cancer cell lines, and restrained tumor growth in vivo. These findings infer the capability of HA-TAT-TMC-TC NPs containing STAT3/PD-L1 siRNAs as a novel tumor-suppressive candidate in cancer treatment.

Bastaki S ，Aravindhan S ，Ahmadpour Saheb N ，Afsari Kashani M ，Evgenievich Dorofeev A ，Karoon Kiani F ，Jahandideh H ，Beigi Dargani F ，Aksoun M ，Nikkhoo A ，Masjedi A ，Mahmoodpoor A ，Ahmadi M ，Dolati S ，Namvar Aghdash S ，Jadidi-Niaragh F ... -  《-》