NANOTECHNOLOGY IN OVARIAN CANCER THERAPY
Zeeshan Ahmad*1, Usama Ahmad2, Juber Akhtar2 1 Makams Industries Private Limited, Bhiwadi, Alwar, Rajasthan-301019, INDIA 2 Faculty of Pharmacy, Integral University, Lucknow-226026, INDIA ABSTRACT Cancer remains the second foremost cause of death subsequent to cardiovascular disease. Ovarian cancer ranks as the fifth leading cause of death due to cancer in women, yet this disease only accounts for ~5% of all female cancer cases. In 2018, there will be just about 22,240 new cases of ovarian cancer diagnosed and 14,070 ovarian cancer deaths in the US. Nanotechnology is a field that can be defined as the practical application of nanoscience leading to a process or a product that is based upon individual or multiple integrated nanoscale components; nanoscale components having at least one dimension in the size range of 1–100 nm. One of the goals of nanotechnology is to develop the techniques used for diagnosis, therapy or combining both (theranostics) in various diseases including cancers. Particulate drug nanocarriers like liposomes, polymeric micelles, niosomes, polymeric nanoparticles and solid lipid nanoparticles have exceptional 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. Normally, conventional chemotherapy applications result in rapid blood clearance, degradation, poor drug accumulation in tumor tissues due to poor penetration capacity, undesirable side effects rooting from drug distribution to healthy tissues and multidrug resistance (MDR). Nanotechnology-based drug delivery systems can be helpful for the controlled delivery of chemotherapeutics by means of location and duration without unwanted side effects by overcoming several drug delivery barriers through passive or active targeting strategies. Key Words: Ovarian cancer, Nanocarriers, Theranostics, Chemotherapeutics
INTRODUCTION In 2018, there will be approximately 22,240 new cases of ovarian cancer diagnosed and 14,070 ovarian cancer deaths in the US. Ovarian cancer accounts for just 2.5% of all female cancer cases, but 5% of cancer deaths because of the disease’s low survival. This is largely because 4 out of 5 ovarian cancer patients are diagnosed with advanced disease that has spread throughout the abdominal cavity. Improving the ability to detect ovarian cancer early is a research priority, given that women diagnosed with localized-stage disease have more than a 90% five-year survival rate. 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. 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).
CLINICAL TRIALs FOR OVARIAN CANCER USING NANOFORMULATIONS
WHAT IS OVARIAN CANCER? The ovaries are a pair of reproductive glands, each about the size of a grape, located on either side of the uterus. They produce eggs that travel through the fallopian tubes into the uterus, where they are fertilized for reproduction. In premenopausal women, the ovaries are the primary source of the hormones estrogen and progesterone, which maintain the health of the female reproductive system. The three major types of ovarian cancer are epithelial, accounting for 90% of cases, germ cell (3%), and sex cord-stromal (2%). Epithelial cancers are further subdivided into serous (52%), endometrioid (10%), mucinous (6%), and clear cell (6%) tumors. The process of epithelial ovarian tumor development has long perplexed researchers. As biological understanding has evolved, epithelial subtypes are increasingly characterized as distinct diseases with different molecular pathways, risk factors, and treatment. Serous tumors are mostly high-grade serous carcinomas, which are characterized by involvement of ovaries, aggressive behavior, late stage diagnosis, and low survival. Accumulating evidence suggests that these tumors actually originate in the epithelial cells of the fallopian tube as microscopic preliminary lesions that subsequently migrate to the ovaries and/or peritoneum (the lining of the pelvis and abdominal cavity), where they are diagnosed. In addition to their common origins, tumors of the fallopian tube and peritoneum are very similar to epithelial ovarian cancer in appearance and behavior, and are now often studied jointly. In contrast, endometrioid and clear cell tumors are thought to originate in the endometrium (lining of the uterus), while mucinous tumors may originate in the ovaries or fallopian tube-peritoneal junction; these subtypes typically affect only one ovary.
NANO DRUG DELIVERY SYSTEMS IN OVARIAN CANCER Drug
Paclitaxel
Parthenolide / Doxorubicin Dosetaksel / gadolinium
Irinotecan / Doxorubicin
Cisplatin / Paclitaxel
R547
Paclitaxel
Delivery System
Targeting Ligand Follicle stimulating hormone polypeptide
Nanoparticle
Micel
Nano-emulsion
Liposome
Micel
Nano-crystal Hydrogel
REFERENCES
PEG-PLA
-
PSMA-b-PS PMSA-b-PBA
Folic acid
Egg lecithin DSPE-PEG2000 DTPA-PE
-
Telo-dendrimer
Carrier Material
-
Transferrin
-
DSPC, Cholesterol
Compound Name
Formulation
Hyaluronic acid
Status for ovarian cancer
Trial No.
Doxorubicin
FDA approved
Liposomal lurotecan Nanoparticle bound albumin paclitaxel
Lurotecan
Phase II Phase II, Approved for breast, small cell and pancreatic cancers
Xyotax
Paclitaxel poliglumex
Paclitaxel
Phase II
Nanotax
Nanoparticle suspension
Phase I
NKTR-102
Etirinotecan pegol
Paclitaxel Topoisomerase I inhibitor
NCT00945139, NCT00862355, NCT00248248 NCT00010179 NCT00466986, NCT00407563 NCT00060359, NCT00017017 NCT00666991
Phase II
NCT00806156103
Doxil
PEGylated liposomal doxorubicin
OSI-211 Abraxane, ABI-007
ACTIVE TARGETING One of the key parameters for anticancer nanocarries is targeting ligands in addition to size and surface properties. In ovarian cancer, highly expressed cell-surface proteins include the folate receptor, EGF receptor (EGFR, HER2), luteinizing hormone receptor, claudins, mucins, and integrins.
Results
Paclitaxel
PASSIVE TARGETING Nano drug delivery systems for targeting tumors are based on the delivery of anti-tumor drugs within nanocarriers capable of targeting tumor tissues by taking advantage of the physiological and pathological characteristics of tumors. The superiority of nanoparticulate systems in cancer treatment is mainly based on the enhanced permeability and retention (EPR) effect of the surrounding vessels of the tumor. Increased accumulation of nanoparticles in tumor sites is due to the abnormal vasculature with a 200-800 nm pore size; whereas normal vessel endothelium has 5-10 nm pores. These wider pores result in the leakage of tumor vessels and reduced lymphatic drainage leading to an EPR effect and accumulation of nanoparticles in the tumor tissue.
NANOCARRIES
Improved cellular uptake Higher drug concentrations in lymph nodes Decreased tumor volume Increased survival time Improved internalization, efficacy and higher cytotoxicity Significantly improved cytotoxicity Extended period of accumulation at tumor site Improvement in therapeutic efficacy due to an increase in systemic drug exposure, with the maintenance of the synergistic molar drug ratio of 1:1 in circulation
Higher cytotoxicity Higher accumulation at the tumor site, (III)PEG5K (COOH)8-L-CA8 antitumor activity Improved Pharmacokinetic
mPEG-PE
Active agent
Improved interaction of Tf-modified micelles with A2780 ovarian carcinoma cells Higher in vitro cytotoxicity Decreased in vivo tumor growth inhibition studies in A2780-tumor bearing mice Greater cytotoxicity and antitumor effect micro particulate PTX gel and free drug Extended survival of tumor-bearing mice
CONCLISION Nanotechnology can be a solution for obstacles of ovarian cancer treatment. Recent studies along with developments in nanobiological fields, nanotechnology was found to have extensively investigated for molecular imaging, drug delivery, treatment and tumor targeting. Drug nanocarriers 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. The use of nanotechnology for ovarian cancer therapy medical care is gaining more and more important day by day due to their admirable properties and potential results. It’s clear that nanoparticle-based technology are going to be a very important a part of up tumour targeting, drug efficaciousness, and toxicity profiles of recent promising methods..
Delie F, Allemann E, Cohen M. Nanocarriers for ovarian cancer active drug targeting. J. Drug Deliv. Sci. Technol., 2012;22(5):421-6. Hascicek C, Gun O. Nano drug delivery systems for ovarian cancer therapy. Integr Cancer Sci Therap., 2017;4(2):1-4. www.cancer.org/content/dam/cancer-org/research/cancer-facts-and-statistics/annual-cancer-facts-and-figures/2018/cancer-facts-and-figures-special-section-ovarian-cancer-2018.pdf
PRESENTED AT “8th VIRTUAL NANTECHNOLGY POSTER CONFERENCE-2018” Organized By: The International NanoScience Community, Budapest, Hungary