Evaluation of linear versus star-like polymer anti-cancer nanomedicines in mouse models.

Nanomedicines are considered next generation therapeutics with advanced therapeutic properties and reduced side effects. Herein, we introduce tailored linear and star-like water-soluble nanosystems as stimuli-sensitive nanomedicines for the treatment of solid tumors or hematological malignancies. The polymer carrier and drug pharmacokinetics were independently evaluated to elucidate the relationship between the nanosystem structure and its distribution in the body. Positron emission tomography and optical imaging demonstrated enhanced tumor accumulation of the polymer carriers in 4T1-bearing mice with increased tumor-to-blood and tumor-to-muscle ratios. Additionally, there was a significant accumulation of doxorubicin bound to various polymer carriers in EL4 tumors, as well as excellent in vivo therapeutic activity in EL4 lymphoma and moderate efficacy in 4T1 breast carcinoma. The linear nanomedicine showed at least comparable pharmacologic properties to the star-like nanomedicines regarding doxorubicin transport. Therefore, if multiple parameters are considered such as its optimized structure and simple and reproducible synthesis, this polymer carrier system is the most promising for further preclinical and clinical investigations.

Regulatory T cells suppress the formation of potent KLRK1 and IL-7R expressing effector CD8 T cells by limiting IL-2.

Regulatory T cells (Tregs) are indispensable for maintaining self-tolerance by suppressing conventional T cells. On the other hand, Tregs promote tumor growth by inhibiting anticancer immunity. In this study, we identified that Tregs increase the quorum of self-reactive CD8+ T cells required for the induction of experimental autoimmune diabetes in mice. Their major suppression mechanism is limiting available IL-2, an essential T-cell cytokine. Specifically, Tregs inhibit the formation of a previously uncharacterized subset of antigen-stimulated KLRK1+ IL-7R+ (KILR) CD8+ effector T cells, which are distinct from conventional effector CD8+ T cells. KILR CD8+ T cells show superior cell-killing abilities in vivo. The administration of agonistic IL-2 immunocomplexes phenocopies the absence of Tregs, i.e., it induces KILR CD8+ T cells, promotes autoimmunity, and enhances antitumor responses in mice. Counterparts of KILR CD8+ T cells were found in the human blood, revealing them as a potential target for immunotherapy.

As well as protecting us from invading pathogens, like bacteria or viruses, our immune system can also identify dangerous cells of our own that may cause the body harm, such as cancer cells. Once detected, a population of immune cells called cytotoxic T cells launch into action to kill the potentially harmful cell. However, sometimes the immune system makes mistakes and attacks healthy cells which it misidentifies as being dangerous, leading to autoimmune diseases. Special immune cells called T regulatory lymphocytes, or 'Tregs', can suppress the activity of cytotoxic T cells, preventing them from hurting the body's own cells. While this can have a positive impact and reduce the effects of autoimmunity, Tregs can also make the immune system less responsive to cancer cells and allow tumors to grow. But how Tregs alter the behavior of cytotoxic T cells during autoimmune diseases and cancer is poorly understood. While multiple mechanisms have been proposed, none of these have been tested in living animal models of these diseases. To address this, Tsyklauri et al. studied Tregs in laboratory mice which had been modified to have autoimmune diabetes, which is when the body attacks the cells responsible for producing insulin. The experiments revealed that Tregs take up a critical signaling molecule called IL-2 which cytotoxic T cells need to survive and multiply. As a result, there is less IL-2 molecules available in the environment, inhibiting the cytotoxic T cells' activity. Furthermore, if Tregs are absent and there is an excess of IL-2, this causes cytotoxic T cells to transition into a previously unknown subset of T cells with superior killing abilities. Tsyklauri et al. were able to replicate these findings in two different groups of laboratory mice which had been modified to have cancer. This suggests that Tregs suppress the immune response to cancer cells and prevent autoimmunity using the same mechanism. In the future, this work could help researchers to develop therapies that alter the behavior of cytotoxic T cells and/or Tregs to either counteract autoimmune diseases, or help the body fight off cancer.

HPMA-based star polymer biomaterials with tuneable structure and biodegradability tailored for advanced drug delivery to solid tumours.

Design, controlled synthesis, physico-chemical and biological characteristics of novel well-defined biodegradable star-shaped copolymers intended for advanced drug delivery is described. These new biocompatible star copolymers were synthesised by grafting monodispersed semitelechelic linear (sL) N-(2-hydroxypropyl)methacrylamide copolymers onto a 2,2-bis(hydroxymethyl)propionic acid (bisMPA)-based polyester dendritic core of various structures. The hydrodynamic diameter of the star copolymer biomaterials can be tuned from 13 to 31 nm and could be adjusted to a given purpose by proper selection of the bisMPA dendritic core type and generation and by considering the sL copolymer molecular weight and polymer-to-core molar ratio. The hydrolytic degradation was proved for both the star copolymers containing either dendron or dendrimer core, showing the spontaneous hydrolysis in duration of few weeks. Finally, it was shown that the therapy with the biodegradable star conjugate with attached doxorubicin strongly suppresses the tumour growth in mice and is fully curative in most of the treated animals at dose corresponding approximately to one fourth of maximum tolerated dose (MTD) value. Both new biodegradable systems show superior efficacy and tumour accumulation over the first generation of star copolymers containing non-degradable PAMAM core.