Improvement of pyrazolo[3,4-d]pyrimidines pharmacokinetic properties: nanosystem approaches for drug delivery

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.

Therapeutic efficacy of nanoparticles and routes of administration

“…Pyrazolo[3,4-d] pyrimidines demonstrated promising anticancer activity against many different cell lines but like many other anticancer compounds, it displayed poor aqueous solubility. This potential limitation was overcome by encapsulating in nanosystems like albumin nanoparticles and liposome and in the end, it showed remarkable pharmacokinetic profile [139].…”

Nanoparticle Functionalization and Its Potentials for Molecular Imaging

“…As biodistribution of particles at nanoscale is dependent on many factors and undesired tissue uptake is well known issue, functionalization of NPs can also assist proper biodistribution74 and enhanced molecular level interaction 75…”

The Pyrazolo[3,4-d]Pyrimidine Derivative Si306 Encapsulated into Anti-GD2-Immunoliposomes as Therapeutic Treatment of Neuroblastoma

“…Its role in tumor progression, maintenance and survival has been associated to several solid and hematologic cancers, such as colon [9], breast [10], lungs [11], liver [12], prostate [13], pancreatic [14], glioblastoma multiforme (GBM) [15,16], NB [17], chronic myelogenous leukemia [18], and lymphomas [19]. As a potent inhibitor of c-Src, Si306 was found to induce apoptosis and to reduce proliferation in GBM [20][21][22][23] and NB [8,24,25] tumor cell lines, while negligible activity was evidenced in non-tumoral cells [8]. In vivo, an oral administration of Si306 showed a delay of tumor growth in a subcutaneous NB animal model [8].…”

“…In vivo, an oral administration of Si306 showed a delay of tumor growth in a subcutaneous NB animal model [8]. However, the limitations to the further development of this promising compound are represented by its low water As a potent inhibitor of c-Src, Si306 was found to induce apoptosis and to reduce proliferation in GBM [20][21][22][23] and NB [8,24,25] tumor cell lines, while negligible activity was evidenced in non-tumoral cells [8]. In vivo, an oral administration of Si306 showed a delay of tumor growth in a subcutaneous NB animal model [8].…”