HSP70s in Breast Cancer: Promoters of Tumorigenesis and Potential Targets/Tools for Therapy

The high frequency of breast cancer worldwide and the high mortality among women with this malignancy are a serious challenge for modern medicine. A deeper understanding of the mechanisms of carcinogenesis and emergence of metastatic, therapy-resistant breast cancers would help development of novel approaches to better treatment of this disease. The review is dedicated to the role of members of the heat shock protein 70 subfamily (HSP70s or HSPA), mainly inducible HSP70, glucose-regulated protein 78 (GRP78 or HSPA5) and GRP75 (HSPA9 or mortalin), in the development and pathogenesis of breast cancer. Various HSP70-mediated cellular mechanisms and pathways which contribute to the oncogenic transformation of mammary gland epithelium are reviewed, as well as their role in the development of human breast carcinomas with invasive, metastatic traits along with the resistance to host immunity and conventional therapeutics. Additionally, intracellular and cell surface HSP70s are considered as potential targets for therapy or sensitization of breast cancer. We also discuss a clinical implication of Hsp70s and approaches to targeting breast cancer with gene vectors or nanoparticles downregulating HSP70s, natural or synthetic (small molecule) inhibitors of HSP70s, HSP70-binding antibodies, HSP70-derived peptides, and HSP70-based vaccines.

The Application of Targeted Nanodrugs with Dual Responsiveness of PH and Ros in Preventing and Treating Vascular Restenosis

In order to study the application of PH- and Ros-responsive targeted nanodrugs in preventing and treating vascular restenosis, a method based on pH-responsive and reactive oxygen species- (ROS-) responsive carrier materials synthesized in the early stage and rapamycin as a model drug was proposed. This method evaluated the therapeutic advantages of PH and Ros dual-responsive nanoparticles and the effect of dual-responsive active targeted drug delivery nanoparticles on vascular restenosis in vivo by comparing with nonresponsive PH or Ros single responsive nanotherapy. By optimizing the feed mass ratio of pH-responsive materials (ACD) and ROS-responsive materials (OCD), the best pH and ROS responsive nanoparticles were prepared. It has been proved that nanoparticles have ultrasmall volume (10–1000 nm) and can easily pass through the blood vessel wall without causing damage and have the characteristics of targeting and sustained release, so they are an ideal carrier for local administration. Nanoparticles as gene vectors have also achieved good results.

Vaccine Production

Introduction Vaccines are biological products that elicit a protective immune response. The details of the manufacturing processes are varied depending on the particular characteristics of the vaccine. There are classically, three basic types of vaccines against viral and bacterial pathogens (For mRNA-, DNA- and vector-vaccines see Chapters 7, 8, 9): Live-attenuated. Killed (non-live). Subunit. “Classical” Vaccine Production The basic classical process includes 5 phases: expression, harvest, inactivation, purification, formulation. The expression systems for viral and bacterial vaccines are distinct. Bacterial expression is performed in fermenters. Viral vaccines are produced in animal cell culture or embryonated chicken eggs. Processes for whole viral or bacterial vaccines often involve only limited processing after expression. Subunit vaccines routinely require the most purification to separate the product from other contaminants. Challenges Challenges for bacterial vaccines include testing to ensure the safety and efficacy of the product. Inactivation procedures need to be carefully controlled. Live attenuated vaccines need to be tested to ensure the vaccine strains are still safe and effective. Viral vaccines require testing to ensure foreign infectious agents are not introduced during processing. Both cultured cells and egg present risks for infection. Live viral vaccines and gene vectors need to be carefully engineered and tested to minimize safety concerns. Highly variable vaccine targets such as influenza need to be re-adapted to current circulating strains.

Implantatüberzüge für die in situ-Transfektion in der regenerativen Medizin

A promising approach in regenerative medicine is to modify cell behaviour with growth factors. However, the side of action has to be in spatial control. We present a new strategy in the field of regenerative medicine based on the combination of implant coatings with nanoscaled gene vectors. This enables the local restricted in situ transfection of cells to induce the production of cytokines. Therewith, the migration and differentiation of cells can be controlled to support tissue regeneration.

Grafting Dendrons onto Pillar[5]Arene Scaffolds

With their ten peripheral substituents, pillar[5]arenes are attractive compact scaffolds for the construction of nanomaterials with a controlled number of functional groups distributed around the macrocyclic core. This review paper is focused on the functionalization of pillar[5]arene derivatives with small dendrons to generate dendrimer-like nanomaterials and bioactive compounds. Examples include non-viral gene vectors, bioactive glycoclusters, and liquid-crystalline materials.

Immune and Cell Cycle Checkpoint Inhibitors for Cancer Immunotherapy

The rational design of immunotherapeutic agents has advanced with a fundamental understanding that both innate and adaptive immunity play important roles in cancer surveillance and tumor destruction; given that oncogenesis occurs and cancer progresses through the growth of tumor cells with low immunogenicity in an increasingly immunosuppressive tumor microenvironment. Checkpoint inhibitors in the form of monoclonal antibodies that block cancer’s ability to deactivate and evade the immune system have been widely indicated for a variety of tumor types. Through targeting the biological mechanisms and pathways that cancer cells use to interact with and suppress the immune system, immunotherapeutic agents have achieved success in inhibiting tumor growth while eliciting lesser toxicities, compared to treatments with standard chemotherapy. Development of “precise” bio-active tumor-targeted gene vectors, biotechnologies, and reagents has also advanced. This chapter presents ongoing clinical research involving immune checkpoint inhibitors, while addressing the clinical potential for tumor-targeted gene blockade in combination with tumor-targeted cytokine delivery, in patients with advanced metastatic disease, providing strategic clinical approaches to precision cancer immunotherapy.

Systemic gene delivery using lipid envelope systems and its potential in overcoming challenges

Nonviral vectors which offer a safer and versatile alternative to viral vectors have been developed to overcome problems caused by viral carriers. However, their transfection efficacy or level of expression is substantially lower than viral vectors. Among various nonviral gene vectors, lipid envelops systems are an ideal platform for the incorporation of safety and efficacy into a single delivery system. Emerging strategies for gene delivery using lipid-based delivery systems mainly aim at improving the transfection efficiency and potency while reducing toxicity, achieving prolonged release, cell-specific targeting, co-delivery of drug and gene. Earlier efforts to improve the transfection efficiency while overcoming the toxicity led to the need for preparing conjugates of lipids with polyamines. In this review, we highlight current lipidic vectors that have been developed for gene therapy, challenges, and their solutions.

Chemogenetic ON and OFF switches for RNA virus replication

Therapeutic application of RNA viruses as oncolytic agents or gene vectors requires a tight control of virus activity if toxicity is a concern. Here we present a regulator switch for RNA viruses using a conditional protease approach, in which the function of at least one viral protein essential for transcription and replication is linked to autocatalytical, exogenous human immunodeficiency virus (HIV) protease activity. Virus activity can be en- or disabled by various HIV protease inhibitors. Incorporating the HIV protease dimer in the genome of vesicular stomatitis virus (VSV) into the open reading frame of either the P- or L-protein resulted in an ON switch. Here, virus activity depends on co-application of protease inhibitor in a dose-dependent manner. Conversely, an N-terminal VSV polymerase tag with the HIV protease dimer constitutes an OFF switch, as application of protease inhibitor stops virus activity. This technology may also be applicable to other potentially therapeutic RNA viruses.