**3.2 Drug delivery**

In this section, we gathered some experiments that used different types of NPs for drug delivery to overcome the common problem in the treatment of OC as a lethal gynecological cancer worldwide, which almost diagnosis in late stages with the high rate of drug resistance for diagnosis and treatment. The advantages encourage researchers to utilized NPs consist of: NPs are used for drug delivery that lead to more effective in OC treatment. Also, reduce side effects due to specificity targeted NPs to OC cells.

SKOV3 and A2780 are the most usable cells for in vitro experiments that are treated by different kinds of drug loaded NPs. NPs are modified by several ligands such as hyaluronic acid, folic acid and HER2-targeted ligand for enhancing target delivery. GSH (Glutathione)-sensitive and pH-sensitive are other properties of these NPs that improve their effectiveness. As results showed the stability and biodistribution of these NPs that encapsulate drugs are very impressive. Increasing cellular uptake and cytotoxicity by inducing apoptosis or necrosis for in vitro experiments, and tumor growth and volume inhibition in the level of in vivo are the usual results that have been obtained.

The most barrier to entrance NPs into the cells through endosomes is an endosomal escape. Transferrin (Tf) and octaarginine (R8) play role in endosomal scape and specific delivery respectively. IAR-CPP R8 and Tf linked to the surface of PEGylated liposomes, which encapsulated doxorubicin (DOX) (DOXIL®) for

### **Figure 2.**

*Drugs or RNA interference (miRNA/siRNA/shRNA) loaded to lipid-based or polymeric nanoparticle as common nanocarriers are designed for delivery to OC cells in order to oncotherapy. Surface of these nanoparticles modified by different ligands such as hyaluronic acid (HA), folic acid (FA), Polyethylene glycol (PEG) and Polyethylenimine (PEI) for enhancing efficiency.*

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*Nano Technology and Gas Plasma as Novel Therapeutic Strategies for Ovarian Cancer…*

specific target therapy in A2780 cells. Results indicated efficiency in both entry

cells. Hyaluronic acid (HA) that is linked to CD44 which is a cell-surface glycoprotein and expresses specifically in tumor cells improves target delivery [30]. In the following, we mention an example that NPs modified by HA. Cisplatin-loaded polyarginine-HA NPs (CIS-pARG-HA NPs) were produced in this study, to overcome peritoneal carcinomatosis which generally diagnosis in the late stage of OC patients. In vitro studies on SKOV-3 cells showed reduced cell viability, by cooperation CD44 in cancer cells and an increase in cellular uptake. Also, the effectiveness of CIS-pARG-HA NPs improved, when these NPs were administered by pressurized intraperitoneal aerosol chemotherapy (PIPAC) due to the penetration into the

Folate receptor α (FRα) is another marker that overexpresses in OC cells, so modifying NPs surface by folic acid (FA) is another mechanism in specific target delivery. Using FA due to low immunogenic, inexpensive and stable properties, is more welcomed. Below we gather two examples in the level of in vitro and in vivo,

PTX loaded PLGA NPs modified by FA for oncotherapy. For comparison, modified NPs with non-modified NPs, were used to treat SKOV3 cells. FA improved the effect of NPs and rise up the cytotoxicity by increasing cellular uptake, and disrupt in cell division and apoptosis process [32]. In another study, Nanoemulsion (NE) as a delivery system was used to loaded docetaxel (DTX) and FA for treating OC. Cell treatment by this nanocarrier enhanced cytotoxicity due to the DTX, while treatment transgenic mouse model of ovarian carcinoma induced inhibition in tumor

The overexpression of the HER2 receptor is another specific marker that contributes to OC. CIS and trastuzumab and HER2-targeted antibody conjugated with poly(lactic-co-glycolic) NPs target HER2 receptor. CIS via impressing on DNA conformational and by a dose-dependent manner cause cytotoxicity and apoptosis in SKOV3 cells. The effectiveness of this delivery system after modifying by trastuzumab and chitosan increased in both in vitro and in vivo experiments [34]. Cell viability in HER-2-overexpressing cell line can also decrement by treating them with poly(butylene adipate-co-butylene terephthalate) (Ecoflex®) NPs by adding an aptamer engineer to improving the efficacy and reducing the side effects of DTX. For evaluating antitumor activity and biodistribution, tumor-bearing B6 athymic mice received NPs intravenously and significant results were obtained [35].

pH-sensitive NPs are widely utilized for drug delivery. Drugs released from NPs are controlled by various factors like pH. A2780 as a CIS sensitive and A2780DDP as a CIS resistant OC cells treated by pH-sensitive Fe3O4 NPs encapsulating CIS for reducing its side effect and drug resistance. NPs@CIS cause more internalization and in the following more drug accumulation in OC cells. In both cell lines, cytotoxicity and apoptosis increased because of the drug entry into the cell nucleus. The existence of an external magnetic field for in vivo experiments enhanced the

In another study, Tariquidar (TQR) and DOX loaded a pH-sensitive liposome formulation (pHSL) (pHSL/TQR/DOX) was prepared to overcome multidrug

to evaluating target delivery by FA ligand which binds to NPs [30].

*3.2.2 Control drug released from NPs: pH and GSH sensitive NPs*

antitumor efficacy and inhibition toxicity in normal tissues [36].

Adding a ligand to the surface of NPs enhances drug delivery effectiveness to OC

*DOI: http://dx.doi.org/10.5772/intechopen.96387*

peritoneal tumor [31].

growth and volume [33].

pathways and accumulation in tumor cells increased [29].

*3.2.1 Modified NPs: HA, FA, HER2 antibody for specific targeting*

specific target therapy in A2780 cells. Results indicated efficiency in both entry pathways and accumulation in tumor cells increased [29].
