HSP90 and Co-chaperones: Impact on Tumor Progression and Prospects for Molecular-Targeted Cancer Therapy.

Heat shock protein 90 (HSP90), a highly and unique chaperone, presents as a double-edged sword. It plays an essential role in many physiological and pathological processes, including tumor development. The current review highlights a recent understanding of the roles of HSP90 in molecular mechanisms underlying cancer survival and progression. HSP90 and its client proteins through the regulation of oncoproteins including signaling proteins, receptors, and transcriptional factors involved in tumorigenesis. It also has potential clinical application as diagnostic and prognostic biomarkers for assessing cancer progression. In this way, using HSP90 to develop new anticancer therapeutic agents including HSP90 inhibitors, anti-HSP90 antibody, and HSP90-based vaccines has been promising.

Expression pattern of hTERT telomerase subunit gene in different stages of chronic myeloid leukemia.

Telomerase is activated in chronic myeloid leukemia (CML); however, it is not known whether the catalytic telomerase reverse transcriptase subunit (hTERT) is vital in the progression of this disease. This study involved patients with CML in the chronic phase (pretreatment and after treatment), accelerated and blastic phase. Expression of the hTERT gene differed significantly among the four major groups (p < 0.05). We also compared hTERT expression according to demographic parameter such as age and sex, and found no significant differences (p > 0.05). Taken together, our findings suggest the importance of hTERT as a valuable molecular marker in the follow-up of patients with CML, which may have clinical implications for the prognosis.

Synthesis and characterization of thiolated carboxymethyl chitosan-graft-cyclodextrin nanoparticles as a drug delivery vehicle for albendazole.

A new strategy for the synthesis of thiolated carboxymethyl chitosan-g-cyclodextrin nanoparticles by an ionic-gelation method is presented. The synthetic approach was based on the utilization of 1,6-hexamethylene diisocyanate during cyclodextrin grafting onto carboxymethyl chitosan. The use of the 1,6-hexamethylene diisocyanate resulted in reactions between cyclodextrin and active sites at the C6-position of chitosan, and preserved amino groups of chitosan for subsequent reactions with thioglycolic acid, as the thiolating agent, and tripolyphosphate, as the gelling counterion. Various methods such as scanning electron microscopy, rheology and in vitro release studies were employed to exhibit significant features of the nanoparticles for mucosal albendazole delivery applications. It was found that the thiolated carboxymethyl chitosan-g-cyclodextrin nanoparticles prepared using an aqueous solution containing 1 wt% of tripolyphosphate and having 115.65 (µmol/g polymer) of grafted thiol groups show both the highest mucoadhesive properties and the highest albendazole entrapment efficiency. The latter was confirmed theoretically by calculating the enthalpy of mixing of albendazole in the above thiolated chitosan polymer.

Preparation and characterization of polylactic-co-glycolic acid/insulin nanoparticles encapsulated in methacrylate coated gelatin with sustained release for specific medical applications.

This study aimed to examine the possibility of using insulin orally with gelatin encapsulation to enhance the usefulness of the drug and increase the lifespan of insulin in the body using polylactic-co-glycolic acid (PLGA) nanoparticles alongside gelatin encapsulation. In this regard, PLGA was synthesized via ring opening polymerization, and PLGA/insulin nanoparticles were prepared by a modified emulsification-diffusion process. The resulting nanoparticles with various amounts of insulin were fully characterized using FTIR, DSC, DLS, zeta potential, SEM, and glucose uptake methods, with results indicating the interaction between the insulin and PLGA. The process efficiency of encapsulation was higher than 92%, while the encapsulation efficiency of nanoparticles, based on an insulin content of 20 to 40%, was optimized at 93%. According to the thermal studies, the PLGA encapsulation increases the thermal stability of the insulin. The morphological studies showed the fine dispersion of insulin in the PLGA matrix, which we further confirmed by the Kjeldahl method. According to the release studies and kinetics, in-vitro degradation, and particle size analysis, the sample loaded with 30% insulin showed optimum overall properties, and thus it was encapsulated with gelatin followed by coating with aqueous methacrylate coating. Release studies at pH values of 3 and 7.4, alongside the Kjeldahl method and standard dissolution test at pH 5.5, and glucose uptake assay tests clearly showed the capsules featured 3-4 h biodegradation resistance at a lower pH along with the sustained release, making these gelatin-encapsulated nanoparticles promising alternatives for oral applications.[Figure: see text].

3D Printed Anchoring Sutures for Permanent Shaping of Tissues.

Sutures are one of the most widely used devices for adhering separated tissues after injury or surgery. However, most sutures require knotting, which can create a risk of inflammation, and can act as mechanically weak points that often result in breakage and slipping. Here, an anchoring suture is presented with a design that facilitates its propagation parallel to the suturing direction, while maximizing its resistive force against the opposite direction of external force to lock its position in tissues. Different microstructures of suture anchors are systematically designed using orthogonal arrays, and selected based on shape factors associated with mechanical strength. 3D printing is used to fabricate different types of hollow microstructured suture anchors, and optimize their structure for the effective shaping of tissues. To define the structural design for fixing tissues, the maximum force required to pull 3D printed anchors in different directions is examined with tissues. The tissue reshaping function of suture anchors is further simulated ex vivo by using swine ear, nose, and skin, and bovine muscle tendon. This study provides advantages for building functional sutures that can be used for permanently reshaping tissues with enhanced mechanical strength, eliminating the need for knotting to improve surgical efficiency.

Bioreducible PEI-functionalized glycol chitosan: A novel gene vector with reduced cytotoxicity and improved transfection efficiency.

Non-viral gene delivery has been well recognised as a potential way to address the main safety limitations of viral gene carriers. A new redox-responsive PEI derivative was designed, synthesized and evaluated for non-viral delivery applications of GFP DNA. Glycol chitosan was covalently attached to highly branched LMW PEI via bio-cleavable disulfide bonds to synthesize a new redox-responsive gene carrier (GCS-ss-PEI). Results showed the enhanced buffering capacity of GCS-ss-PEI, 43.1%, compared to the buffering capacities of both LMW PEI and HMW PEI, 23.2% and 31.5%, respectively, indicating more likely endosomal escape of the entrapped gene for GCS-ss-PEI. Moreover, electrophoretic gel retardation assay, performed to investigate the binding strength of GCS-ss-PEI to GFP DNA, showed stronger complexation with GFP DNA in GCS-ss-PEI at non-GSH condition. Employing GCS and incorporation of disulfide bonds in the structure of the PEI-based gene carrier resulted in improved redox-responsivity, reduced toxicity, enhanced endosomal escape and GFP DNA transfection. The facilitated intracellular gene release along with excellent redox-responsive characteristics and dropped cytotoxicity suggests the potential of GCS-ss-PEI as a candidate for developing highly efficient and safe gene vectors.

Dual effect of F-actin targeted carrier combined with antimitotic drug on aggressive colorectal cancer cytoskeleton: Allying dissimilar cell cytoskeleton disrupting mechanisms.

A recent approach to colon cancer therapy is to employ selective drugs with specific extra/intracellular sites of action. Alteration of cytoskeletal protein reorganization and, subsequently, to cellular biomechanical behaviour during cancer progression highly affects the cancer cell progress. Hence, cytoskeleton targeted drugs are an important class of cancer therapy agents. We have studied viscoelastic alteration of the human colon adenocarcinoma cell line, SW48, after treatment with a drug delivery system comprising chitosan as the carrier and albendazole as the microtubule-targeting agent (MTA). For the first time, we have evaluated the biomechanical characteristics of the cell line, using the micropipette aspiration (MA) method after treatment with drug delivery systems. Surprisingly, employing a chitosan-albendazole pair, in comparison with both neat materials, resulted in more significant change in the viscoelastic parameters of cells, including the elastic constants (K1 and K2) and the coefficient of viscosity (µ). This difference was more pronounced for cancer cells after 48h of the treatment. Microtubule and actin microfilament (F-actin) contents in the cell line were studied by immunofluorescent staining. Good agreement was observed between the mechanical characteristics results and microtubule/F-actin contents of the treated SW48 cell line, which declined after treatment. The results showed that chitosan affected F-actin more, while MTA was more effective for microtubules. Toxicity studies were performed against two cancer cell lines (SW48 and MCF10CA1h) and compared to normal cells, MCF10A. The results showed cancer selectiveness, safety of formulation, and enhanced anticancer efficacy of the CS/ABZ conjugate. This study suggests that employing such a suitable pair of drug-carriers with dissimilar sites of action, thus allying the different cell cytoskeleton disrupting mechanisms, may provide a more efficient cancer therapy approach.

Microfluidic Manipulation of Core/Shell Nanoparticles for Oral Delivery of Chemotherapeutics: A New Treatment Approach for Colorectal Cancer.

A microfluidics approach to synthesize core-shell nanocarriers with high pH tunability is described. The sacrificial shell protects the core layer with the drugs and prevents their release in the severe pH conditions of the gastrointestinal tract, while allowing for drug release in the proximity of a tumor. The proposed nanoparticulate drug-delivery system is designed for the oral administration of cancer therapeutics.

Classification of stimuli-responsive polymers as anticancer drug delivery systems.

Although several anticancer drugs have been introduced as chemotherapeutic agents, the effective treatment of cancer remains a challenge. Major limitations in the application of anticancer drugs include their nonspecificity, wide biodistribution, short half-life, low concentration in tumor tissue and systemic toxicity. Drug delivery to the tumor site has become feasible in recent years, and recent advances in the development of new drug delivery systems for controlled drug release in tumor tissues with reduced side effects show great promise. In this field, the use of biodegradable polymers as drug carriers has attracted the most attention. However, drug release is still difficult to control even when a polymeric drug carrier is used. The design of pharmaceutical polymers that respond to external stimuli (known as stimuli-responsive polymers) such as temperature, pH, electric or magnetic field, enzymes, ultrasound waves, etc. appears to be a successful approach. In these systems, drug release is triggered by different stimuli. The purpose of this review is to summarize different types of polymeric drug carriers and stimuli, in addition to the combination use of stimuli in order to achieve a better controlled drug release, and it discusses their potential strengths and applications. A survey of the recent literature on various stimuli-responsive drug delivery systems is also provided and perspectives on possible future developments in controlled drug release at tumor site have been discussed.