Abstract
Pyrazolo[3,4-d]pyrimidines are a class of compounds with a good activity against several cancer cell lines. Despite the promising anticancer activity, these molecules showed a poor aqueous solubility. This issue could threat the future development of pyrazolo[3,4-d]pyrimidines as clinical drug candidates. With the aim of improving their solubility profile and consequently their pharmacokinetic properties, we have chosen four compounds (1–4) on the base of their anti-neuroblastoma activity and we have developed albumin nanoparticles and liposomes for the selected candidates. Albumin nanoparticles and liposomes were prepared and characterized regarding size and ζ-potential distribution, polidispersity index, entrapment efficiency and activity against SH-SY5Y human neuroblastoma cell line. The most promising nanosystem, namely LP-2, was chosen to perform further studies: confocal microscopy, stability and drug release in physiological conditions, and biodistribution. Altogether, the obtained data strongly indicate that the encapsulation of pyrazolo[3,4-d]pyrimidines in liposomes represent an effective method to overcome the poor water solubility.
Highlights
Neuroblastoma (NB) is the most common extracranial solid tumor in early childhood
Among the compounds previously characterized, pyrazolo[3,4-d]pyrimidine 1–4 were chosen for their ability to inhibit c-Src and for their activity against NB cells[25,26,27]
With the aim determining if the use of albumin nanoparticles and liposomes could represent a possible strategy to improve pharmacokinetic properties of our compounds, four pyrazolo[3,4-d]pyrimidines (1–4), selected from our library of compounds, were encapsulate in these nanosystems
Summary
Neuroblastoma (NB) is the most common extracranial solid tumor in early childhood (the median age at diagnosis is 17 months). The search for novel drugs to improve NB treatment options still represents an outstanding pharmaceutical issue[3] In this context, Tyrosine Kinases (TKs) represent an interesting target for cancer treatment because of their involvement in several altered cellular pathways[4]. The development of pyrazolo[3,4-d]pyrimidines as potential anticancer drugs, represents a major research focus of our group This family of compounds showed a good cytotoxicity profile against several cancer cell lines: NB25–27, CML28, glioblastoma (GB)[29], rhabdomyosarcoma (RMS)[30], osteosarcoma (OS)[31], prostate cancer (PC)[32]. The selected lead compound was able to induce a tumor volume reduction greater than 50% in a NB subcutaneous xenograft mouse model[25] Given their unique physicochemical features, albumin nanoparticles and liposomes have showed a great potential as drug-carriers able to modify pharmacokinetic and pharmacodynamic properties of compounds. A breakthrough for albumin-based nanotechnology was the commercialization of Abraxane©, a solvent-free formulation of paclitaxel, where albumin binds paclitaxel to carry it through the endothelial cells to the tumor area[37]
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