Development of a T Cell-targeted siRNA Delivery System Against HIV-1 Using Modified Superparamagnetic Iron Oxide Nanoparticles: An In Vitro Study.

In spite of the promising properties of small interfering RNAs (siRNAs) in the treatment of infectious diseases, safe and efficient siRNA delivery to target cells is still a challenge. In this research, an effective siRNA delivery approach (against HIV-1) has been reported using targeted modified superparamagnetic iron oxide nanoparticles (SPIONs). Trimethyl chitosan-coated SPION (TMC-SPION) containing siRNA was synthesized and chemically conjugated to a CD4-specific monoclonal antibody (as a targeting moiety). The prepared nanoparticles exhibited a high siRNA loading efficiency with a diameter of about 85 nm and a zeta potential of +28 mV. The results of the cell viability assay revealed the low cytotoxicity of the optimized nanoparticles. The cellular delivery of the targeted nanoparticles (into T cells) and the gene silencing efficiency of the nanoparticles (containing anti-nef siRNA) were dramatically improved compared to those of nontargeted nanoparticles. In conclusion, this study offers a promising targeted delivery platform to induce gene silencing in target cells. Our approach may find potential use in the design of effective vehicles for many therapeutic applications, particularly for HIV treatment.

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.

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

PURPOSE: Hypoxia-inducible factor (HIF) is one of the critical components of the tumor microenvironment that is involved in tumor development. HIF-1α functionally and physically interacts with CDK1, 2, and 5 and stimulates the cell cycle progression and Cyclin-Dependent Kinase (CDK) expression. Therefore, hypoxic tumor microenvironment and CDK overexpression lead to increased cell cycle progression and tumor expansion. Therefore, we decided to suppress cancer cell expansion by blocking HIF-1α and CDK molecules. METHODS: In the present study, we used the carboxylated graphene oxide (CGO) conjugated with trimethyl chitosan (TMC) and hyaluronate (HA) nanoparticles (NPs) loaded with HIF-1α-siRNA and Dinaciclib, the CDK inhibitor, for silencing HIF-1α and blockade of CDKs in CD44-expressing cancer cells and evaluated the impact of combination therapy on proliferation, metastasis, apoptosis, and tumor growth. RESULTS: The results indicated that the manufactured NPs had conceivable physicochemical properties, high cellular uptake, and low toxicity. Moreover, combination therapy of cancer cells using CGO-TMC-HA NPs loaded with HIF-1α siRNA and Dinaciclib (SCH 727965) significantly suppressed the CDKs/HIF-1α and consequently, decreased the proliferation, migration, angiogenesis, and colony formation in tumor cells. CONCLUSIONS: These results indicate the ability of CGO-TMC-HA NPs for dual drug/gene delivery in cancer treatment. Furthermore, the simultaneous inhibition of CDKs/HIF-1α can be considered as a novel anti-cancer treatment strategy; however, further research is needed to confirm this treatment in vivo. Graphical Abstract The suppression of HIF-1α and CDKs inhibits cancer growth. HIF-1α is overexpressed by the cells present in the tumor microenvironment. The hypoxic environment elevates mitochondrial ROS production and increases p38 MAP kinase, JAK/STAT, ERK, JNK, and Akt/PI3K signaling, resulting in cyclin accumulation and aberrant cell cycle progression. Furthermore, the overexpression of HIF-1α/CDK results in increased expression of genes such as BCL2, Bcl-xl, Ki-67, TGFß, VEGF, FGF, MMP2, MMP9, and, HIF-1α and consequently raise the survival, proliferation, angiogenesis, metastasis, and invasion of tumor cells. In conclusion, HIF-1α-siRNA/Dinaciclib-loaded CGO-TMC-HA NPs can inhibit the tumor expansion by blockage of CDKs and HIF-1α (JAK: Janus kinase, STAT: Signal transducer and activator of transcription, MAPK: mitogen-activated protein kinase, ERK: extracellular signal-regulated kinase, JNK: c-Jun N-terminal kinase, PI3K: phosphatidylinositol 3-kinase).

Design and fabrication of dual-targeted delivery system based on gemcitabine-conjugated human serum albumin nanoparticles.

Dual-targeted drug delivery system has established their reputation as potent vehicles for cancer chemotherapies. Herein, gemcitabine (Gem) was conjugated to human serum albumin (HSA) via dithiodipropionic anhydride to fabricate Gem-HSA nanoparticles. It was hypothesized that this system can enhance the low stability of Gem and can improve its intracellular delivery. Furthermore, folate was applied as targeting agent on HSA nanoparticles for increasing the tumor selectivity of Gem. To evaluate the structural properties of synthesized products, 1 H NMR and FT-IR were performed. Moreover, HPLC was implemented for confirming the conjugation between HSA and Gem. Nanoparticles have shown spherical shape with negative charge. The release rate of Gem was dependent to the concentration of glutathione and pH. Folate-targeted HSA nanoparticles have shown higher cytotoxicity, cellular uptake, and apoptosis induction on folate receptor overexpressing MDA-MB-231 cells in comparison to non-targeted nanoparticles. Finally, it is considered that the developed dual-targeted nanoparticles would be potent in improving the stability and efficacy of intracellular delivery of Gem and its selective delivery to cancer cells.

Thiolated carboxymethyl dextran as a nanocarrier for colon delivery of hSET1 antisense: In vitro stability and efficiency study.

Gene therapy is an optimistic approach in cancer treatment. However, for efficient delivery of gene materials, designing an appropriate vector is necessary. Polyelectrolyte complexes (PECs) of chitosan and dextran could be considered a proper nanoparticulate carrier for sensitive biomaterials. In this study, PECs of chitosan and thiolated dextran were used as either an injectable or oral gene delivery system. hSET1 antisense was loaded into the PECs to suppress proliferation of colon cancer cell line. The prepared nanoparticles have ~115nm diameter size and positive zeta potential with high mucoadhesion properties. They are able to protect antisense from degradation in serum and biorelevant fluids (FaSSIF and FaSSGF). Furthermore, prepared nanoparticles demonstrated superior cellular penetration and inhibitory effect on SW480 colon cancer cell proliferation. All nanoparticles significantly down regulated hSET1 in comparison with naked antisense. It can be concluded that thiolated PECs have potential use for injectable or oral delivery of nucleic acids such as antisense.

Hydrogels composed of cyclodextrin inclusion complexes with PLGA-PEG-PLGA triblock copolymers as drug delivery systems.

Although conventional pharmaceuticals have many drug dosage forms on the market, the development of new therapeutic molecules and the low efficacy of instant release formulations for the treatment of some chronic diseases and specific conditions encourage scientists to invent different delivery systems. To this purpose, a supramolecular hydrogel consisting of the tri-block copolymer PLGA-PEGPLGA and α-cyclodextrin was fabricated for the first time and characterised in terms of rheological, morphological, and structural properties. Naltrexone hydrochloride and vitamin B12 were loaded, and their release profiles were determined.

Preparation of a sustained release drug delivery system for dexamethasone by a thermosensitive, in situ forming hydrogel for use in differentiation of dental pulp.

In situ forming delivery systems composed of block copolymers are attracting substantial attention due to their ease of use, biocompatibility, and biodegradability. In this study, the thermoresponsive triblock copolymer PLGA-PEG-PLGA was studied as a dexamethasone delivery system. Dexamethasone, a synthetic glucocorticoid, is used clinically to improve inflammation, pain, and the hyperemesis of chemotherapy, and it is applied experimentally as a differentiation factor in tissue engineering. PLGA-PEG-PLGA was synthesised under microwave irradiation for 5 min. The obtained copolymer was characterised to determine its structure and phase transition temperature. An in vitro release study was conducted for various copolymer structures and drug concentrations. The yield of the reaction and HNMR analysis confirmed the appropriateness of the microwave-assisted method for PLGA-PEG-PLGA synthesis. Phase transition temperature was affected by the drug molecule as well as by the copolymer concentration and structure. An in vitro release study demonstrated that release occurs mainly by diffusion and does not depend on the copolymer structure or dexamethasone concentration.

Biodegradable In Situ Gel-Forming Controlled Drug Delivery System Based on Thermosensitive Poly(ε-caprolactone)-Poly(ethylene glycol)-Poly(ε-caprolactone) Hydrogel.

Traditional drug delivery systems which are based on multiple dosing regimens usually pose many disadvantages such as poor compliance of patients and drug plasma level variation. To overcome the obstacles of traditional drug formulations, novel drug delivery system PCL-PEG-PCL hydrogels have been purposed in this study. Copolymers were synthesized by rapid microwave-assisted and conventional synthesis methods. Polymer characterizations were done using gel permeation chromatography and (1)H-NMR. Phase transition behavior was evaluated by inverting tube method and in vitro drug release profile was determined using naltrexone hydrochloride and vitamin B(12) as drug models. The results indicated that loaded drug structure and copolymer concentration play critical roles in release profile of drugs from these hydrogels. This study also confirmed that synthesis of copolymer using microwave is the most effective method for synthesis of this kind of copolymer.