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Targeting macrophages is a promising strategy for improved therapy of intracellular infections as macrophages exhibit rapid phagocytosis of particles >200 nm. Entrapment of Curcumin (CUR) in nanocarriers could provide bioenhancement and macrophage targeting. We present a simple and facile in situ nanoprecipitation approach for instantaneous and on-site generation of curcumin nanoparticles (ISCurNP). ISCurNP optimised by Box-Behnken design exhibited average size of 208.25 AE 7.55 nm and entrapment efficiency of 90.16 AE 1.17%. Differential scanning calorimetry and X-Ray diffraction confirmed amorphization of CUR in ISCurNP. Sustained release was observed over 72 hr in vitro at lysosomal pH 4.5. Rapid and high uptake in RAW 264.7 macrophages was confirmed by flow cytometry and high performance liquid chromatography. Confocal microscopy established localisation of ISCurNP in lysosomal compartment. The facile in situ nanoprecipitation method provides simple, scalable technology to enable macrophage targeted delivery of CUR, with great promise for improved therapy of intracellular infections. K E Y W O R D SCurcumin, in situ, nanoparticles, macrophages, nanoprecipitation, intracellular uptake, Box Behnken 1 | INTRODUCTION Curcumin (CUR), a natural polyphenol has generated tremendous excitement as a nutraceutical due to its multifarious pharmacological activities.1,2 The anticancer 3-6 and anti-inflammatory 7,8 properties of CUR have been widely explored. CUR, an established anti-infective for eons, is currently being extensively researched for antibacterial including antimycobacterial, antiviral, and antifungal activity. 9-11Despite the excellent therapeutic potential, a considerable impediment in exploitation of CUR as a therapeutic agent is its hydrophobic nature and consequently poor aqueous solubility. 12Nanonization of particles has proven to be a competent approach to enhance solubility and bioavailability of hydrophobic poorly soluble drugs. 13,14 Furthermore, such drugs when entrapped in nanocarriers with size titrated in the range of 200-600 nm can aid targeting to the reticuloendothelial system (RES) organs and cells, especially macrophages, the primary site of various intracellular infections. 15-18Macrophages constitute defense system of the body and exhibit rapid phagocytosis of particles >200 nm. | ISCurNPPreconcentrates were added to filtered distilled water for instantaneous formation ISCurNP. | Optimization of ISCurNP 2.4.1 | Preliminary screeningPreliminary screening was carried out using the one variable at a time | Design of experiment: Box-Behnken designISCurNP was optimized by applying Box-Behnken design. Independent variables selected were concentration of Soluplus ® (X1), concentration of PLGA (X2), and volume of DMA (X3) in the preconcentrate and the dependent variables (responses) were particle size (PS; Y1), and percent entrapment efficiency (%EE; Y2) of the generated ISCurNP. Curcumin concentration (10 mg) and aqueous dilution volume (10 ml) were maintained constant. The indepen...

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