Journal of Pharmaceutical and Biological Sciences

Journal of Pharmaceutical and Biological Sciences ISSN: 2320-1924; CODEN: JPBSEV Published by Atom and Cell Publishers © All Rights Reserved Available online at: http://www.jpabs.org/ Review Article

Solid lipid nanoparticles a tool combating Ovarian Cancer Pragya Nigam, Bina Gidwani, Anshita Gupta, Chanchal Deep Kaur* Shri Rawtpura Sarkar Institute of Pharmacy Kumhari, Durg (C.G.), India Received: 05-05-2016 / Revised Accepted: 13-07-2016 / Published: 25-08-2016

ABSTRACT The most common type of cancer, comprising more than 95% of cases is ovarian carcinoma. Survival of the patients is dependent on the disease stage of the patients such as stage I, II, III, and IV ovarian cancer have median 5-year survival rates of approximately 93%, 70%, 37%, and 25%, respectively. Ovarian cancer increases from 35 year and reaches a peak between the ages 55-64. In 2012, ovarian carcinoma occurred in 239,000 women and resulted in 152,000 deaths worldwide. Various chemotherapeutic agents provide health effective benefits in ovarian cancer. Considerable works have been done on herbal constituents, synthetic drug and there combinations have been marketed as anticancer drugs. The use of nanotechnology in drug delivery contributes to their nano size (10 – 100 nm), which improves the circulation, therapeutic effectiveness, reduces side effects of the drug, provides long circulation half-lives, enhanced permeation and retention effect. The use of solid lipid nanoparticle provides uniform drug targeting at the active site in desired concentration and improved therapeutic efficacy. SLN enhance the bioavailability of the poorly soluble herbal drug. Keywords: ovarian carcinoma, chemotherapeutic, Solid lipid nanoparticles, bioavailability

INTRODUCTION

Classification of epithelial ovarian cancer

Ovarian cancer is lethal gynecologic malignancy. It appears that the vast majority of primary epithelial ovarian and primary peritoneal carcinomas is, in fact, secondary from the fimbria, the most distal part of the fallopian tube.[1] Women having two ovaries which located in pelvis and both side of uterus. The main function of ovaries is to produce female hormones and eggs. Increase in oxidative stress results high risk of ovarian cancer. [2] Common areas to which the cancer may spread includes lining of the abdomen, lining of the bowel and bladder, lymph nodes, lungs, and liver. [3] The risk of ovarian cancer mainly increases in women who have ovulated more over their lifetime. This include those women who have never had children, those who begin ovulation at a younger age or reach menopause at an older age.[4]

Ovarian cancer is classified in two categories: Type I: This type of tumors is clinically indolent and usually present at a low stage. Type I tumors include: a) low-grade serous b) low-grade endometrioid c) clear cell d) mucinous carcinomas Type II: These tumors exhibit papillary, grandular, and solid patterns, are highly aggressive and almost always present in advanced stage. Type II tumor include: a) high-grade serous b) high-grade endometrioid c) undifferentiated carcinomas.[1,5,6]

*Corresponding Author Address: Chanchal Deep Kaur, Shri Rawtpura Sarkar Institute of Pharmacy Kumhari, Durg (C.G.), India; email: [email protected]

Kaur et al., J Pharm Biol Sci 2016; 4(5): 160-169

Stages Of Ovarian Cancer [7,8] S. No. 1.

Stages I IA IB IC

Description Tumor is completely limited to the ovary. It involves one ovary; capsule intact, no tumor on ovarian surface. It involves both ovaries; capsule intact; no tumor on ovarian surface. Tumor is in the ovary and on the surface of one ovary.

2.

II IIA IIB IIC

Pelvic extension of the tumor involves one or both ovaries Cancer found on uterus or fallopian tubes. Tumor has spread to the bowel or bladder. Tumor cell also found in the fluid of the abdomen.

3.

III

Tumor found outside the pelvis or in the retroperitoneal lymph nodes, involves one or both ovaries. Tumor cell are in the lining of the abdomen. Cancer of 2cm. or smaller are in the lining of the abdomen. Tumor is in the lymph nodes.

IIIA IIIB IIIC 4.

IV IVA IVB

Involves distant metastasis (i.e. outside of the peritoneum). Pleural effusion containing tumor cells. Cancer distant organs (including the parenchyma of the spleen or liver), or metastasis to the inguinal and extra-abdominal lymph nodes.

Figure.1: Stages of Ovarian Cancer Signs and symptoms: The early stages of ovarian cancer to be painless unless the growing mass causes ovarian torsion[9]. The typical symptoms include bloating, abdominal or pelvic pain or discomfort, back pain, irregular menstruation or postmenopausal vaginal bleeding, pain or bleeding after or during sexual intercourse, difficulty eating, loss of appetite, fatigue, diarrhea, indigestion, heartburn, constipation, nausea.[10]

Risk Factors: Mainly the risk for ovarian cancer is related to the amount of time spent in ovulation. Thus not having children is the risk factor for ovarian cancer,because ovulation is not suppressed due to pregnancy. Both obesity and hormone replacement therapy also responsible for the risk[9]. Various factors are:

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Hormones: Use of fertility medication contribute to ovarian tumor formation [11]. Those who have treated for infertility are at higher risk for epithelial ovarian cancer,however, those who are successfully treated for the infertility and subsequently give birth are at no higher risk. This may be due to the shedding of precancerous cells during pregnancy [12] . Genetics: The major genetic risk factor is a mutation in BRCA1 or BRCA2 DNA mismatch repair genes, which present in 10% of ovarian cancer cases. The gene may be inherited through either the maternal or paternal line, but has variable penetrance [12].Though mutations in these genes are associated with increased risk of breast cancer [9] . Environmental factors: Industrialized nations have high rates of epithelial ovarian cancer, which may be due to diet in those countries. White people are at a 30-40% higher risk for ovarian cancer. White women have fewer children and different rates of gynecologic surgeries that affect risk for ovarian cancer [12] . Other factors: Increased age (up to the 70s) is a cause for epithelial ovarian cancer because more mutations in cells can accumulate and eventually cause cancer [12].

Smoking tobacco is associated with higher risk of mucinous ovarian cancer [13] . Trans men who have ovaries may at higher risk of ovarian cancer. Potential factors include testosterone therapy [14]. Higher levels of C-reactive protein are also associated with a higher risk of developing ovarian cancer.[15] Prevention: People who have strong genetic risk for ovarian cancer may consider the surgical removal of their ovaries as a preventative measure. This is done after completion of childbearing years. This reduces the chances of developing breast cancer (by around 50%) and ovarian cancer (by about 96%) in people. Women associated with BRCA gene mutations usually also have their Fallopian tubes removed at the same time (salpingo-oophorectomy).[16] Drug Used in Ovarian cancer (A) Synthetic drug used in ovarian cancer: For the treatment of ovarian cancer various chemotherapeutic cytotoxic drug are used. These drugs are used either alone or in combination. The details of marketed products of synthetic drugs are discussed in table 1.

Table 1: Marketed drug products used in ovarian cancer S.N o. 1.

Name Drug Paclitaxel

of

Category Mitotic Inhibitor

Marketed Product Altaxel

Dosage

Route

30mg/5ml

Intravenous

Betaxel

100mg/ml

Intravenous

2.

Carboplatin

Alkylating Agent

Biocarb Blastoplatin Carboteen

15ml,450mg 450mg 150mg

Intravenous Intravenous Intravenous

3.

Cisplatin

Alkylating Agent

Cisplan Cisplat Cismax

50mg 100mg,50mg 10mg,50mg


4.

Docetaxel

Plant Alkaloid

Docemax

120mg,20mg, 80mg

Intravenous

5.

Doxorubicin

Antibiotics

Dobixin Doxobin Adriamycin

25ml 50mg 50mg


6.

Melphalan

Alkylating Agent

Alkacel

5mg

7.

Topotecan

Miscella-neous

Cantop

2.5mg

Intravenous

Topotel

2.5mg

Intravenous

162


8.

Gemcitabin

Anti Metabolites

Gemzar

200mg

Intravenous

9.

Irinotecan

Plant Alkaloid

Camptosar

20mg

Intravenous

10.

Etoposide

Mitotic Inhibitor

Actitop

100mg

Intravenous

Eside

50mg

Capsule

Hexalen

50mg

Capsule

11.

Altretamine

Alkylating Agent

3)

Drugs Used In Combination: Sometime single drug is unable to treat ovarian cancer completely. In this situation it is essential to follow combination therapy. The various combination of chemotherapeutic drugs used in the long-term treatment of ovarian cancer are as follows: 1) Carboplatin-Paclitaxel[17] 2) Gemcitabin-Cisplatin[17] Table 2: List of Herbal constituents [21,22] S. No Plant Family

4) 5)

Paclitaxel-Cisplatin[18] Docetaxel-Carboplatin[19] Docetaxel-Gemcitabin[20]

(B) Herbal Phytoactives Used In Ovarian Cancer: Various herbal constituents are used in the treatment of ovarian cancer discussed below:

1.

Taxus baccata

Taxaceae

Active Constituent Docetaxel

2.

Taxus brevifolia

Taxaceae

Paclitaxel

3.

Andrographis paniculata

Acanthaceae

Andrographolide

4.

Catharanthus roseus

Apocynaceae

Vincristine,

5.

Ginkgo biloba

Ginkgoaceae

Ginkgetin

6.

Glycine max

Fabaceae

Genistein

163

Structure


7.

Gossypium hirsutum

Malvaceae

Gossypol

8.

Oldenlandia diffusa

Rubiaceae

β –Sitosterol

9.

Panax ginseng

Araliaceae

Ginsenoside

10.

Podophyllum hexandrum

Podophyllaceae

Podophyllotoxin

11.

Rubia cordifolia

Rubiaceae

Rubiadin

12.

Viscum album

Santalaceae

Digallic Acid

13.

Zingiber officinale

Zingibera-ceae

Zingerols

 

Nanotechnology: Nanotechnology is the preparation of Nanosized structures containing the API [23]. Nanotechnology, is defined as the study and use of structures in the size range of 1 to 100 nm. The goal of nanotechnology is to diagnose as accurately and early as possible and to treat as effectively as possible without any side effects using controlled and targeted drug delivery approach [24]. Important Drug Delivery System developed using Nanotechnology principles areNanoparticles, Solid Lipid Nanoparticles, Nanosuspension, Nanoemulsion, Nanocrystals [25]. Nanoparticles are the nanosized particles, which transport pharmaceutical agents to achieve improved or enhanced pharmacological effects. The use of nanotechnology with combination chemotherapy provides synergistic in drug delivery. Advantages of nanoparticle-based drug delivery therapy are:

   

It enhances therapeutic effectiveness Reduces side effects of the drug payloads by improving their pharmacokinetics properties Provides long circulation half lives Enhanced permeation and retention effect Drug safety Patient compliance

Some of the nanoparticles used in ovarian cancer are:  Liposomes  Niosomes  Dendrimers  Lipid nanoparticles  Polymeric nanoparticles  Polymeric micelles Solid Lipid Nanoparticles Introduction: Solid Nanoparticles are the nanosized particles, which transport pharmaceutical 164


agents to achieve enhanced pharmacological effects [26] . It is a sub-micron colloidal carriers ranging from 50 to 1000 nm, which are composed of physiological lipid, dispersed in water or in aqueous surfactant solution. SLN has unique properties such as small size, large surface area, high drug loading and the interaction of phases at the interface and are attractive for their potential to improve performance of pharmaceuticals [27].

Surface erosion proceeds at constant velocity. For bulk eroding polymers such as poly (d,l-lactic acid) (PLA) and poly(d,l-lactic-co-glycolic acid) (PLGA),things are more complicated as they have no constant erosion velocity.[32] SLN have versatile potential for efficient exploitation of different drug delivery formulation & routes because of the property provide by the small size. nanoparticles have greater efficiency in enhancing permeation of drug into skin.[33]

SLN are manufactured from synthetic or natural polymers and suited to optimize drug delivery and reduce toxicity. The successful implementation of SLN for drug delivery depends on their ability to penetrate through several anatomical barriers, sustained release of their contents and their stability in the nanometer size [28,29] .

Advantages of SLN  Control or target drug release.  Its easy to scale up and sterilize.  Its better control over release kinetics of encapsulated compounds.  It Enhanced bioavailability of entrapped bioactive compounds.  Chemical protection of incorporated compounds.  Much easier to formulate than biopolymeric nanoparticles.  special solvents are not required.  It provide very high long-term stability.[27,34]

Nanoparticles are effective formulation for encapsulating wide variety of drugs from small molecular weight compound to larger molecules. Now nanoparticles are more focused on herbal drug formulations. Drug release from nanoparticles is either through by bulk erosion in the matrix or by surface erosion in the polymer depend on the nature of drug and method of preparation adopted [30] .

SLN have Possibility of controlled drug release, Increased drug stability, High drug pay load, No bio-toxicity of the carrier, Avoidance of organic solvents, incorporation of lipophilic and hydrophilic drugs[27,35]

Polymer containing Reactive groups such as anhydrides tend to fast degradation therefore show surface erosion whereas polymers containing less reactive groups i.e., esters tend to bulk erosion [31].

Fig. 2: Structure of solid lipid nanoparticle (SLN)

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Surface erosion Bulk erosion Fig 3 : Mechanism of drug release Methods of preparation of nanoparticles[36]

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Solid lipid nanoparticles for some important drugs used in Ovarian Cancer:  Qing et. al. in 2014 reported docetaxel-loaded solid lipid nanoparticles (DSNs) to reduce systemic toxicity of docetaxel. The DSNs showed lower cytotoxicity as compared with the docetaxel (Taxotere) and induced more apoptosis at 24 hours after treatment in vitro.[37]  Shahrooz et.al. in 2013 evaluated a nanoparticulate system with mucoadhesion properties composed of a core of polymethyl methacrylate surrounded by a shell of thiolated chitosan (Ch-GSH-pMMA) for enhancing oral bioavailability of docetaxel (DTX). DTX-loaded nanoparticles prepared by the emulsion polymerization method using cerium ammonium nitrate as an initiator. The pharmacokinetic study carried out in vivo using wistar rats.DTX-loaded NPs showed more specific permeation across the Caco-2 cell monolayer in comparison to the DTX.[38]  Zhang et.al. in 2013 reported docetaxel nanoformulations which can improve its water solubility, minimize the side effects and increase the tumor-targeting distribution by passive or active targeting.[39]  Sarah et.al. in 2014 evaluated a PEGylated liposomal nanoencapsulation of doxorubicin.[40]  Yumei et.al.in 2009 investigate nanoparticles containing liposomal doxorubicin which localize chemotherapies to lymphatic tissues. Animal study indicate that nanoparticles made up of natural or synthetic polymers and liposomal carriers have higher accumulation in the lymph nodes and surrounding lymphatics compared to conventional intravenous therapies. This combination of therapeutic agent has potential to both reduce nonspecific organ toxicities and increase the chemotherapeutic dose to the most likely sites of locoregional cancer metastasis. [41]  Parviz et.al.in 2014,studied Hyaluronate targeted SLNs containing etoposide which increased the cytotoxicity of etoposide on SKOV-3 cells which helps in reducing the prescribed dose and systemic side effects of this drug in epithelial ovarian carcinoma. The cytotoxicity of targeted and nontargeted SLNs of etoposide were compared to free drug on the SK-OV-3 cells by MTT assay method.[42]  Varshosaz et.al.in 2014 evaluate hyaluronan (HA) targeted solid lipid nanoparticles (SLNs) of etoposide by an emulsification-solvent evaporation method and physically coated with HA.Optimized formulation of SLNs was obtained by SA, the equal proportion of cetyl















alcohol and cationic lipid, the ratio of 1.5 for lipid to HA, and 10% of organic phase to aqueous phase.[43] Bhattacharyya et.al.in 2014 formulate polypeptide nanoparticles containig Gemcitabine which overcome the limited efficacy and systemic toxicity of current Gemcitabine. The novel polypeptide drug delivery system where Gemcitabine is covalently attached to a genetically engineered chimeric polypeptide (CP) through a pH sensitive linker such that covalent conjugation of multiple copies of Gemcitabine at one end of the CP triggers the formation of sub 100 nm size nanoparticles that are ideal for targeting solid tumors through enhanced permeability and retention (EPR) effect.[44] Lee et.al. in 2013 developed an urokinase plasminogen activator receptor (uPAR)targeted magnetic iron oxide nanoparticles (IONPs) carrying chemotherapy drug gemcitabine for targeted delivery into uPARexpressing tumor and stromal cells thus it helps in overcoming the physical barrier of the stroma.[45] Cucinotto et.al.in 2013 investigated albumin bound paclitaxel nanoparticles. Nabpaclitaxel enhance the activity and reduce the toxicity of chromophore-diluted compound.[46] Wang et.al.in 2014 develop Cisplatin-alginate conjugate liposomes with enhanced efficacy and minimal adverse effects.[47] Yuan et.al.in 2014 investigate transferrin modified docetaxel-loaded long circulating liposome for ovarian tumor to To reduce the toxic effect on normal cells and improve the treatment effects of docetaxel. The transferrin-modified long-circulating liposomes loaded with docetaxel (TF-LPDOC) prepared by post-insertion method and exhibited excellent characteristics in terms of particle size, encapsulation efficiency and stability. In vitro and in vivo results showed that TF-LP-DOC were successfully established and presented an enhanced targeting ability.[48] Sarah et.al.in 2014 studied PEGylated liposomal nanoencapsulation of doxorubicin.[49] Shen et.al.in 2015 investigate the impacts of a novel liposome-encapsulated paclitaxel.[50]

Conclusion Cancer is an abnormal malignant growth of tissue. A cancerous growth is called a malignant tumor or malignancy. A noncancerous growth is called benign tumor. This paper will concentrate on the herbal traditional constituents, synthetic approaches and their combination helpful in ovarian cancer. 167


SLN offer unique properties such as small size, large surface area, high drug loading and the interaction of phases at the interface thus it helps in enhancing the effectiveness, efficacy of medication and also helpful in reducing the adverse effect of herbal/synthetic constituents. The study indicates that solid lipid nanoparticles of different chemotherapeutic agent help in survival of patient of ovarian cancer.

Acknowledgment The authors are thankful to Management and Principal, for providing the necessary facilities for this work. The authors acknowledge Chhattisgarh Council of Science and Technology, 1106/ CCOST/MRP/2015 for providing financial assistance to this work.

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