Hydrogels incorporating GdDOTA: towards highly efficient dual T1/T2 MRI contrast agents.

Do not tumble dry: Gadolinium-DOTA encapsulated into polysaccharide nanoparticles (GdDOTA NPs) exhibited high relaxivity (r(1) =101.7 s(-1) mM(-1) per Gd(3+) ion at 37 °C and 20 MHz). This high relaxation rate is due to efficient Gd loading, reduced tumbling of the Gd complex, and the hydrogel nature of the nanoparticles. The efficacy of the nanoparticles as a T(1)/T(2) dual-mode contrast agent was studied in C6 cells.

Targeting Ovarian Carcinoma with TSP-1:CD47 Antagonist TAX2 Activates Anti-Tumor Immunity.

TAX2 peptide is a cyclic peptide that acts as an orthosteric antagonist for thrombospondin-1 (TSP-1) interaction with CD47. TAX2 was first described for its anti-angiogenic activities and showed anti-cancer efficacy in numerous preclinical models. Here, we aimed at providing an extensive molecular characterization of TAX2 mode of action, while evaluating its potential in ovarian cancer therapy. Multidisciplinary approaches were used to qualify a TAX2 drug candidate in terms of stability, solubility and potency. Then, efficacy studies, together with benchmark experiments, were performed in relevant mouse models of ovarian carcinoma. TAX2 peptide appears to be stable and soluble in clinically relevant solvents, while displaying a favorable safety profile. Moreover, clinical data mining allowed for the identification of TSP-1 as a relevant pharmacological target in ovarian cancer. In mice, TAX2 therapy inhibits ovarian tumor growth and metastatic dissemination, while activating anti-cancer adaptive immunity. Interestingly, TAX2 also synergizes when administered in combination with anti-PD-1 immune checkpoint inhibitiors. Altogether, our data expose TAX2 as an optimized candidate with advanced preclinical characterization. Using relevant syngeneic ovarian carcinoma models, we highlighted TAX2's ability to convert poorly immunogenic tumors into ones displaying effective anti-tumor T-cell immunity.

Enhanced immune response induced by BSA loaded in hydroxyethylstarch microparticles.

Microparticles and nanoparticles represent promising carriers for the in vivo delivery of peptides, proteins or deoxyribonucleic acid (DNA). In this study, new hydroxyethylstarch (HES) microparticles were obtained by interfacial cross-linking with terephtaloyl chloride. These microparticles exhibit the characteristics required to improve antigen release and presentation to antigen presentating cells compared to free antigens. The adjuvant activity of HES microparticles as vaccine carrier was investigated in mice using bovine serum albumin (BSA) as model antigen. We showed HES microparticles were phagocyted by peritoneal mononuclear cells. The immunization with BSA-microparticles induced antibody synthesis that was predominantly immunoglobulin G1 (IgG1). Aluminium hydroxide remained more efficient to induce IgG synthesis. The analysis of the cytokine profile from spleen cells revealed that BSA-microparticles induced the secretion of both interferon-gamma (IFN-gamma) and interleukin-4 (IL-4). However, the immune responses induced by BSA-microparticles were qualitatively and quantitatively affected by the route of injection. Taken together, these results demonstrate that HES microparticles induce a mixed T helper 1/T helper 2 response against BSA and may be a suitable delivery and presentation system in the field of vaccine development.

Tuning the composition of biocompatible Gd nanohydrogels to achieve hypersensitive dual T1/T2 MRI contrast agents.

A series of hydrogel nanoparticles incorporating MRI contrast agents (GdDOTP and MS325) as potential cross-linkers were elaborated by an easy and robust ionotropic gelation process. By this process, high Gd loadings were obtained (between 1.8 and 14.5 × 104 Gd centres per NP). By tuning the cross-linker ionization degree and the nature of the polymer matrix it was possible to boost the r1 relaxivity per Gd centre up to 22-fold. The greatest gains in relaxivity were observed for nanogels for which the polymer matrix was constituted of chitosan and hyaluronan. Relaxivities per Gd centre as high as 100 s-1 mM-1 at 30 MHz can be reached, which highlighted the fact that molecular motion of the Gd chelate was effectively restricted and water access to the inner core of these nanogels was not limited.

Encapsulated Ruthenium(II) Complexes in Biocompatible Poly(d,l-lactide-co-glycolide) Nanoparticles for Application in Photodynamic Therapy.

The elaboration, characterisation and efficiency of potential two-photon-excited photodynamic therapy (PDT) treatment of new poly(d,l-lactide-co-glycolide) nanoparticles loaded with ruthenium(II) complexs are presented. The materials are based on the encapsulation of RuII complexes through an all-biocompatible process. The size of the nanoparticles is around 100 nm. The internal concentration is several orders of magnitude higher than the overall concentration, which leads to a more efficient and targeted effect. The therapeutic potential for PDT of these nanoparticles has been studied in vitro on C6 glioma cells.

Etoposide encapsulation in surface-modified poly(lactide-co-glycolide) nanoparticles strongly enhances glioma antitumor efficiency.

Etoposide (VP-16) is a hydrophobic anticancer agent inhibiting Topoisomerase II, commonly used in pediatric brain chemotherapeutic schemes as mildly toxic. Unfortunately, despite its appropriate solubilization in vehicle solvents, its poor bioavailability and limited passage of the blood-brain barrier concur to disappointing results requiring the development of new delivery system forms. In this study, etoposide formulated as a parenteral injectable solution (Teva®) was loaded into all-biocompatible poly(lactide-co-glycolide) (PLGA) or PLGA/P188-blended nanoparticles (size 110-130 nm) using a fully biocompatible nanoprecipitation technique. The presence of coprecipitated P188 on encapsulation efficacies and in vitro drug release was investigated. Drug encapsulation was determined using HPLC. Inflammatory response was checked by FACS analysis on human monocytes. Cytotoxic activity of the various simple (Teva®) or double (Teva®-loaded NPs) formulations was studied on the murine C6 and F98 cell lines. Obtained results suggest that, although noninflammatory neither nontoxic by themselves, the use of PLGA and PLGA/P188 nanoencapsulations over pre-existing etoposide formulation could induce a greatly improved cytotoxic activity. This approach demonstrated a promising perspective for parenteral delivery of VP16 and potential development of a therapeutic entity.

In vivo anti-melanoma activities of the Melan-A/MART-1(101-115) T CD4+ cell peptide.

Malignant melanoma causes significant health problems. The identification of tumour-associated antigens has led to novel approaches to increase T cell mediated anti-tumour immune response. Melan-A/MART-1 has been use as target antigen for several T cell based immunotherapeutic treatments. More recently, the critical role of CD4+ T cells in inducing and maintaining anti-tumour immunity has been increasingly recognized. In order to optimize tumour immunotherapy, greater efforts have been concentrated on the identification of tumour antigens presented by MHC class II molecules to CD4+ T cells. In a publication, Tiwari et al. (2004) [1] have identified by a computational approach the 15-mer amino-acid sequence 101-115 (PPAYEKLSAEQSPPP) of the Melan-A/MART-1 as a good target for a vigorous and safe immunotherapy. Therefore, we have investigated the in vivo anti-tumour activity of this peptide in a murine melanoma model. For the prophylactic treatment, 20microg or 50microg peptide was subcutaneously injected in mice once a week during 3 weeks before tumour induction. Treatment with 50microg peptide significantly affected tumour development. Thus, our preliminary data demonstrate potential in vivo prophylactic activity of the 101-115 peptide-based vaccine to control melanoma growth.