The development of therapeutic resistance to targeted anticancer therapies remains a significant clinical problem, with intratumoral heterogeneity playing a key role. In this context, improving the therapeutic outcome through simultaneous targeting of multiple tumor cell subtypes within a heterogeneous tumor is a promising approach. Liposomes have emerged as useful drug carriers that can reduce systemic toxicity and increase drug delivery to the tumor site. While clinically used liposomal drug formulations show marked therapeutic advantages over free drug formulations, ligand-functionalized liposomes that can target multiple tumor cell subtypes may further improve the therapeutic efficacy by facilitating drug delivery to a broader population of tumor cells making up the heterogeneous tumor tissue. Ligand-directed liposomes enable the so-called active targeting of cell receptors via surface-attached ligands that direct drug uptake into tumor cells or tumor-associated stromal cells, and so can increase the selectivity of drug delivery. Despite promising preclinical results demonstrating improved targeting and anti-tumor effects of ligand-directed liposomes, there has been limited translation of this approach to the clinic. Key challenges for translation include the lack of established methods to scale up production and comprehensively characterize ligand-functionalized liposome formulations, as well as the inadequate recapitulation of in vivo tumors in the preclinical models currently used to evaluate their performance. Herein, we discuss the utility of recent ligand-directed liposome approaches, with a focus on dual-ligand liposomes, for the treatment of solid tumors and examine the drawbacks limiting their progression to clinical adoption.

Graft-versus-host disease (GVHD) remains a major problem after allogeneic haematopoietic stem cell transplantation, a curative therapy for haematological malignancies. Previous studies have demonstrated a role for the adenosine triphosphate (ATP)-gated P2X7 receptor channel in allogeneic mouse models of GVHD. In this study, injection of human peripheral blood mononuclear cells (PBMCs) into immunodeficient non-obese diabetic-severe combined immunodeficiency-interleukin (NOD-SCID-IL)-2Rγ (NSG) mice established a humanized mouse model of GVHD. This model was used to study the effect of P2X7 blockade in this disease. From five weeks post-PBMC injection, humanized mice exhibited clinical signs and histopathology characteristic of GVHD. The P2X7 antagonist, Brilliant Blue G (BBG), blocked ATP-induced cation uptake into both murine and human cells in vitro. Injection of BBG (50 mg/kg) into NSG mice did not affect engraftment of human leucocytes (predominantly T cells), or the clinical score and survival of mice. In contrast, BBG injection reduced circulating human interferon (IFN)-γ significantly, which was produced by human CD4 and CD8 T cells. BBG also reduced human T cell infiltration and apoptosis in target organs of GVHD. In conclusion, the P2X7 antagonist BBG reduced circulating IFN-γ in a humanized mouse model of GVHD supporting a potential role for P2X7 to alter the pathology of this disease in humans.

BackgroundTranslationally controlled tumour protein TCTP is an anti-apoptotic protein frequently overexpressed in cancers, where high levels are often associated with poor patient outcome. TCTP may be involved in protecting cancer cells against the cytotoxic action of anti-cancer drugs. Here we study the early increase of TCTP levels in human colorectal cancer (CRC) and the regulation of TCTP expression in HCT116 colon cancer cells, in response to treatment with the anti-cancer drugs 5-FU and oxaliplatin.MethodsUsing immunohistochemistry, we assessed TCTP levels in surgical samples from adenomas and adenocarcinomas of the colon, compared to normal colon tissue. We also studied the regulation of TCTP in HCT116 colon cancer cells in response to 5-FU and oxaliplatin by western blotting. TCTP mRNA levels were assessed by RT-qPCR. We used mTOR kinase inhibitors to demonstrate mTOR-dependent translational regulation of TCTP under these conditions. Employing the Real-Time Cell Analysis (RTCA) System and the MTS assay, we investigated the effect of TCTP-knockdown on the sensitivity of HCT116 cells to the anti-cancer drugs 5-FU and oxaliplatin.Results1. TCTP levels are significantly increased in colon adenomas and adenocarcinomas, compared to normal colon tissue. 2. TCTP protein levels are about 4-fold upregulated in HCT116 colon cancer cells, in response to 5-FU and oxaliplatin treatment, whereas TCTP mRNA levels are down regulated. 3. mTOR kinase inhibitors prevented the up-regulation of TCTP protein, indicating that TCTP is translationally regulated through the mTOR complex 1 signalling pathway under these conditions. 4. Using two cellular assay systems, we demonstrated that TCTP-knockdown sensitises HCT116 cells to the cytotoxicity caused by 5-FU and oxaliplatin.ConclusionsOur results demonstrate that TCTP levels increase significantly in the early stages of CRC development. In colon cancer cells, expression of this protein is largely upregulated during treatment with the DNA-damaging anti-cancer drugs 5-FU and oxaliplatin, as part of the cellular stress response. TCTP may thus contribute to the development of anti-cancer drug resistance. These findings indicate that TCTP might be suitable as a biomarker and that combinatorial treatment using 5-FU/oxaliplatin, together with mTOR kinase inhibitors, could be a route to preventing the development of resistance to these drugs.Electronic supplementary materialThe online version of this article (doi:10.1186/s12964-017-0164-3) contains supplementary material, which is available to authorized users.