Current treatment options and drug delivery systems as potential therapeutic agents for ovarian cancer: A review

Materials Science and Engineering C 45 (2014) 609–619

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Current treatment options and drug delivery systems as potential therapeutic agents for ovarian cancer: A review Hongye Ye a,⁎, Anis Abdul Karim a, Xian Jun Loh a,b,c,⁎⁎ a b c

Institute of Materials Research and Engineering (IMRE), A*STAR (Agency for Science, Technology and Research), 3 Research Link, Singapore 117602, Singapore Department of Materials Science and Engineering, National University of Singapore, 9 Engineering Drive 1, Singapore 117576, Singapore Singapore Eye Research Institute, 11 Third Hospital Avenue, Singapore 168751, Singapore

a r t i c l e

i n f o

Article history: Received 2 April 2014 Accepted 9 June 2014 Available online 20 June 2014 Keywords: Ovarian cancer Intraperitoneal Chemotherapy Drug delivery Nanoparticles Co-delivery

a b s t r a c t Ovarian cancer is one of the most common and deadliest gynecologic cancer with about 75% of the patients presenting in advanced stages. The introduction of intraperitoneal chemotherapy in 2006 had led to a 16 month improvement in the overall survival. However, catheter-related complication and the complexity of the procedure had deterred intraperitoneal route as the preferred route of treatment. Other alternative treatments had been developed by incorporating other FDA-approved agents or procedures such as pegylated liposomal doxorubicin (PLD), hyperthermic intraoperative intraperitoneal chemotherapy (HIPEC) and the administration of bevacizumab. Various clinical trials were conducted on these alternatives as both the firstline treatment and second- or third-line therapy for the recurrent disease. The outcome of these studies were summarized and discussed. A prospective improvement in the treatment of ovarian cancer could be done through the use of a drug delivery system. Selected promising recent developments in ovarian cancer drug delivery systems using different delivery vehicles, surface modifications, materials and drugs were also reviewed. © 2014 Elsevier B.V. All rights reserved.

1. Introduction Ovarian cancer is the fifth leading cause of cancer-related deaths among women. It is one of the most common and the deadliest gynecologic cancer, with reported 14,436 deaths in 2009 and a projected incidence of about 21,980 and deaths of about 14,270 in 2014 [1,2]. About three-quarters of patients who present with peritoneal metastasis at the time of diagnosis [3,4] had a five-year survival rate of merely 26.9% [1,2]. Ovarian cancer is relatively asymptomatic at its early stages with rare cases of incidental early diagnosis due to other diseases or symptoms, and this led to low chance of early detection [3]. The Féderation Internationale de Gynécologie et d’Obstétrique (FIGO) developed an ovarian cancer staging system, the most common staging criteria used. A brief summary of each stage has been included in Table 1 [5]. Tumor cells could metastasize to within the vast capacity of the pelvis and the ovaries before stage III. By the time patients present with symptoms such as loss of weight, abdominal bloatedness and early satiety, metastasis had occurred into and beyond the peritoneal cavity. Although patients with low-risk, stage I cancer could expect to have a five-year-survival rate of greater than 90%, approximately 75% ⁎ Corresponding author. Tel.: +65 6514 8746. ⁎⁎ Correspondence to: X.J. Loh, Department of Materials Science and Engineering, National University of Singapore, 9 Engineering Drive 1, Singapore 117576, Singapore. Tel.: +65 6513 1612. E-mail addresses: [email protected] (H. Ye), [email protected] (X.J. Loh).

http://dx.doi.org/10.1016/j.msec.2014.06.002 0928-4931/© 2014 Elsevier B.V. All rights reserved.

of ovarian cancer patients present only in stages III and IV, having survival rates of 30%–50% and 13% respectively [6–9]. 2. Current treatment options Early stage ovarian cancer patients would undergo either prophylactic oophorectomy or salpingo oophorectomy, shown to greatly improve chance of survival. No chemotherapy is required post-surgery unless the tumors are of grade III and above. Patients with early stage ovarian cancer are currently undergoing clinical trials for chemotherapy and radiation therapy after surgery for additional benefits on survival [5,10–14]. The first-line standard treatment for advanced stage ovarian cancer patients includes an optimal cytoreduction surgery — tumors greater than a diameter of 1 cm are removed (most often via a minimally invasive laparoscopic surgery), followed by intravenous (IV) or intraperitoneal (IP) chemotherapy with a platinum-based agent such as cisplatin (Fig. 1A) and taxol such as paclitaxel (Fig. 1C) [8,15,16]. The IV therapy involves six cycles of IV platinum (75 mg/m2 of cisplatin or AUC 6 or 7 of carboplatin (Fig. 1B), calculated using the Calvert formula) and paclitaxel (135 mg/m2) once every three weeks [17,18]. Patients recommended for IP chemotherapy receive 135 mg/m2 of paclitaxel IV after the optimal cytoreductive surgery, followed by 100 mg/m2 of cisplatin and 60 mg/m2 of paclitaxel through an implanted catheter once every three weeks, for six cycles [18]. The catheter and its attached subcutaneous port for regular IP drug solution infusion are implanted during the cytoreduction surgery.

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Table 1 A description of the FIGO staging system for the diagnosis of ovarian cancer [5].

Early stages Late stages

Stages

Description

I II III

Tumor growth is confined to the ovaries. Tumor growth is confined to the pelvic region. Metastasis to the organs of the peritoneal cavity (omentum, small intestines, superficial surface of the liver etc) and/or regional lymph nodes. Distant metastasis beyond the peritoneal cavity.

IV

The Gynecology Oncology Group (GOG) had conducted three large randomized phase III trials, comparing IV cisplatin treatment regimens to IP cisplatin treatment [17–20]. The group concluded that IP cisplatin treatment regimen was able to prolong overall survival from 49.7 months in IV treatment to 65.6 months (p = 0.03) [18]. This vast improvement in overall survival of 16 months was rarely observed in clinical trials. However, while 83% of subjects completed all cycles of the IV therapy, only 42% of subjects completed all cycles of the IP therapy. The primary reason for early termination of the IP treatment was catheter-related complications [21,22]. The implantation site was susceptible to infection and inflammation over the entire 18 weeks period of treatment, and the long catheter was susceptible to obstruction [22]. Furthermore, many medical practitioners in smaller centers were unable to recommend the treatment modality due to lack of familiarity among clinicians with this intraperitoneal administration and catheter-placement techniques [18,23]. Additional criticism on IP chemotherapy was that although local drug concentration was higher than systemic drug concentration, the drug penetration depth into the tumor tissue was only around 1–3 mm [24–26]. IP chemotherapy would therefore only be recommended for patients with small residual tumors in the peritoneal cavity after the cytoreduction surgery [21,27]. This implied more extensive tumor debulking and therefore set more demanding criteria for surgery. For the reasons illustrated above, IP chemotherapy proved to benefit only a small portion of patients with advanced ovarian cancer. The most widely practiced first-line treatment regimen remained as six cycles of IV platinum (preferably carboplatin) with paclitaxel infusion once every three weeks. Carboplatin (Fig. 1B), an analog to cisplatin that was later developed with more tolerable side-effects in patients, had only been approved for IV administration. An ongoing clinical trial was conducted by the GOG (GOG 252), comparing treatment outcome of IV versus IP carboplatin with the maintenance of bevacizumab to verify carboplatin treatment in IP administration [28]. In general, poor treatment outcome and high relapse occurrence in ovarian cancer indicated further efforts to improve the therapeutic regimen for ovarian cancer patients.

3. Adjuvant therapies 3.1. Increased number of courses of treatment Two independent groups of researchers conducted clinical trials to investigate the effect of increased number of treatment courses on the outcome of treatment. One group compared five cycles versus ten cycles of treatment with cyclophosphamide, doxorubicin (Fig. 1D) and cisplatin at a frequency of one cycle for every four weeks. The results showed that ten cycles of treatment induced higher toxicity myelosuppression, hospital admission for nadir fever, nephrotoxicity and neurotoxicity than the five cycles of treatment while causing no improvement to the number of complete responses and survival [29]. A phase III clinical trial was also conducted to observe the effect of no further treatment versus six further courses of paclitaxel after the usual six courses of platinum and paclitaxel IV chemotherapy. The trial showed that the extra six courses of paclitaxel failed to prolong either OS or PFS [30].

3.2. Third therapeutic agent Attempts to improve the treatment outcome of ovarian cancer in recent years included the addition of a third cytotoxic agent to the current IV regimen [31]. A multinational collaborative phase III clinical trial was conducted by the Gynecologic Cancer InterGroup (GCIG) to investigate the change to the overall survival (OS) and progression-free survival (PFS) of advanced-stage ovarian cancer patients after either topotecan, gemcitabine or methoxypolyethylene glycosylated liposomal doxorubicin (PLD) was incorporated to the standard IV carboplatin and paclitaxel treatment regimen. Results from 4312 patient enrolled showed that the addition of the three agents did not cause any statistically significant improvements to OS or PFS. PLD will be described in detail in Section 3.3. 3.3. Liposomal formulation Doxorubicin belongs to a class of drug called anthracycline (Fig. 1D), a cytostatic antibiotic used to treat various types of cancers such as breast cancer, lymphoma, leukemia and ovarian cancer [32]. Anthracycline was used as the first-line treatment for ovarian cancer before the introduction of taxanes. Doxorubicin is a topoisomerase II inhibitor and promotes tumor cell DNA fragmentation. Its antitumor activity and drug toxicity can also be resulted from the formation of oxygen free radicals when doxorubicin is reduced inside the cell [33]. However, it is also associated with severe cardiotoxicities such as cardiomyopathy and congestive heart failure [32,34,35]. The pegylated liposomal doxorubicin or methoxypolyethylene glycosylated liposomal doxorubicin (PLD) as shown in Fig. 2 aimed to reduce the side effects of free doxorubicin and to enhance its antitumor activities. The liposomes, approximately 100 nm in diameter, prevent the drug from entering healthy tissues such as cardiac and gastrointestinal tissues, thus reducing its toxicity to those organs [35,37,38]. The poly (ethylene glycol) layer around the liposome is hydrophilic, preventing the attack of reticuloendothelial system in the systemic circulation. PLD has more favorable pharmacokinetics compared to free doxorubicin. The volumes of distribution of PLD and free doxorubicin in vivo were 4.1 L and 254 L respectively, and the plasma clearance rate was 0.08 L/h and 45.3 L/h respectively [33]. Consequently, the elimination half-life of PLD was found to be 20–30 h therefore PLD has a larger area under the concentration time curve (AUC) that is at least 60-fold that of free doxorubicin [39]. The promising pharmacokinetics of PLD called forth multiple phase I, II and III trials to investigate the treatment outcome of PLD in ovarian cancer patients at different stages of the disease progression. A randomized, multicenter phase III clinical trial was conducted to compare carboplatin/PLD regimen with the standard carboplatin/paclitaxel regimen in platinum-sensitive relapse or recurrent ovarian cancer patients after first- or second-line platinum/taxane-based therapies [40]. This trial involving 976 patients proved that carboplatin/PLD arm had a statistically significantly longer PFS of 11.3 months versus 9.4 months in the carboplatin/paclitaxel arm (p = 0.005, hazard ratio = 0.821). There was a higher incidence of alopecia, sensory neuropathy and hypersensitive reaction in the carboplatin/paclitaxel arm, while the carboplatin/PLD arm experienced more hand–foot syndrome, nausea and mucotitis [40,41]. The superiority of PLD in prolonging PFS and its reduced neurotoxicity suggested the possibility of including PLD as a first-line treatment agent. Two main phase III trials were conducted to compare the treatment outcome of carboplatin/paclitaxel versus carboplatin/PLD as a first-line treatment for ovarian cancer. The Multicenter Italian Trials in Ovarian Cancer-2 (MITO-2) enrolled 820 patients with stage III to IV ovarian cancer [41]. Carboplatin was dosed at an AUC of 5 (Calvert formula) and paclitaxel was dosed at 175 mg/m2 once every three weeks in the standard arm. The experimental arm dosed patients at AUC 5 of carboplatin and 30 mg/m2 of PLD once every three weeks.

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Fig. 1. The chemical structures of the common chemotherapeutic agents used in the treatment of ovarian cancer.

The MITO-2 trial showed no significant difference between PFS and OS for the two arms. The toxicity profiles of the two arms were, however, very different: the standard arm experienced significantly

worse alopecia, diarrhea and neuropathy, while the experimental arm had significantly more frequent and severe thromobocytopenia and anemia, skin and mucosal toxicities. These toxicities were

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Fig. 2. A schematic demonstrating the structure of the pegylated liposomal doxorubicin. Reproduced from reference [36] with permission.

consistent with the previous finding phase III clinical trial for recurrent ovarian cancer. Another multiple international phase III trial conducted by the Gynecologic Cancer InterGroup (GCIG) compared four other treatment regimens to the standard carboplatin/paclitaxel therapy [31]. 4312 women from across different countries and demographics were enrolled. The patients in the standard arm were treated with six courses of carboplatin (AUC 6) and paclitaxel (175 mg/m2) once every three weeks. One of the experimental arms was treated with carboplatin (AUC 6) once every three weeks and PLD (30 mg/m2) at once every alternate cycle, half the cumulative dose as MITO-2. This was to reduce the unacceptable risk of muscosal, skin and/or hematological side effects. The results showed no significant improvement to PFS and OS compared to the standard treatment of carboplatin and paclitaxel. These phase III trials on PLD as a first-line ovarian cancer treatment produced relatively consistent results. Carboplatin/PLD therapy showed a similar treatment efficacy (as observed from the lack of significant difference in PFS and OS) compared to carboplatin/paclitaxel but PLD resulted in a different toxicity profile. Patients could therefore be recommended for different treatment regimens based on their susceptibility to each type of side effects. 3.4. Hyperthermic intraperitoneal chemotherapy (HIPEC) Hyperthermia was proven to increase the cytotoxicity of cisplatin and other chemotherapeutic drugs (such as doxorubicin) in both cancer cell lines and animal models. The success was due to having a direct cytotoxic effect as well as a synergistic effect with drugs to enhance the elimination of tumor cells [42,43]. The elevated temperature could impair DNA repair mechanism, denature protein, induce apoptosis and inhibit angiogenesis [43–45]. Hyperthermia was also reported to improve the penetration depth of the chemotherapeutic agent into the tumors when delivered locally [46,47]. The most significant advantage of HIPEC was to enhance pharmacokinetics of drug. Studies have shown that at mild hyperthermia of 40.6 °C to 41 °C, the ratio of peritoneal to plasma area under the time concentration curve (AUC) of cisplatin was 6.9 and 21 respectively [48,49]. This improved retention time of cisplatin implied a more effective treatment. General administration of HIPEC occurred during surgery (or intraoperative), specifically after cytoreduction and before closure of the surgical incisions. The inflow Tenckhoff catheter was placed centrally in the peritoneal cavity or at a location with the highest recurrence probability. Two outflow catheters were placed below the diaphragm and at the lower pelvis area. Heated cytotoxic agent, typically 41 to 43 °C, was infused for 60 min or longer [43]. Manual stirring of the intraperitoneal organs during perfusion improved the temperature distribution. Temperature sensors might also be placed in the esophagus

or larynx to prevent excessive heating that might cause injuries to other healthy tissues. The first conclusive randomized clinical trial was conducted in patients with peritoneal carcinomatosis of colorectal origin in 2003 [50,51]. The study demonstrated that HIPEC had an improvement in the disease free survival (DFS) of 7.7 months in the control arm and 12.6 months in the HIPEC arm (p = 0.020). The median diseasespecific survival was also increased from 12.6 months in the control arm to 22.2 months in the HIPEC arm (p = 0.028) [50]. Since then, HIPEC had been broadly used to treat peritoneal carinomatosis of various origins such as gastric cancer, colorectal cancer, mesothelioma and pseudomyxoma [52–55]. Stage III and above ovarian cancer involves metastasis of tumors into the peritoneal cavity. This makes ovarian cancer a very suitable disease for the treatment with the combination of hyperthermia and intraperitoneal chemotherapy. Various clinical trials that involved hyperthermic IP chemotherapy were conducted either as the first-line treatment or as the second-line treatment for recurrent ovarian cancer patients. However, each of these studies was usually small-scaled and the treatment was administered at different stages of the disease progression. The lack of homogeneity of the studies resulted in a broad range of treatment outcomes. The largest study on HIPEC for ovarian cancer was a retrospective bicentric study that tracked the treatment outcome of 246 patients with peritoneal tumors from both recurrent and chemoresistant ovarian cancer. The five-year overall and free survival rates were 35% and 10% respectively with a median overall survival of 49 months and a median disease free survival of 13 months. This study concluded that HIPEC contributed to the longest median survival in recurrent peritoneal carcinomatosis from ovarian cancer [56,57]. These encouraging results presented hyperthermia as an easy-to-administer and promising addition to the intraperitoneal chemotherapy.

3.5. Immunotherapy Vascular endothelial growth factor (VEGF) played a key role in angiogenesis and disease progression in ovarian cancer. It has been shown that vascular endothelial growth factor (VEGF) was overexpressed in ovarian cancer cells but not in the normal ovarian tissues [9,58]. VEGF and angiogenesis correlated directly with the severity of ovarian cancer and inversely with PFS and OS [59–61]. Bevacizumab, a 149-kDa human monoclonal antibody directed against VEGF, is an FDA-approved drug for the treatment of various cancers such as metastatic colorectal cancer, breast cancer and non-small cell lung cancer [27,62,63]. Preclinical studies suggested that a combination therapy of bevacizumab and other chemotherapeutic agents such as doxorubicin, topotecan, paclitaxel, docetaxel, or radiotherapy could bring about synergistic tumor growth inhibition [64]. It was reported that bevacizumab changed vascular functions such that it caused an increase in intratumoral uptake of chemotherapeutic agents and resulted in delayed tumor growth and extended survival [62–65]. Fig. 3 describes the four main mechanisms by which bevacizumab helps reduce tumor progression by VEGF depletion [66]. Several phase II trials had shown promising results with bevacizumab [67,68]. One of the phase II clinical trials for the treatment of recurrent or persistent epithelial ovarian cancer (EOC) or primary peritoneal cancer (PPC) showed that bevacizumab was able to inhibit tumor progression when used as a single therapeutic agent [58]. The study involved 62 patients who had developed either primary or secondary platinum resistance and had undergone two to three doses of chemotherapeutic treatment. Bevacizumab was dosed at 15 mg/kg of patient’s body weight once every three weeks. This dose was derived from the halflife of bevacizumab in plasma over 21 days. The patients showed a median PFS of 4.7 months and a median OS of 16.9 months, with 40.3% of the patients surviving progression free for at least 6 months. Although there were some adverse side effects such as hypertension

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Fig. 3. Four primary mechanisms by which vascular endothelial growth factor (VEGF) depletion may affect tumor progression. (a, b) Vascular sensitization: VEGF acts as a survival factor for endothelial cells, and its removal by bevacizumab can sensitize the tumor vasculature to the cytotoxic effects of chemotherapy. This mechanism probably plays a role during the concurrent administration of chemotherapy and bevacizumab. (c, d) Angiogenic switch: tumors recruit vasculature to expand and VEGF is critical for triggering this expansion. By extraction of VEGF, bevacizumab is able to delay or even prevent angiogenesis and the growth of these tumors. (e, f) Metastatic delay: bevacizumab helps reduce the leakiness of the tumor blood vessels and therefore delay metastasis. (g, h) Control of the metastatic niche: VEGF affects the composition of immune infiltrates in the perivascular niche that supports metastatic tumor cells. With continuous suppression of VEGF, bevacizumab can hinder the growth of the metastatic tumors. This mechanism could be of particular importance in the maintenance setting with singleagent bevacizumab. Reproduced from reference [66] with permission.

and pulmonary embolism, the side effects were considered to be welltolerated. The success of such phase II trials led to three phase III trials for the treatment of both primary/first-line and recurrent ovarian cancer. The Gynecologic Oncology Group (GOG) from the United States and the International Collaborative Ovarian Neoplasm group (ICON) made up of various European countries each conducted a large-scale phase III trial for the treatment of primary ovarian cancer. Both studies compared the treatment outcome of ovarian cancer patients when treated with the standard IV carboplatin/paclitaxel treatment regimen (control

group), against the standard IV chemotherapy with the addition of IV bevacizumab (experimental group). The GOG study 218 recruited 1873 women and the bevacizumab group was dosed with 15 mg/kg once every three weeks. It showed a median PFS of 10.3 months in the control group and 14.1 months in the bevacizumab group, with a hazard ratio of 0.717 (p b 0.001). Although there was no significant difference in the median overall survival between the two groups, there was a 28% reduction in the risk of disease progression with the use of bevacizumab [69].

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In the ICON study 7, 1528 patients were enrolled in the study and bevacizumab was administered at 7.5 mg/kg once every three weeks. The median PFS at 42 months follow-up was 22.4 months for the control group and 24.1 months for the bevacizumab group (p = 0.04). A subset of the patients who were considered having high-risk for disease progression benefited more from the addition of bevacizumab with a median PFS of 14.5 months in control group and 18.1 months in the bevacizumab group, and a median OS of 28.8 months in the control group and 36.6 months in the bevacizumab group. There was an increased incidence of toxic side-effects in both studies (such as hypertension and gastrointestinal perforation) in the bevacizumab group [27]. The Ovarian Cancer Study Comparing Efficacy and Safety of Chemotherapy and Anti-Angiogenic Therapy in Platinum-Sensitive Recurrent Disease (OCEANS) conducted a randomized phase III double-blind study comparing the efficiency of the addition of bevacizumab to the gemcitabine and carboplatin treatment regimen for the recurrent ovarian cancer patients. The 484 patient study showed a median PFS of 12.4 months for the bevacizumab group versus 8.4 months in the placebo group, but there was also an increase in the incidence of hypertension and gastrointestinal perforation in the bevacizumab group [70], consistent with the GOG 218 and ICON-7 studies. These large phase III clinical trials clearly proved that the addition of bevacizumab to the current chemotherapeutic treatment regimen improved the treatment outcome of both primary and recurrent ovarian cancer. However, the increased systemic toxicity caused by bevacizumab resulted in early termination of the bevacizumab administration in some patients. Further work on the optimization of the delivery of bevacizumab could allow patients to benefit from bevacizumab treatment without suffering from its toxicities. 4. Drug delivery systems One other approach to improve the delivery of chemotherapeutic drugs for the treatment of ovarian cancer involved the drug delivery systems. Drug laden particles were administered either IV or IP to deliver various drugs. In principal, the approach regarded the particles as new drug formulation to release drug over an extended period. It usually aimed to prolong the biological half-life of the drug and extend the area under the concentration time curve (AUC). Correspondingly, some particles have the ability to be targeted to a particular cell type to minimize the drug-induced toxicity caused to the other healthy tissues. Other particles were capable of encapsulating the hydrophobic drug to improve its solubility in vivo. The size of these particles usually ranges between 10 nm to 100 nm. Particle size of less than 10 nm would be rapidly cleared by the kidneys and size larger than 100 nm would risk being recognized and eliminated by the macrophage cells in the blood stream [71,72]. This size range facilitates the preferential uptake of the particles by the tumors via the enhanced permeation and retention (EPR) effect. EPR occurred as a result of the leaky vasculature and impair lymphatic clearance in tumor tissues [73]. Moreover, as drug resistance and even multi-drug resistance have become a prevailing problem in chemotherapy, these particles aimed to reduce the drug resistance mechanism by reducing systemic exposure to the drug and improving drug retention inside the cancer cells. The first biodegradable polymeric nanoparticle formulations using poly (lactic-co-glycolic) acid have been reported in 1996. Various advancements in and modifications to the material and nanoparticle synthesis methods had been reported since. There had also been a recent interest in the use of naturally available protein cages such as viral particles as delivery vehicle [74,75]. For the treatment of ovarian cancer, most work had been done in the development of nanoparticles to deliver cisplatin, doxorubicin and paclitaxel. The polymers included poly lactic acid (PLA), poly (lactic-co-glycolic) acid (PLGA), poly (γ-Lglutamylglutamine) (PGG), poly (ethylene oxide)-modified poly (beta-amino ester) (PEO-PbAE), poly (ethylene oxide)-modified poly

(epsilon-caprolactone) (PEO-PCL), polypropylenimine (PPI) and so on [32,71,76–79]. In addition to varying the nanoparticle material, other surface modifications could be made to these nanoparticles for targeted delivery or enhanced drug stability. 4.1. Single agent delivery systems Most nanoparticles aimed to encapsulate or embed at least one chemotherapeutic agent for enhanced cancer treatment. A list of single agent delivery systems is shown in Table 2. Cisplatin, as previously mention, is the drug used in the first line of treatment of ovarian cancer but it is dose-limited primarily by nephrotoxicity. Multiple research groups had come up with ways to enhance the delivery of cisplatin to the tumors and reduce the toxicity to kidneys by means of surface-modifications as well as engineering the size and shape of the nanoparticles. A cisplatin nanoparticle was developed by complexing platinum (Pt) to each of the monomer units of polyisobutylene-maleic acid (PIMA) that is conjugated to glucosamine (GA) at various polymer to Pt ratios [71]. In vitro cell viability studies demonstrated that these PIMA-GA-CisPt nanoparticles are as efficient at killing Lewis lung carcinomas (IC50 = 4.25 ± 0.16 µM) as cisplatin (IC50 = 3.87 ± 0.37 µM) and is superior to carboplatin (IC50 = 14.75 ± 0.38 µM). Both a murine model bearing 4T1 tumors and a genetically modified K-rasLSL∕+∕Ptenfl∕fl ovarian cancer model were used to evaluate the treatment efficacy and toxicities of these nanoparticles compared to free cisplatin in vivo. The results showed that for the K-rasLSL∕+∕Ptenfl∕fl ovarian cancer model, free cisplatin (3 mg/kg) and PIMA-GA-CisPt (1.25 mg/kg) exhibited similar tumor inhibition with free cisplatin causing a greater reduction of body weight, indicating higher systemic toxicity. Increasing the dose of PIMA-GA-CisPt to 3 mg/kg resulted in more pronounced tumor growth inhibition without a significant increase in body weight loss. Kidney histology slides were stained for treatment-induced apoptosis to qualify the extent of nephrotoxicity. PIMA-GACisPt nanoparticles of both 1.25 mg/kg and 3 mg/kg caused less nephrotoxicity than the free cisplatin of 3 mg/kg. Measurements of cisplatin distributed to various tissues indicated that the PIMA-GACisPt nanoparticles lead to preferred drug distribution to the tumors and reduced drug concentrations in the kidneys, spleen and liver compared to free cisplatin. Paclitaxel is a chemotherapeutic agent commonly enhanced with a drug delivery system. Paclitaxel is a hydrophobic small molecule that has a logP of about 3.5 (DrugBank, DB01229). Due to its hydrophobicity and therefore low aqueous solubility, clinical formulation of paclitaxel dissolved it in dehydrated ethanol called Cremophor EL. Cremophor EL is biologically and pharmacologically active and is known to result in acute hypersensitivity [77,79]. ABI-007 (Abraxane®) was developed more recently to increase the solubility of paclitaxel without using Cremophor EL. It is an albumin-bound paclitaxel nanoparticle that has received the Food and Drug Administration (FDA) approval for use in treatment of non-small cell lung cancer, metastatic pancreatic cancer and recurrent breast cancer. It has been established as a good alternative to paclitaxel in Cremophor EL. A novel nanoparticle consisted of paclitaxel (PTX) linked to PGG via ester bond was developed by Feng et al. [79]. In vivo comparison in multiple murine xenograft models including an ovarian cancer model demonstrated superior tumor growth inhibition compared to ABI-007. In the 2008 human ovarian cancer xenograft model, the tumor volume at the end of the treatment period of 91 days was reduced by 75% when treated with these PGG-PTX nanoparticles compared to ABI-007 (p = 0.0025). The toxicity measured by animal body weight loss was 10% ± 1% for PGG-PTX and 7% ± 3% for ABI-007. This suggested that PGG-PTX nanoparticles have the potential to out-perform ABI-007 in improving the treatment outcomes of ovarian cancer. Nanoparticles could also be pH responsive for preferential release of drugs in the low pH tumor microenvironment. Paclitaxel-encapsulated

Table 2 Table of single agent delivery systems for the treatment of ovarian cancer.

Single agent delivery

Delivery vehicle

Nanoparticle Synthesis Method

Agent Delivered

Targeting Ability

Description

Reference

Polylactic acid

Ultrasonic emulsification

Paclitaxel

Lymph node targeting

Lu et al. [77]

Paclitaxel

–

Reduced tumor weight and ascites volume in vivo Induced apoptosis in vivo Lymphatic targeting to for enhanced drug delivery Three xenograft models used: NCI H460 human lung cancer, 2008 human ovarian cancer and B16 melanoma Enhanced solubility of paclitaxel Compared to Abraxane: - Produced significantly greater inhibition of tumor growth when given single equitoxic dose in vivo - Generated less weight loss in mice bearing H460 tumors The pH responsive nanoparticles release hydrophobic drug in the low pH of tumor interstitial microenvironment Tumor growth inhibited significantly after intravenous administration in SKOV3 nu/nu mice Improved therapeutic efficacy vs paclitaxel aqueous solution Lower toxicity profile vs paclitaxel aqueous solution CMV is a 29 nm icosahedral plant virus CMV rigid protein capsids provide natural molecular scaffold that allow precise modification for selectivity Significantly decrease the accumulation of doxorubicin in myocardial cells and improve the uptake of in the ovarian cancer, leading to less cardiotoxicity and enhanced antitumor effect in OVCAR-3 xenograft Selectively accumulate into tumors by the enhanced permeability and retention (EPR) effect Releases cisplatin in a pH-dependent manner at pH 5.5, mimicking the acidic pH of the endolysosomal compartment of the tumor The nanoparticles are rapidly internalized into the endolysosomal compartment of cancer cells Exhibit an IC50 comparable to that of free cisplatin, and superior to carboplatin Improved antitumor efficacy in terms of tumor growth delay in breast and lung cancers cells Tumor regression in a genetically modified ovarian cancer model Reduced systemic and nephrotoxicity with decreased biodistribution of cisplatin to the kidneys, spleen and liver compared to free cisplatin' SN-38 is a potent topoisomerase I inhibitor that is extremely hydrophobic and unstable Cellular uptake of PLGA-PEG-HA NPs was 8- and 16fold higher in CD44-positive cell lines, SKOV-3 and OVCAR-8, as compared to CD44-negative cells (CHO) in vitro

Poly-(γ-L-glutamylglutamine) (PGG)

Solvent displacement method

Paclitaxel

–

Cucumber mosaic virus (CMV) cages

Cucumber inoculated with CMV strain Fny. Viral RNA (CMV RNA) purified, dissociated CMV coat protein (CMV CP) collected, CMV particles were liberated by RNase treatment and dialysis

Doxorubicin

Folate acid to target the folate receptors on OVCAR-3 tumor cells

Glucosamine-functionalized polyisobutylene-maleic acid (PIMA), Platinum (Pt) complexed to the monomeric units using a monocarboxylato and an O → Pt coordinate bond

PIMA-GA monomer complexed to cis[Pt(NH3)2(OH2+)]through dicarboxylato linkages

Cisplatin

–

Hyaluronic acid (HA) decorated poly(lactic-co-glycolic acid)-polyethylene glycol (PLGA-PEG) nanoparticles

Single-emulsion (O/W) solvent evaporation method

SN-38

Hyaluronic acid targets CD44-positive ovarian cancer cells

Devalapally et al. [78]

Zeng et al. [32]

Paraskar et al. [71]

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pH responsive poly(ethylene oxide)modified poly(beta-amino ester) (PEOPbAE) and poly(ethylene oxide)-modified poly(epsilon-caprolactone) (PEO-PCL)

Feng et al. [79]

Vangara et al. [76]

615

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Fig. 4. A schematic illustration of the formation and structure of the CMV nanoparticle. Reproduced from reference [32].

PEO-PbAE (pH responsive) and PEO-PCL (non pH-responsive control) nanoparticles were developed with surface charges of +39.0 mV and −30.8 mV respectively [78]. Both types of nanoparticles were prepared by solvent displacement method. PbAE is biocompatible and easily degradable via hydrolytic reaction and would release paclitaxel slowly over time. The main advantage of these nanoparticles would be their easily tunable properties such as water-solubility, charge density,

crystallinity and degradation kinetics. These nanoparticles were tested in ovarian cancer cell line SKOV-3 orthotopic murine model, against the conventional IV administration of paclitaxel at a dose of 20 mg/kg. The tumor burden for the PEO-PbAE and PEO-PCL nanoparticles at the end of the treatment period of 25 days was 0.07 g and 0.13 g respectively, while the free paclitaxel group had a tumor burden of 0.35 g and control group a tumor burden of 0.54 g. There was no significant toxicity as

Table 3 Table of co-delivery systems for the treatment of ovarian cancer.

Co-delivery

Delivery vehicle

Nanoparticle Synthesis Method

Agent Delivered

Targeting Ability

Description

Reference

Poly(ethylene oxide)-modified poly(epsilon-caprolactone) (PEO-PCL)

Solvent displacement method

Paclitaxel Ceramide

–

Devalapally et al. [81]

Iron oxide nanoparticles modified with polyethylene glycol and luteinizing hormone-releasing hormone (LHRH) peptide

–

Doxorubicin Hyperthermia

LHRH target LHRH receptors in human ovarian cancer cells

Modified paclitaxelpolypropylenimine (PPI) dendrimer conjugate with α-maleimide-ω-Nhydroxysuccinimide ester polyethylene glycol (MAL-PEGNHS) and luteinizing hormonereleasing hormone (LHRH) 188Re-labeled albumin nanoparticles

–

CD44 siRNA Paclitaxel

LHRH target LHRH receptors in human ovarian cancer cells

Enhance intracellular ceramide accumulation providing favorable pro-apoptotic outcomes in cancer chemotherapy Resulted in significant tumor growth suppression in both SKOV3 and multidrug resistant SKOV3(TR) xenograft models Heat generated in an alternating magnetic field (AMF) synergistically increases cytotoxicity to drug resistant A2780/AD cell line Modified with PEG which improved its biocompatibility LHRH to target human ovarian cancer cells Induced cell death Suppress CD44 mRNA and protein in ovarian cancer cells Prevent metastases Decreased viability of ascitic cells

–

Cisplatin Radiotherapy Hyperthermia

Target folate receptors

Tang et al. [82]

Lipid-based nanoparticles

Oil/water microemulsion

Doxorubicin Paclitaxel

–

Supramolecular micelles — PEI-CyD (PC) composed of betacyclodextrin (beta-CyD) and polyethylenimine (PEI) and guest adamantine conjugated PTX (Ada-PTX)

–

Paclitaxel shRNA

–

The combination of cisplatin chemotherapy, radiation and hyperthermia inhibited tumor growth the most in the SKOV3 xenografts P-glycoprotein inhibition and ATP depletion: Doxorubicin and paclitaxel nanoparticles showed lower IC50 values in PEGylated paclitaxel nanoparticles showed marked anticancer efficacy in nude mice bearing resistant NCI/ADR-RES tumors Favorable to cell uptake and intracellular trafficking Efficient reduction in the survivin and Bcl-2 expression Synergistic cell apoptotic induction in the in vitro study Suppresses cancer growth more effectively than delivery of either paclitaxel or shRNA in ovarian cancer therapy

Taratula et al. [72]

Shah et al. [84]

Dong et al. [80]

Hu et al. [83]

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demonstrated by the animal body weight over the treatment period of 28 days and the complete blood count on Day 28. This demonstrated that a sustained release of paclitaxel from such a nanoparticle is efficacious in tumor treatment without inducing toxicities. Doxorubicin (Dox), another commonly used chemotherapeutic agent in the treatment of ovarian cancer is known to cause severe cardiotoxicity. To reduce its severity, a drug delivery system could be used for encapsulation and targeted release of doxorubicin. Zeng et al. utilized naturally available biological scaffold to synthesize a doxorubicinreleasing nanoparticle with the cucumber mosaic virus (CMV) [32]. CMV, a 29 nm icosahedral plant virus has a rigid protein capsid. Folic acid (FA) was conjugated to the amine group on the outer surface of the protein capsid to allow for the targeting towards folate-positive ovarian cancer cells. Dox was bound to the viral RNA within the viral particles (loading efficiency of 14.1% ± 0.5%). A schematic illustration of the CMV nanoparticles with doxorubicin encapsulated inside the viral capsule is shown in Fig. 4. The particles showed a linear sustained release profile in vitro. The release rate could be further controlled by the addition of RNase. Incubating these CMV-Dox and FA-CMV-Dox particles in mouse cardiomyocytes showed a reduced toxicity compared to free Dox. FA-CMV-Dox induced the highest cytotoxicity against OVCAR-3 human ovarian cancer cells in vitro as verified by the MTT cell viability assay and TUNEL staining. In vivo mouse xenograft also proved that the FA-CMV-Dox induced the greatest amount of apoptosis compared to free Dox, CMV-only and CMV-Dox as verified by tumor histology and TUNEL staining. Histology and macroscopic observations on the heart tissues also indicated a reduction in cardiotoxicity when treated with the CMV particles versus free Dox in vivo. This novel approach of using a plant virus as a carrier with folic receptor targeting ability for the delivery of doxorubicin demonstrated great potential in enhancing the treatment efficacy and reducing the cardiotoxicity of the free drug. It also offered a tool to investigate the mechanisms of doxorubicin-induced cardiotoxicity. 4.2. Co-delivery nanoparticles Drugs, antibodies and/or siRNA could be integrated into these nanoparticles to allow for the co-delivery of multiple agents [72,80–84]. Magnetic materials could also be incorporated into the nanoparticles both to induce direct heat-related cytotoxicity and to allow for thermal activation to enhanced cellular uptake. These various nanoparticles are listed in Table 3. An example of co-delivery was that of paclitaxel and ceramide using poly (ethylene oxide) modified poly (epsilon-caprolactone) (PEO-PCL) nanoparticles [81]. It was reported that ceramide accumulation inside the cancer cells would promote apoptosis and enhance the outcome of chemotherapy. However, ceramide could not be administered directly

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systemically due to its hydrophobicity, low cell permeability and high susceptibility to metabolic inactivation in the systemic circulation. Therefore, a paclitaxel and ceramide co-delivery biodegradable polymeric nanoparticle was developed to improve the treatment outcome of ovarian cancer. Using a dose of 20 mg/kg paclitaxel and 100 mg/kg ceramide, these co-delivery nanoparticles showed a 4.3-fold increase in tumor growth time, and a 3.6-fold increase in tumor volume doubling time compared to the no treatment control in SKOV-3 xenograft models. Tumor growth suppression was also demonstrated in the multidrug resistant SKOV-3TR xenograft model suggesting the potential to overcome drug-resistance with co-delivery of a pro-apoptosis agent. Systemic toxicity as measured by body weight changes and blood cell counts showed no difference between the different treatment regimens. These particles showed that co-administration of paclitaxel and ceramide enhanced tumor suppression, capable of overcoming drug resistance and induced less toxicity to the xenograft model in vivo. Various drug-siRNA co-delivery vehicles have also been developed in recent years. A novel dendrimer was developed, using polypropylenimine (PPI) as the base material, to effectively transport siRNA targeted to CD44 mRNA and paclitaxel [84]. CD44, a cell-surface glycoprotein, played a role on metastasis and cancer progression. It was hypothesized that the suppression of the CD44 cell surface marker with siRNA would prevent the development of metastasis and enhanced the efficiency of chemotherapy. As siRNA has poor ability of penetrating the cell membrane, a delivery vehicle had to be used. A polypropylenimine (PPI) dendrimer was developed to co-deliver the siRNA for suppression of CD44 and paclitaxel. A synthetic analog of luteinizing hormonereleasing hormone (LHRH) was also added for the additional tumor targeting function. In vitro and in vivo testing of such dendrimer demonstrated efficient tumor cell death induction and significant tumor growth retardation without causing toxic side-effects. The in vitro cell viability on malignant ovarian cancer cells was reduced more than 10-fold with respect to the untreated controls and more than 5-fold when compared to free paclitaxel. Advanced ovarian cancer patients treated with the intraperitoneal infusion of tumor-targeted siRNA and paclitaxel co-delivery dentrimers showed a complete suppression of tumor growth in xenografts. This PPI-based dendrimer helped to verify that the suppression of CD44 expression enhanced the antitumor activity of paclitaxel. In view of the promising outcomes exhibited by hyperthermic intraperitoneal chemotherapy (HIPEC), researchers have developed nanoparticles to combine hyperthermia and conventional chemotherapy [72]. Magnetic iron oxide nanoparticles could be surface engineered to become a delivery vehicle for doxorubicin, another drug used for the treatment of recurrent ovarian cancer patient [72]. Fig. 5 shows the schematic of the surface-engineered drug-loaded thermo-sensitive

Fig. 5. A schematic that explains the components of the surface-engineered drug-loaded thermo-sensitive nanoparticles. These nanoparticles were evaluated in multidrug resistant human ovarian cancer cell line A2780/AD. The red fluorescence image showed the high uptake of the nanoparticles by the cancer cells. The temperature–time plot shows the temperature change to the A2780/AD cells transfected with the nanoparticles when they were exposed to alternating magnetic field (AMF) of 33.5 kA/m and 393 kHz. Reproduced from reference [72] with permission.

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nanoparticles and how it co-delivers both a chemotherapeutic drug and heat. Drug release was then triggered by the application of an alternating magnetic field (AMF). In these paclitaxel thermo-sensitive nanoparticles, the encapsulation efficiency of 83% ± 3% was able to release paclitaxel 46 times higher at 43 °C compared to at 37 °C upon activation by AMF. These nanoparticles were tested on the human cervical cancer cell line (HeLa) and demonstrated superior cytotoxicity compared to hyperthermia or paclitaxel alone. The doxorubicin nanoparticle was also coated on the surface with luteinizing hormone-releasing hormone (LHRH) for targeting human ovarian cancer cells which expresses the LHRH receptors on their surfaces. The evaluation of these doxorubicin and LHRH thermosensitive nanoparticles was performed on the multidrug resistant human ovarian cancer cell line A2780/AD. It demonstrated that the combinatorial treatment with both hyperthermia and chemotherapeutic drug was able to eliminate more than 95% of the cancer cells, compared with nanoparticles with doxorubicin but without AMF or with nanoparticles with AMF but without doxorubicin encapsulated that resulted in only a 27% and 72% reduction in cell viability respectively. The combination of drug and heat delivery upon activation allowed better therapeutic outcomes with fewer side effects in the treatment of ovarian cancer. These multi-platform drug delivery systems described above and others listed in Table 3 hold promise for the future advancements in ovarian cancer and other cancer therapies. 5. Conclusion Ovarian cancer is one of the deadliest gynecologic cancers with high risk of drug-resistance and recurrence after rounds of chemotherapies. The standard-of-care for treatment would be via intravenous infusion of platinum-based agent (usually cisplatin or carboplatin) and a taxanebased agent (such as paclitaxel). A significant improvement of 16 months in the overall survival rate had been shown with the administration of these chemotherapeutic agents via the intraperitoneal route. However, catheter-related complications and stringent surgical requirements remained as limitations to the credibility of this method. Alternatives to current treatment options — increasing the number of courses and adding a third therapeutic agent to the drug combination showed minimal improvements to the treatment outcome. The IV administration of carboplatin/PLD resulted in similar efficacy but different toxicity profile compared to carboplatin/paclitaxel regimen and could be recommended to patients based on their risks to the side effects. Hyperthermic intraperitoneal chemotherapy (HIPEC) was able to prolong the median survival in recurrent peritoneal tumors and presented as a complementary addition to the IP treatment regimen. For IV therapy, bevacizumab improved the treatment efficacy of both primary and recurrent ovarian cancer. Nonetheless, it posed an increased risk for hypertension and gastrointestinal perforation. One other approach to improve treatment efficacy and reduced toxicity would be the use of drug delivery systems. These drug delivery systems could be engineered for a more targeted drug delivery of either one agent or multiple agents, with cancer cell-specific targeting functions and triggered drug release (such as in low pH or with the application of an alternating magnetic field). To date, these new drug delivery systems have only been tested in preclinical models. Advancement in treatment of ovarian cancer is currently being conducted in phases, suggesting promising development in the area. Proposing a new drug combination or delivery system capable of delivering a sound balance of efficacy and reduced toxicity would be greatly anticipated for clinical trials, and ultimately for the application into ovarian cancer treatment. References [1] American Cancer Society, 2013. [http://www.cancer.org/cancer/ovariancancer/ detailedguide/ovarian-cancer-key-statistics, Last Medical Review: 03/21/2013 Last Revised: 02/06/2014].

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