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

Abstract

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.

In vivo distribution of zoledronic acid in a bisphosphonate-metal complex-based nanoparticle formulation synthesized by a reverse microemulsion method

“…Most of the reported formulations, such as the bisphosphonate-encapsulated liposomes (e.g. liposomal Zol or Col) and the Zol-embedded pre-formed calcium phosphate and cationic lipids hybrid nanoparticles, have been shown to be able to change the biodistribution of the bisphosphonates (Marra et al, 2012; Salzano et al, 2011; Salzano et al, 2016; Shmeeda et al, 2013). Compared to those formulations, the delivery systems based on the bisphosphonate-metal complexes recently reported by Au and colleagues offer an alternative platform: spherical Zol-Ca complexes were prepared using a RM technique, and the complexes were then coated with folic acid-modified lipids for targeted delivery of Zol into subcutaneous tumors in a mouse model (Au et al, 2016).…”

“…zoledronic acid (Zol), clodronic acid (Clo)) into functional liposomes causes significant changes in their tissue distribution, as well as an increase of bisphosphonate levels in tumors (Marra et al, 2011; Shmeeda et al, 2013; Zeisberger et al, 2006). Caraglia and colleagues have also developed an advanced Zol delivery system based on the self-assembly of calcium phosphate nanoparticles and cationic lipids, which significantly enhanced the accumulation of Zol in extraskeletal tumors (Marra et al, 2012; Salzano et al, 2011; Salzano et al, 2016). …”

Targeting cellular pathways in glioblastoma multiforme

“…Tf-PLCaPZ showed significant in vitro LN229 cell growth inhibition, Tf-PLCaPZ also showed anti-tumor activity in vivo in a U373MG xenograft model. 120 , 121 These promising preclinical results make ZOL an exciting potential therapy for GBM.…”

Nanomaterials as nanocarriers: a critical assessment why these are multi-chore vanquisher in breast cancer treatment

“…Use of transferrin targeted zoledronic acid (ZA) nanoparticles. Transferrin is used to complex with nanoparticles because transferrin receptors over express intra as well as extra cellularly [43]. Tumour has been treated with zoledronic acid and temozolomide.…”