# Biodegradable and Biocompatible Systems Based on Hydroxapatite Nanoparticles
## 4 Functional HAp Biocomposites through Modification/Encapsulation Techniques
### Hydroxyapatite Nanoparticles As Carriers for Drug Delivery Systems
More recently, the particle size and the specific surface area of different types of HAp nanoparticles were correlated with cytotoxicity to human gastric cancer cells, being clearly determined a higher toxicity when the smallest particles were employed [161]. Significant differences were found between rod shaped crystals with an average size of about 50 nm in length and 15 nm in width and needle-like crystals with dimensions close to 150 nm in length and 20 nm in diameter. Enhanced permeability and retention (EPR) is a characteristic phenomenon of cancer tissues that promotes angiogenesis, hypervascular, defective vascular architecture and increased production of permeability mediators [162; 163]. Some cancer treatments takes advantage of EPR for selective targeting of cancer tumors by nanoparticles, being HAp highly promising due to its good biological characteristics and the potential control over morphology and size. It is also interesting the surface modification of nanoparticles and specially the coating of HAp with positively charged polymers such as CHI since electrostatic interactions will lead to an increased uptake efficiency by negatively charged cancer cell membranes [164; 165]. This approach has been considered for treatment of colon cancer, which is the second leading cause of cancer-related deaths. Specifically, celecoxib was encapsulated in the HAp coated system due to its high efficiency in patients with precancer disease of the colon. Results proved that loaded nanoparticles were more potent in inhibiting tumor growth than free celecoxib, acting as a safe vehicle for targeted delivery that did not cause any serious side effect [162]. Human colon cancer cell untreated (control), or treated with free celecoxib, HAp-CHI or celecoxib-loaded HAp-CHI nanoparticles had 0.71% \(\pm\) 0.34%, 39.14% \(\pm\) 0.47%, 6.21% \(\pm\) 0.75% and 62.33% \(\pm\) 5.22% of apoptosis, respectively. Smart theranostic nanoplatforms (i.e., integration of therapeutic payloads and diagnosis agents) based on neodymium doped HAp have been proposed for colon cancer detection and targeted therapy [166]. The incorporation of neodymium endowed near-infrared fluorescence ability to HAp particles for diagnosis as above explained. In addition, drug loaded HAp nanoparticles were coated with ALG (Figure 14) to get a pH responsiveness that was ideal for targeted drug delivery after oral administration. Size, morphology and negative zeta potential of nanoparticles were appropriate to favor cell internalization. Figure 14: Scheme sowing the doping with Nd\({}^{3+}\) cations of nHAp particles previously loaded with 4-amino salicylic acid as a model drug. Nanoparticles were subsequently coated with ALG via aminopropyltriethoxysilane (APTS) and 1-ethyl-3-(-3-dimethylaminopropyl) carbodimide hydrochloride (EDC) mediated synthesis. Adapted from [166], Elsevier, 2016. The hydrophilic hyaluronic acid (HA) is a promising candidate polymer for targeting the CD44 glycoprotein that is overexpressed in tumor cells [167]. Therefore, attempts to coat nHAp particles with HA have been undertaken. Results indicated that a 9.4 times increment of the nanoparticle internalization by tumor cells was obtained [168]. In addition, the surface properties provided by HA (i.e., hydrophilicity and negative charge) could assist nanoparticles in evading the uptake by immune cells. In summary, HA was expected to facilitate tumor targeting delivery of nHAp particles, thereby it could enhance the in vivo efficacy of typical anticancer drugs as DOX (Figure 15). Cancer can be treated by means of cytotoxic ROS and free radicals (i.e., photodynamic therapy) produced by exposing a photosensitizer to a specific light wavelength [169]. The technique is limited due to the low tissue penetration depth of visible light (620-690 nm) [170]. Therefore, new agents based on high atomic metallic ions are gaining interest because their ability to interact with ionizing radiation and generate free radicals for deeper cancer treatment.