**5. Routes of administration of nanoparticles**

SFN have proven to be extremely versatile for the transport of therapeutic compounds such as small drugs, proteins and DNA molecules [110]. The functionality of these compounds is closely related to the route of administration. For example, nanoparticles can be injected into the bloodstream and make use of the EPR effect for passive accumulation in metastatic tumors or they can be injected directly into the tumor mass [111]. On the other hand, they can be applied topically for the treatment of skin cancer [112] and in a similar way for lung treatments [113, 114]. SFN have been used in a wide variety of routes of administration [54]. For the sake of simplicity, only the main routes of administration will be mentioned: parental, oral, transdermal and pulmonary, and some of the studies that address the use of SFN for these different routes of administration will be cited as examples.

#### **5.1 Parenteral**

Parenteral administration forms are intended for administration by injection, which can be subdivided into intravenously (into a vein), intramuscular (into the muscle), subcutaneous (under the skin), or intradermal (into the skin). Parenteral administration acts faster than topical or enteral administration, and the onset of action often occurs in a range of seconds to minutes. Essentially, the bioavailability of the injected drug is 100% and its distribution is systemic, which means that it is potentially capable of reaching the entire body. This last concept paired with the EPR effect as mentioned above is of special interest for the treatment of tumor masses. For example, ZhuGe et al. [115] prepared SFN with their surface functionalized by proanthocyanidins and loaded with indocyanine green. Indocyanine can absorbe near-infrared light (650-900 nm) and producing a thermal effect both in vitro and in vivo. This photothermic compound is approved by the FDA and can be used to kill cells by photothermolysis. To test their functionality, the researchers injected the loaded nanoparticles intravenously into mice bearing C6 glioma. The pharmacokinetic study showed that the nanoparticles managed to reach the gliomas after intravenous administration in vivo, while the pharmacological study demonstrated inhibition of tumor growth after irradiation with near-infrared light. On the other hand, nanoparticles also offer temporary release control. Recently, in another study, Zhan et al. [116] administered Celastrolloaded SFN to rats intravenously. The results showed that an increase in the total exposure time to the drug is reduced by increasing its residence time and reducing its metabolism.

#### **5.2 Oral**

Oral administration is the most common route and probably the one preferred by patients when receiving medications. However, conventional formulations, such as tablets and capsules, can release drugs in a rapid and poorly controlled manner, which can result in degradation and alteration of the drug due to the environment of the gastrointestinal tract (variations in pH and the presence of digestive enzymes and microbiota). Furthermore, the common mechanism of drug absorption through the gastrointestinal tract is passive diffusion. Consequently, most of the initial dose is not absorbed but is metabolized and excreted. SFN possess favorable characteristics to overcome the aforementioned problems and become candidates of interest for the oral administration of therapeutic compounds. Firstly, due to their mucoadhesive capacity, SFN can adhere firmly to the gastrointestinal mucosa or intestinal epithelial cells (Peyer's lymphatic M cells), followed by cell

internalization via endocytosis [117]. Thus, encapsulated drugs can enter the bloodstream effectively and intact. Zhan et al. [116] increased more than doubled the absolute bioavailability of Celastrol from 3.14% to 7.56% by loading the drug in SFN and administering it orally to rodents.
