# Synthesis of High-Precision Sub-Micron CaCO\({}_{3}\) Anticancer Drug Carriers from Coral Remains
## 1 Introduction  
Environmental degradation and disease are the two major challenges of this century. This study explores a novel solution to deal these issues by addressing the accumulated coral remains in Taiwan and their potential application in cancer drug development, one of the leading causes of death worldwide. Coral remains are composed of coral fragments resulting from weathering, waves, or trampling. It is a unique environmental issue in Taiwan. Despite coral remains being non-toxic and harmless, the accumulation of coral causes lots of problems along the coast in Penghu, one of the counties in Taiwan. Coral remains accumulating along the coast lead to a reduction in marine life living spaces and the obstruction of fishing routes, impacting fishermen's livelihoods. The local government tried to dredge the coral remains and place them onto the beach. Unfortunately, the resulting odor and damage to the landscape continued to constitute serious problems. Coral remains consist of CaCO\({}_{3}\), which is known as a safe, cheap, and clean industrial mineral. Compared to oyster shells, coral remains do not require a significant amount of time for washing and cleaning, making them an ideal material for this study. Cancer is one of the most critical issues around the world. The International Agency for Research on Cancer (IARC) and the Union for International Cancer Control (UICC) reported nearly 19.3 million cancer cases, with the death toll reaching up to 10 million in 2020 [1]. Moreover, cancer has been the leading cause of death in Taiwan since 1982, accounting for 28.98% of all deaths in 2020, totaling 50,161 people [2]. Due to the toxicity of cancer drugs, the precision of drug delivery is a significant feature in curing cancers. Therefore, a growing amount of research is committed to loading drugs into unique containers to improve theprecision of drug delivery, i.e., drug carriers [3; 4]. There is currently a variety of drug carriers such as liposomes, solid lipid nanoparticles, gold nanoparticles, etc. However, they still have some critical problems that must be dealt with, e.g., bio-toxicity, aggregation, and high cost. CaCO\({}_{3}\) is a promising and novel material for drug carriers. It possesses several properties, including high biocompatibility, substantial drug loading capacity, pH sensitivity, low cost, and the capability to carry multiple drugs simultaneously [5; 6; 7; 8; 9]. It is widely used as an industrial mineral [10; 11; 12; 13; 14; 15; 16; 17; 18; 19] and a raw material for pharmaceutical products [20; 21]. CaCO\({}_{3}\) has been utilized as a carrier to deliver proteins and genes [22]. Therefore, the public acceptability of CaCO\({}_{3}\) is better than that of other materials. Moreover, according to the report from [PERSON] et al. [23], CaCO\({}_{3}\) costs only 0.2-0.4 USD/g, which is significantly lower than the 100 USD/g cost of liposomes. CaCO\({}_{3}\) is widely used in industry as a filler. It can not only lower the cost but also improve the properties of products [24; 25]. CaCO\({}_{3}\) has three major anhydrous phases: calcite, aragonite, and vaterite [26; 27]. Calcite is the most stable phase among them, followed by aragonite and vaterite [28; 29; 30; 31]. Vaterite is the least stable but the most promising phase for a drug carrier due to its high porosity, large surface, and higher solubility. Vaterite will gradually dissolve and recrystallize into calcite in water, which is an imperative mechanism for drugs to be released from vaterite (Figure 1). Owing to the instability of vaterite, the synthesizing process must be studied to control the morphology, particle size, and purity of it. To manipulate the morphologies and particle sizes of CaCO\({}_{3}\), the addition of additives is the general approach for achieving this [32; 33; 34; 35; 36; 37; 38]. [PERSON] et al. reported that polyol can inhibit CaCO\({}_{3}\) from growing into other phases [39]. Thus, we used ethylene glycol (EG) as an additive to maintain the vaterite phase [40; 41; 42].