**4.2 Curcumin-loaded nanoparticles and their anticancer activities**

Over the years, different nanoformulations have been investigated in order to enhance the delivery of curcumin to tumor sites [128, 145, 146]. Different nanoparticle-based approaches have been explored, such as solid-lipid microparticles based on bovine serum albumin [147, 148], encapsulation in liposomes [149], and chitosan [150]. These nanoparticles are tailored in a precise dimension for the purpose of increasing absorption and permeation, which then result in more bio-distribution and longer circulation in the body [151]. Nanoformulations are used primarily for enhancing the solubility of curcumin in water [152]. To enhance solubility, curcumin is prepared using pH-driven loading method, in this method, hydrophobic phytochemicals such as curcumin are deprotonated and dissolved under alkaline conditions to overcome solubility challenges [152, 153].

Preferably, curcumin nanoformulation would exhibit increased anticancer activity over free curcumin, while remaining nontoxic to normal cells. Chabib et al. [154] compared the anticancer activity of pure curcumin with curcumin-loaded nanoparticles, and found that curcumin-loaded nanoparticles were more effective than curcumin on its own against breast cancer cells T47D. A study by Bisht et al. [155] had previously demonstrated that pancreatic cancer can be effectively treated with polymer-based curcumin-loaded nanoparticles, which induced apoptosis

and obstructed the activation of NFκB in BxPC3 pancreatic cancer cells. Recently, the use of curcumin-loaded nanoparticles in combination with anticancer drugs have been shown to enhance their chemotherapeutic effect in ovarian carcinoma by inhibiting proliferation via modulation of JAK/STAT3 and PI3K/Akt signaling pathways [156].

Curcumin-loaded nanoparticles showed increased anticancer effect in lung cancer [157], prostate cancer [158], breast cancer [154], colon cancer [159], brain cancer [160] and oral cancer [161]. Additionally, curcumin-loaded nanoparticles have been shown to interact with plasma proteins, providing a new platform for improving cancer treatment [162]. Based on these results, it is not surprising that the usage of curcuminloaded nanoparticles is gaining momentum in anticancer therapeutics [163].

#### **4.3 Strategies to improve curcumin nanoparticles**

Numerous *in vitro* and *in vivo* studies have shown that nanoparticles may enhance the anticancer effects of curcumin [164, 165]. However, there are still some concerns about the cost, safety, side-effects, and long-term toxicity of curcuminloaded nanoparticles, leading to the development of a new field of study called nanotoxicology [166].

To improve curcumin nanoparticles, curcumin-loaded nanoparticles should be tested in a larger population to determine their toxicity and efficacy. Furthermore, clinical trials are necessary to evaluate their anticancer activities and determine side effects and toxicity in human subjects [167]. The safety concerns associated with nanomedicine-based delivery systems include neuroinflammation, excitotoxicity, and DNA damage [168]. Although they are methods that are currently explored to reduce the toxicity of nanoparticles [169], developing DNA/RNA nano-carriers to eliminate cancer cells can be a promising plan of action.
