Hydroxy-Propil-β-Cyclodextrin Inclusion Complexes of two Biphenylnicotinamide Derivatives: Formulation and Anti-Proliferative Activity Evaluation in Pancreatic Cancer Cell Models

Rosa Maria Iacobazzi,Angela Stefanachi,Valentino Laquintana,Antonio Lopalco,Annalisa Cutrignelli,Amalia Azzariti,Angela Assunta Lopedota,Simona Serratì,Letizia Porcelli,Massimo Franco,Roberta Di Fonte,Francesco Leonetti,Nunzio Denora,Saverio Cellamare,Nicola Silvestris

doi:10.3390/ijms21186545

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive malignancies, with poor outcomes largely due to its unique microenvironment, which is responsible for the low response to drugs and drug-resistance phenomena. This clinical need led us to explore new therapeutic approaches for systemic PDAC treatment by the utilization of two newly synthesized biphenylnicotinamide derivatives, PTA73 and PTA34, with remarkable antitumor activity in an in vitro PDAC model. Given their poor water solubility, inclusion complexes of PTA34 and PTA73 in Hydroxy-Propil-β-Cyclodextrin (HP-β-CD) were prepared in solution and at the solid state. Complexation studies demonstrated that HP-β-CD is able to form stable host–guest inclusion complexes with PTA34 and PTA73, characterized by a 1:1 apparent formation constant of 503.9 M−1 and 369.2 M−1, respectively (also demonstrated by the Job plot), and by an increase in aqueous solubility of about 150 times (from 1.95 µg/mL to 292.5 µg/mL) and 106 times (from 7.16 µg/mL to 762.5 µg/mL), in the presence of 45% w/v of HP-β-CD, respectively. In vitro studies confirmed the high antitumor activity of the complexed PTA34 and PTA73 towards PDAC cells, the strong G2/M phase arrest followed by induction of apoptosis, and thus their eligibility for PDAC therapy.

Highlights

SSiinnccee PPDDAACC iiss ggeenneerraallllyy ddiiaaggnnoosseedd aatt aann aaddvvaanncceedd ssttaaggee, ssyysstteemmiicc tthheerraappyy iiss tthhee mmaaiinn ssttrraatteeggyy ooff ttrreeaattmmeenntt
A remarkable antitumor activity of these molecules at low doses was assessed in a Pancreatic ductal adenocarcinoma (PDAC) model, MIA PaCa-2 cells [7], confirming that targeting microtubule dynamics could be effective against the abnormal proliferation of PDAC cancer cells [8,9,10]
The solubility of PTA73 and PTA34 was determined at 37 ± 0.5 ◦C in ultra-pure water, and the results showed that the solubility is critical for the bioavailability of these compounds

Summary

Introduction

SSiinnccee PPDDAACC iiss ggeenneerraallllyy ddiiaaggnnoosseedd aatt aann aaddvvaanncceedd ssttaaggee,, ssyysstteemmiicc tthheerraappyy iiss tthhee mmaaiinn ssttrraatteeggyy ooff ttrreeaattmmeenntt. CCuurrrreenntltyly,, tthhee mmoosstt ssuucccceessssffuull cchheemmootthheerraappyy rreeggiimmeennss ffoorr tthhiiss ttyyppee ooff ttuummoorr aarree ggeemmcciittaabbiinnee,, FFOOLLFFIIRRIINNOOXX,, aanndd tthhee ccoommbbiinnaattiioonn ggeemmcciittaabbiinnee//nnaabbppaacclliittaaxxeell. HHoowweevveerr,, tthhee cclliinniiccaall mmaannaaggeemmeenntt ooff ppaattiieennttss ssttiillll rreemmaaiinnss aann ooppeenn cchhaalllleennggee,, bbeeccaauussee iinn mmoosstt ccaasseess ppaattiieennttss hhaavvee iinnhheerreenntt rreessiissttaannccee ttoo tthheerraappiieess. A remarkable antitumor activity of these molecules at low doses was assessed in a PDAC model, MIA PaCa-2 cells [7], confirming that. A remarkable antitumor activity of these molecules at low doses was assessed in a PDAC model, MIA PaCa-2 cells [7], confirming that targeting microtubule dynamics could be effective against the abnormal proliferation of PDAC cancer cells [8,9,10]. The improvement of the aqueous solubility for the new PTA’s formulations was an urgent need

Methods

Results

Conclusion