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Curcumin (CUR) is a natural polyphenol present in the rhizomes of Curcuma longa and possesses diverse pharmacological effects, especially anti-carcinogenic effects against several types of cancers. Unfortunately, this novel compound has poor aqueous solubility and bioavailability that limit its pharmaceutical effects. The use of polymeric nanocapsules has been applied in order to overcome such problems. Thus, our present study aimed at developing two novel polymeric nanoparticles (NPs) systems that encapsulate either curcumin alone (CURN) or with piperine (CURPN), which acts as a glucuronidation inhibitor and increases the bioavailability of CUR. The NPs were successfully designed by self-assembled nanoprecipitation method and their characteristics were identified by Fourier Transform Infrared Spectroscopy (FTIR), X-ray Diffraction (XRD), Scanning Electron Microscopy (SEM), Dynamic Light Scattering (DLS), and Zeta potential analysis. The drug release profiles of NPs were monitored under different pH, and their cytotoxic effects were assessed in vitro against Caco-2 cells and in vivo against dimethylhydrazine-induced colon cancer in mice. The FTIR and XRD analyses and SEM images showed amorphous and spherical shaped CURN and CURPN of 80–100 nm sized diameter. In vitro drug release study showed that pH triggered the maximum release of CUR in basic medium compared to acidic and neutral media, and following Higuchi model. CUR nanoencapsulation enhanced its physiochemical properties and drug loading and release. In vitro and in vivo studies showed that CUR NPs exerted selective and potential cytotoxic effects against colon cancer cells. The addition of piperine facilitated the encapsulation and drug loading of CUR. Thus, CUR nanoencapsulation enhanced the solubility and bioavailability of curcumin rendering it more effective against colon cancer. Previous article in issueNext article in issue Keywords CurcuminNanocapsulesColon cancerPiperinePolyallyamine hydrochloride 1. Introduction Curcumin (CUR), also called diferuloylmethane, is a well-documented natural polyphenol derived from the turmeric spice. Turmeric is the rhizome of the herbaceous perennial plant Curcuma longa that belongs to the ginger family [1]. CUR has received much attention from the medical and scientific communities since it possesses anti-inflammatory, antioxidant, and anti-carcinogenic properties [2]. This agent holds great promise in the fields of cancer chemoprevention and suppression [3]. Globally, colorectal cancer (CRC) is the third common cancer [4]. Since several epidemiological studies attributed the low incidence rates of CRC in India to the antitumor properties of CUR-enriched diets, plethora of research regarding CUR's potential antitumor effects has been conducted [5]. Due to being more bioavailable in the gastrointestinal tract than other organs, CUR became a well-documented molecule that potentially treats many gastrointestinal diseases including inflammatory bowel diseases and CRC [6]. At the molecular level, CUR has been shown to reduce cancer cell proliferation through arresting the cell cycle, activating apoptosis, and mitigating inflammation [7,8]. In addition, several in vivo studies have proven the chemopreventive and antitumor efficacy of curcumin against CRC [[9], [10], [11], [12], [13]]. Although CUR possesses anti-tumor and chemopreventive bioactivities, it has poor aqueous solubility and bioavailability that reduce its pharmaceutical effectiveness [14,15]. To enhance its solubility and subsequent bioavailability, applying nanotechnological approaches in order to develop curcumin nanocapsules can be performed [16,17]. Moreover, due to the serious side effects of the conventional cancer treatment methods, such as surgery, radiotherapy and chemotherapy, nanomedicine aims to design therapeutic modalities with higher safety, effectiveness, lower side effects, and to improve the preferential accumulation of antitumor therapeutics in cancer cells [[18], [19], [20]]. Nanotechnology involves the use of various nanomaterials such as liposomes, inorganic nanoparticles (NPs), solid lipid NPs, fullerenes, nanocrystals, quantum dots, dendrimers, and polymeric nanocapsules [21]. Recently, the use of nanocapsules on the basis of well-documented biocompatible polymers, such as polyallylamine hydrochloride (PAH), for targeted drug delivery is being applied in the treatment of many diseases [[22], [23], [24]]. The degradable and biologically compatible characteristics of polymeric nanoparticles make them the most preferred method for drug delivery [25,26]. Moreover, these systems display other benefits including the ability to incorporate poorly-water soluble molecules, control of drug accumulation in different organs and tissues depending on particle size, and substantial decrease in the amount of drug needed to trigger treatment [27]. Over the past decade, a great progress has been shown in the use of CUR nanocapsules against Alzheimer's disease and different cancers of the breast, brain, prostate, pancreas, and colon [[28], [29], [30], [31], [32]]. Furthermore, CUR's complexation with piperine (PIP), an inhibitor of glucuronidation, was administered to rats and humans aiming to increase CUR's bioavailability [33]. Studies in humans showed that PIP combination to CUR increases CUR's bioavailability, doubled its absorption and elevated its tissue-uptake [33]. CUR- PIP nanocapsules overcame the bioavailability limitations associated with poor CUR absorption and exerted direct cancer cell targeting effects [34] and were able to target and treat multidrug-resistant cancers [35]. To our knowledge, there is no report on effect of PIP during CUR encapsulation and release. This is the first attempt in this regard. Moreover, effects CUR nanocapsules in the presence of PIP against particularly colon cancer have not been properly investigated both in vitro and in vivo. This is also the first time we aimed in this study to develop polymeric nanoparticle systems that encapsulate CUR into PAH assembled nanocapsules (CURN) by simple nanoprecipitation method, incorporate PIP into the CUR-PAH nanocapsules (CURPN), characterize the physiochemical properties of the two types of nanocapsules using Fourier Transform Infrared Spectroscopy (FTIR), Scanning Electron Microscopy (SEM), X-Ray Diffraction (XRD), Dynamic Light Scattering (DLS), and zeta potential, monitor the drug delivery of both NPs at different pH (4, 6, 7, 8, and 10), investigate the in vitro cytotoxic effects of CUR nanocapsules against Caco-2 (human epithelial colon cancer cells) cell line, and examine the in vivo antitumor effects of CUR nanocapsules against dimethylhydrazine (DMH)-induced CRC in mice.