Transferrin-Targeted Nanoparticles Containing Zoledronic Acid as a Potential Tool to Inhibit Glioblastoma Growth.

The treatment of glioblastoma (GBM) is a challenge for the biomedical research since cures remain elusive. Its current therapy, consisted on surgery, radiotherapy, and concomitant chemotherapy with temozolomide (TMZ), is often uneffective. Here, we proposed the use of zoledronic acid (ZOL) as a potential agent for the treatment of GBM. Our group previously developed self-assembling nanoparticles, also named PLCaPZ NPs, to use ZOL in the treatment of prostate cancer. Here, we updated the previously developed nanoparticles (NPs) by designing transferrin (Tf)-targeted self-assembling NPs, also named Tf-PLCaPZ NPs, to use ZOL in the treatment of brain tumors, e.g., GBM. The efficacy of Tf-PLCaPZ NPs was evaluated in different GBM cell lines and in an animal model of GBM, in comparison with PLCaPZ NPs and free ZOL. Tf-PLCaPZ NPs were characterized by a narrow size distribution and a high incorporation efficiency of ZOL. Moreover, the presence of Tf significantly reduced the hemolytic activity of the formulation. In vitro, in LN229 cells, a significant uptake and cell growth inhibition after treatment with Tf-PLCaPZ NPs was achieved. Moreover, the sequential therapy of TMZ and Tf-PLCaPZ NPs lead to a superior therapeutic activity compared to their single administration. The results obtained in mice xenografted with U373MG, revealed a significant anticancer activity of Tf-PLCaPZ NPs, while the tumors remained unaffected with free TMZ. These promising results introduce a novel type of easy-to-obtain NPs for the delivery of ZOL in the treatment of GBM tumors.

Self-assembly nanoparticles for the delivery of bisphosphonates into tumors.

Bisphosphonates (BPs) are molecules able to induce apoptosis in several cancer cell lines. However, their short half-life and the rapid uptake and accumulation within bone, limit its use as antitumor agent for extra-skeletal malignancies. Here we proposed a new delivery system to avoid BP accumulation into the bone, thus improving extra-skeletal bioavailability. In this work, we used the zoledronic acid (ZOL), a third generation bisphosphonate, able to induce apoptosis at micromolar concentration. We developed ZOL-containing self-assembly PEGylated nanoparticles (NPs) based on ZOL complexes with calcium phosphate NPs (CaPZ NPs) and cationic liposomes. PEGylation was achieved by two different strategies. CaPZ NPs were covered with PEGylated liposomes (pre-PLCaPZ NPs); alternatively, CaPZ NPs were previously mixed with cationic liposomes and then PEGylated by post-insertion method (post-PLCaPZ NPs). The NPs were fully characterized in terms of mean diameter and size distribution, morphology, ZOL loading, antiproliferative effect on different cell lines. Pre-PLCaPZ NPs showed the best technological characteristics, with a narrow size distribution and a high ZOL loading. Moreover, on different cancer cell lines, these NPs enhanced the antiproliferative effect of ZOL. Finally, in an animal model of prostate cancer, a significant reduction of tumor growth was achieved with pre-PLCaPZ NPs, while the tumor was unaffected by ZOL in solution.

PARP1 is activated at telomeres upon G4 stabilization: possible target for telomere-based therapy.

New anti-telomere strategies represent important goals for the development of selective cancer therapies. In this study, we reported that uncapped telomeres, resulting from pharmacological stabilization of quadruplex DNA by RHPS4 (3,11-difluoro-6,8,13-trimethyl-8H-quino[4,3,2-kl]acridinium methosulfate), trigger specific recruitment and activation of poly-adenosine diphosphate (ADP) ribose polymerase I (PARP1) at the telomeres, forming several ADP-ribose polymers that co-localize with the telomeric repeat binding factor 1 protein and are inhibited by selective PARP(s) inhibitors or PARP1-specific small interfering RNAs. The knockdown of PARP1 prevents repairing of RHPS4-induced telomere DNA breaks, leading to increases in chromosome abnormalities and eventually to the inhibition of tumor cell growth both in vitro and in xenografts. More interestingly, the integration of a TOPO1 inhibitor on the combination treatment proved to have a high therapeutic efficacy ensuing a complete regression of the tumor as well as a significant increase in overall survival and cure of mice even when treatments started at a very late stage of tumor growth. Overall, this work reveals the unexplored link between the PARP1 and G-quadruplex ligands and demonstrates the excellent efficacy of a multi-component strategy based on the use of PARP inhibitors in telomere-based therapy.