Nano drug delivery systems for ovarian cancer therapy

Ovarian cancer is the second most common gynecologic cancer in Europe and the USA, and the most fatal gynecologic malignancy among all cancers with a mortality rate of 6%. The traditional treatment of ovarian cancer includes cytoreductive surgery and platinum-taxane combined chemotherapy. Although the response to the standard treatment scheme is promising at first, the disease often recurs and eventually treatment fails with the development of chemoresistance as the main cause of failure of treatment. The purpose of this brief review is to summarize the new strategies, especially in terms of nanotechnology, for the treatment of ovarian cancer.


Introduction
Ovarian cancer is the most lethal gynecologic cancer due to its high recurrence rate [1][2][3] even though it is one of the most sensitive tumors, even at advanced stage [4]. Today, it globally ranks fifth place among the causes of death for women [2,3]. The first-line treatment of ovarian-cancer is cytoreductive surgery followed by platinum-based chemotherapy [2][3][4][5][6][7][8]. Despite improvements in the field of medicine, the reason for high mortality in ovarian cancer is late diagnosis because of nonspecific symptoms [9] (almost 75% [8,10] at stage III or later), and relapse of the disease [1][2][3] . The most significant reason for the recurrence of ovarian cancer is resistance to platinum-based chemotherapy in the majority of patients in progressive stages, although the initial success in treatment with agents such as cisplatin or carboplatin is more than 70% [3,11]. It is known that resistant cancer cells develop resistance to platinum compounds by reducing cell uptake, increasing elimination, inactivation/detoxification of drugs, and accelerating DNA repair [12][13][14]. Efforts are being made to develop new treatment options due to the frequency of platinum resistance [3,15]. For this purpose, various drug delivery and administration approaches have been developed such as the use of the intraperitoneal route, use of passive and/or active targeting nano drug delivery systems [16,17]. Nanotechnology can be a solution for obstacles of ovarian cancer treatment. When recent studies were reviewed, along with developments in nanobiological fields, nanotechnology was found to have extensively investigated for molecular imaging, drug delivery, treatment and tumor targeting. Particulate drug nanocarriers such as liposomes, niosomes, polymeric micelles, solid lipid nanoparticles and polymeric nanoparticles have unique features for interacting with tumor microenvironments and tumor targeting as their submicron size, functional surfaces, stability, possibility to encapsulate hydrophobic drugs, prolong the residence time in systemic circulation [18,19]. Generally, conventional chemotherapy applications result in rapid blood clearance, degradation, undesirable side effects rooting from drug distribution to healthy tissues, poor drug accumulation in tumor tissues due to poor penetration capacity and multidrug resistance (MDR) [20].
Nanotechnology-based drug delivery systems can be beneficial for the controlled delivery of chemotherapeutics by means of location and duration without undesirable side effects by overcoming several drug delivery barriers through passive or active targeting strategies [11,20] SKOV3 cells, indicating a strong synergism. Optimal cytotoxicity was observed at a 2:1 ratio of cisplatin:paclitaxel. In in-vivo fluorescence optical imaging studies, fluorescent dye encapsulated telodendrimers accumulated mainly at the SKOV-3 tumor xenograft, 4-fold higher than other organs; whereas free dye showed very weak tumor fluorescence.
The pharmacokinetic behaviour of the free drug cisplatin was enhanced with slower clearance rates and higher plasma half-life. Furthermore, in-vivo anti-tumor efficacy studies indicated that the average tumor volume decrease was significantly higher for animal group treated with two drugs loaded telodendrimer group similar to in-vitro studies [25]. Integr Cancer Sci Therap, 2017 doi: 10.15761/ICST.1000235

Active targeting
One of the key parameters for anticancer nanocarries is targeting ligands in addition to size and surface properties [24]. In ovarian cancer, highly expressed cell-surface proteins include the folate receptor, EGF receptor (EGFR, HER2), luteinizing hormone receptor, claudins, mucins, and integrins [3].
Fan et al. developed a nanoparticle system targeting the folliclestimulating hormone receptor (FSHR) loaded with paclitaxel to prevent lymphatic metastasis of ovarian cancer. Targeted nanoparticles showed improved cellular uptake into FSHR positive cells, NuTu-19, while there was no difference for non-targeted nanoparticles between FSHR positive and negative cells. In a model of ovarian cancer with lymphatic metastasis in rats, the drug concentration in lymph nodes for the animal group treated with targeted nanoparticles was observed to increase over time and was significantly higher than the free drug and non-targeted nanoparticle group. Moreover, the size and weight of the lymph nodes were reduced and average survival time was longer for the targeted nanoparticle group [26].
Since many genes involved in the regulation of proliferation and angiogenesis have been mutated during cancer, gene silencing via RNA interferences (RNAi) mediated by short interfering RNA (siRNA) is a great therapeutic target for cancer therapy. Hypoxic inducible factor-1a (HIF-1a) is an overexpressed protein in ovarian cancer and associated with cancer progression. Based on this information Li et al. developed tumor-targeting siRNA/folic acid-poly(ethylene glycol)chitosan oligosaccharide lactate (FA-PEG-COL) nanoparticles for HIF-1a suppression and therefore inhibition of angiogenesis and tumor growth. In vitro gene silencing studies made via Western Blot and Real time PCR demonstrated that siRNA delivery by FA-PEG-COL nanoparticles significantly reduced both protein and mRNA levels of HIF-1a, leading to a strong suppression of cell proliferation in human ovarian cancer cells. When fluorescent dye loaded FA-PEG-COL nanoparticles iv administered to nude mice bearing OVK18#2 human ovarian cancer cells, significant accumulation at the tumor site was seen at 3 h post injection with subsequent increase at the 12 and 24 h time while significant liver accumulation was observed with COL nanoparticles treated animal group, indicating the active targeting ability of FA-PEG-COL nanoparticles [27].
Because of its multi-functional properties nanotechnology allows co-delivery of targeting ligands, drugs and imaging agents, which enables therapeutic, diagnostic and real-time traceable drug delivery goals to be achieved at the same time. This approach is called nanotheranostic [28]. By taking advantage of this superior property of nanotechnology Ganta et al. developed a folate targeted gadolinium decorated theranostic nanoemulsion of docetaxel for overcoming efflux transporters which are one of the chemoresistance mechanisms of ovarian cancer and tracing drug distribution. According to cellular uptake studies theranostic nanoemulsion uptake into folate receptor positive SKOV3 ovarian cancer cell line was time dependent and higher than nontargeted nanoparticles. MTT studies demonstrated that IC 50 value of chemoresistant SKOV3TR decreased 270-fold compared to free drug. Magnetic resonance imaging study made thanks to gadolinium showed that folate targeted theranostic nanoparticles accumulated over the period of 24 hour at tumor site [29].

Intraperitoneal chemotherapy
Intraperitoneal (i.p) chemotherapy in other words the infusion of chemotherapeutic agents directly into the peritoneum is a promising option for ovarian cancer therapy due to spread of the disease to the peritoneal cavity [7,30,31]. Although there are some common drawbacks about i.p administration such as complications related to i.p infusion, including abdominal pain, intolerance to a high level of drug, and discomfort related to the catheter implantation, i.p chemotherapy can be beneficial to maintain an effective local drug concentration for a prolonged period and maximize the locoregional effects on residual tumors [30]. Another problem about i.p chemotherapy is rapid clearance of small molecule drugs from peritoneal cavity and necessity of frequent dosing [30]. In order to increase the residence time of the chemotherapeutics in the peritoneal cavity controlled release drug carriers, such as microparticles, hydrogels and bioadhesive nanoparticels [31].
Sun et al. developed a system comprising of in-situ crosslinkable hydrogel depot containing paclitaxel nanocrystals (PNC). PNC with 258 ± 28.1 nm particle size and −5.51 ± 0.42 mV zeta potential was produced by anti-solvent and temperature induced crystallization method while hyaluronic acid gel was produced by crosslinking HAadipic acid dihydrazide (HA-ADH) and HA-aldehyde (HA-CHO) in situ. PNC were more cytotoxic than microparticulate PTX in SKOV3 cell culture due to cellular PTX retention. After single dose intraperitoneal administration in vivo studies demonstrated that PNC-gel was more toxic than microparticulate PTX gel and extended survival of tumor-bearing mice because of greater antitumor effect than microparticulate PTX gel and free drug [30] (Table 1).

Conclusion
The use of nano drug delivery systems for ovarian cancer therapy is gaining more and more importance day by day due to their excellent properties and promising results. There are lots of nano-sized drug delivery systems designed for diagnosis and therapy under preclinical and clinical development and will be marketed a lot more in the near future.

Funding
The author(s) received no financial support for the research, authorship, and/or publication of this article.