(M1330-04-20) Tailoring the In Vitro Release of Reparixin-Loaded PLGA Microspheres

Purpose: Reparixin is a potent inhibitor for the two chemokine receptors (CXCR-1 and CXCR-2), which are overexpressed in cancer stem cells (CSCs). The recurrence of oral squamous cell carcinoma (OSCC) is mainly related to the presence of active CSCs, which are responsible for the very poor prognosis for recurrent tumor growth. Treatment of OSCC with reparixin is expected to diminish their tumorigenesis and metastatic potentials (1). The purpose of this study is to prepare a controlled release microparticulate dosage form of reparixin as an improved option for the treatment of OSCC.

Methods: Reparixin-loaded PLGA microspheres (MSs) were prepared by a single emulsion/solvent evaporation technique using PLGA 503H polymer. Different formulation variables such as polymer concentration and drug loading were used to optimize the drug encapsulation efficiency and in vitro release of the prepared MSs as determined by UPLC. The particle size, surface morphology, and possible drug-polymer interaction were investigated.

Results: The drug-loaded MSs were spherical with a smooth surface as shown in (Figure 1). The average particle size of the drug-loaded MSs ranged from 27 to 89 µM. Drug encapsulation efficiency was high and ranged from 81% to 95% at 10-30% theoretical loading. Increasing drug loading from 10% to 30% w/w decreased the burst drug release while sustained drug release over 4-weeks as represented in (Figure 2). Results of Differential Scanning Calorimetry (DSC) showed that 10% w/w drug-loaded MSs exhibited a complete absence of drug endothermic peak which suggests complete drug transformation into an amorphous state and its molecular dispersion into the polymeric matrix. However, the highest drug-loaded MSs of 30% w/w drug loading showed a broad endothermic peak of the drug starting at a lower melting temperature. These results suggest that increasing drug loading showed the presence of some encapsulated drug in the form of a crystalline state which might contribute to its slower in vitro release.

Conclusion: Formulation parameters such as polymer concentration and drug loading significantly affected the in vitro release profile of reparixin from PLGA microspheres. Preparation of controlled release microparticulate dosage form of reparixin will help to target the cancer stem cells of the OSCC.

References: Susan R. Mallery, Daren Wang, Brian Santiago, Ping Pei, Caroline Bissonnette, Jayanetti Asiri Jayawardena, Steven P. Schwendeman, Richard Spinney, James Lang (2019). Fenretinide, Tocilizumab & Reparixin Provide Multifaceted Disruption of Oral Squamous Cell Carcinoma Stem Cell Properties: Implications for Tertiary Chemoprevention. Mol Cancer Ther; 18(12): 2308–2320. doi:10.1158/1535-7163.MCT-19-0361.


Figure 1: Scanning electron microscope image of Reparixin-loaded PLGA microspheres


Figure 2: Effect of % drug loading on in vitro drug release of reparixin-loaded microspheres. 80% is indicating the polymer concentration, numbers of 40,80, and 120 are representing drug amounts in (mg), and DL is drug loading.