Water Solubility Enhancement of Pyrazolo[3,4-d]pyrimidine Derivatives via Miniaturized Polymer–Drug Microarrays

Abstract

A miniaturized assay was optimized to evaluate the enhanced apparent water solubility of pyrazolo[3,4-]pyrimidine derivatives used extensively as anticancer drug scaffolds. The applied amount of drugs used in the reported strategy ranged from 5 to 10 μg per formulation which were dispensed by an inkjet 2D printer directly into a 96-well plate. The selected polymer/drug formulations with high water solubility demonstrated improved cytotoxicity against a human lung adenocarcinoma cancer cell line (A549) compared to the free drugs. We attribute the enhanced efficacy to the improved apparent-solubility of the drug molecules achieved via this methodology. This novel miniaturized method showed promising results in terms of water solubility improvement of the highly hydrophobic pyrazolo[3,4-]pyrimidine derivatives, requiring only a few micrograms of each drug per tested polymeric formulation. In addition, the reported experimental evidence may facilitate identification of suitable polymers for combination with drug, leading to investigations on biological properties or mechanisms of action in a single formulation.

Development of Pyrazolo[3,4-d]pyrimidine Kinase Inhibitors as Potential Clinical Candidates for Glioblastoma Multiforme

“…To overcome the water solubility limitation of SI306, which may affect further in vivo studies and future oral administration routes, we performed a preliminary formulation screening process based on 2D inkjet printing, building on an approach previously validated by our group. 39,47,48 Different commercial polymers were combined with SI306 and the apparent-solubility (ΔA%) value of each formulation was calculated in order to identify the polymers able to solubilize our lead compound (Figure 5). Data demonstrate that two surfactants (Pluronic F-68 and Tween 80) and the amphiphilic copolymer PVPVA showed notably higher ΔA% average values compared to the highly hydrophilic homopolymers (PEG8000−20000) (see Supporting Information, Table 1SI and Figures 1SI and 2SI for further details).…”

SRC Kinase in Glioblastoma: News from an Old Acquaintance

“…S1221 showed more significant cytotoxic effect, higher metabolic stability, and a better potential to cross the BBB as compared with PP2 [ 113 ]. Studies to increase its solubility in water could further increase its potentialities [ 135 ].…”

Starch/Poly(glycerol-adipate) Nanocomposites: A Novel Oral Drug Delivery Device

“…Analysis of the variation of the absorbance between the free drugs in water and their PGA formulation was assessed by UV-vis spectroscopy [22] and revealed an enhancement of the apparent water solubility of both compounds after encapsulation (Figure 1b).…”

“…It has been successfully demonstrated that solid dispersions of pyrazolo [3,4-d]pyrimidine analogous containing an hydrophilic polymer as inert carrier possess an increased apparent water solubility due to enhanced interactions between the hydrophilic polymeric chain and the hydrophobic drug scaffold leading. It was further shown that the polymer-drug interactions led to the nano-microaggregates of the formulations assembling themselves [22]. For this reason, we selected SI214, as a pyrazolo [3,4-d]pyrimidine model, for the following study.…”