Perspectives of Nanoemulsion Strategies in The Improvement ... · Perspectives of Nanoemulsion Strategies in The Improvement of Oral, Parenteral and Transdermal Chemotherapy Manisha

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Perspectives of Nanoemulsion Strategies in The Improvement of Oral, Parenteral and Transdermal Chemotherapy

Manisha Pandey1*, Hira Choudhury1, Ong C. Yeun2, Hoh M. Yin2, Tan W. Lynn2,

Celine L.Y. Tine2, Ng S. Wi2, Kelly Chau C. Yen2, Cheng S. Phing2,

Prashant Kesharwani3, Subrat K. Bhattamisra4 and Bapi Gorain5*

1Department of Pharmaceutical Technology, School of Pharmacy, International Medical University, Kuala Lumpur

57000, Malaysia; 2Bachelor of Pharmacy student, School of Pharmacy, International Medical University, Kuala Lum-

pur 57000, Malaysia; 3Pharmaceutics Division, CSIR-Central Drug Research Institute, Lucknow, UP, 226031 India; 4Department of Life Sciences, School of Pharmacy, International Medical University, Kuala Lumpur 57000, Malaysia; 5Faculty of Pharmacy, Lincoln University College, Petaling Jaya, Selangor, 47301, Malaysia

Abstract: Background: Targeting chemotherapeutic agents to the tumor tissues and achieving accu-

mulation with ideal release behavior for desired therapy requires an ideal treatment strategy to inhibit

division of rapid growing cancerous cells and as an outcome improve patient’s quality of life. Howev-

er, majority of the available anticancer therapies are well known for their systemic toxicities and mul-

tidrug resistance.

Methods: Application of nanotechnology in medicine have perceived a great evolution during past few

decades. Nanoemulsion, submicron sized thermodynamically stable distribution of two immiscible liq-

uids, has gained extensive importance as a nanocarrier to improve chemotherapies seeking to over-

come the limitations of drug solubilization, improving systemic delivery of the chemotherapeutics to

the site of action to achieve a promising inhibitory in tumor growth profile with reduced systemic tox-

icity.

Results and Conclusion: This review has focused on potential application of nanoemulsion in the

translational research and its role in chemotherapy using oral, parenteral and transdermal route to en-

hance systemic availability of poorly soluble drug. In summary, nanoemulsion is a multifunctional

nanocarrier capable of enhancing drug delivery potential of cytotoxic agents, thereby, can improve the

outcomes of cancer treatment by increasing the life-span of the patient and quality of life, however,

further clinical research and characterization of interactive reactions should need to be explored.

A R T I C L E H I S T O R Y

Received: February 20, 2018

Revised: May 06, 2018 Accepted: June 01, 2018

DOI:

10.2174/1389201019666180605125234

Keywords: Chemotherapy, nanoemulsion, active targeting, oral chemotherapy, intravenous chemotherapy, transdermal chemo-therapy.

1. INTRODUCTION

According to the GLOBOCAN 2012, cancer is the major cause of morbidity and mortality worldwide [1-3]. There were around 14 million new cases of cancer and 70% rise in new cases is expected in the next 2 decades. According to the World Health Organisation (WHO), it has been estimated in 2015 that approximately 8.8 million deaths globally

*Address correspondence to these authors at the Faculty of Pharmacy, Lin-coln University College, Kelana Jaya, Selangor 47301, Malaysia; Tel: +603-

7806-3478; Fax: +603-7806-3479; E-mails: [email protected]; [email protected], Dr. Manisha Pandey, Department of Pharmaceutical

Technology, School of Pharmacy, International Medical University, Bukit Jalil, 57000, Kuala Lumpur, Malaysia; Tel: +6032317575;

E-mail: [email protected]

occurred due to cancer [4]. It leads to about 1 in 6 deaths globally. Lung, liver, colorectal, stomach, and breast carci-nomas are the most common causes of cancer death, with incidences of 1.69, 0.788, 0.774, 0.754, and 0.571 million deaths, respectively [4]. With respect to gender, lung cancer is the most common form of cancer in men (3240 cases) fol-lowed by colorectal, nasopharynx, prostate, and stomach cancer in Malaysia based on the WHO Cancer Country Pro-file 2014 [5]. On the other hand, breast cancer is the most commonly diagnosed cancer among women (5410 cases) followed by cervix uteri, colorectal, lung, and ovary cancer. Besides that, lung cancer and breast cancer also have the high-est mortality rate per 100,000 with age standardisation in men and women, respectively [5].

Perspectives of Nanoemulsion Strategies in The Improvement of Oral Current Pharmaceutical Biotechnology, 2018, Vol. 19, No. 4 277

To reduce the mortality rate due to cancer, there are several cancer therapies available in the market, such as chemotherapy, immunotherapy, radiotherapy, targeted therapy, and surgery [2, 3, 6-8]. The main goal of the treatment is to increase the life span and improve quality of life of the patient by curing can-cer [4]. A specific regimen of treatment, which consists of one or more modalities, is required for different cancer types. Hence, it is important to obtain the correct cancer diagnosis in order to achieve effective treatment on time [2]. For in-stance, chemotherapy will be specified to patients who have small cell lung cancer [9, 10], but most of the patients with non-small cell lung cancers (NSCLC) in stage I and II re-ceive surgery whereas those in stage III and IV receive chemotherapy alone or with radiation [3, 10]. Other than chemotherapy and surgery, immunotherapy against T cells’ programmed cell death receptor, and targeted therapy drugs, such as anaplastic lymphoma kinase are used in NSCLC [3]. Alternatively, androgen deprivation therapy, prostatectomy, radiation, or combination are used to treat prostate cancer [3, 7]. Abiraterone and enzalutamide are the newer form of hormone therapy that are approved recently to treat advanced prostate cancer [3].

Besides that, transdermal or systemic route of administration of cytotoxic drugs are also available in cancer treatment when oral administration is not favourable. For example, topical and injectable formulations of 5-Fluorouracil (5-FU) is available in current market to enhance its systemic bioavailability and pre-vent adverse effects caused by its oral administration [11]. Although there are advancements in current therapies, the success rate is very limited [6, 12], which may be due to some inherent factors, such as poor aqueous solubility, low oral bioavailability, short half-life, serious side effects, lack of specificity, etc. [2, 13-15]. Similarly, use of hormone therapy can increase the risk in cardiovascular disease and also death [16, 17]. Hence, long term treatment using chemo-therapy drugs is not suitable [3].

Although oral route is the most common and preferable routes of drug administration, low oral bioavailability or drug-food interaction can lead to failure in chemotherapy [18]. For instance, toxoids (docetaxel (DTX) and paclitaxel (PTX)) have poor water solubility and undergo rapid efflux due to high affinity to P-glycoprotein (P-gp), which ultimately lead to poor bioavailability [19]. Simultaneously, use of lycobetaine (LBT) in treating lung cancer is limited due to its short half-life (only 30 seconds in blood) [12]. Besides oral administration, systemic administration also shows some limitation due to low bioavailability. To illustrate this, tocotrienols (T3) used in skin cancer treatment have lipophilic nature and hence low water miscibility and absorption from the site of administration [20]. Less than 10% of bioavailability was achieved after a single bolus dose of 10 mg/kg T3. Patients feel uncomfortable due to pain at injection site because of frequent dosing because of rapid fluctuation of drug plasma level [18]. In addition, serious autoimmune-related side effects or even death by im-munotherapy drugs (such as ipilimumab used in melanoma) may occur [3, 21]. Immune mediated toxicities such as pneumonitis and nephritis can also be caused by immuno-therapy drugs for lung cancer treatment [3]. Surgery, radio-therapy, and some chemotherapies can lead to infertility as they affect the reproductive organs in males and females. For example, radical prostatectomy and radioactive iodine in

thyroid cancer treatment can lead to erectile dysfunction [3, 22]. As a result, a more selective delivery system is needed in order to transport hydrophobic chemotherapeutic drugs to achieve a more successful therapeutic effect and target spe-cifically on cancerous cells [2, 18, 23]. Connecting section of the article has been emphasized with the modern nanotech-nology based drug delivery systems incorporated in cancer therapy.

2. TREND OF RECENT NANOTECHNOLOGICAL RESEARCH IN CANCER THERAPY

2.1. Different Nanocarriers in Cancer

Chemotherapy is the mainstay treatment for cancer, but it has a few setbacks typically in the use of conventional thera-peutic agents. These agents are often accompanied by un-wanted side effects and systemic toxicity, which hampers the use of the chemotherapeutics safely by the patients. Further, non-specificity causes them to target both healthy and can-cerous cells which is another reason for the setbacks [23]. In recent years, important outcomes with acceptable pharmaco-logical properties of various nanocarriers, such as micelles, liposomes, solid-lipid carriers, carbon nanotubes, nanoemul-sions, nanoparticles, solid lipid nanoparticles, polymeric micelle, nanoemulgel, and dendrimers, have been explored and developed to cater for several illnesses, including tumor, and targeting therapies [24-31]. Modifications of physico-chemical properties of the chemotherapeutics with nanocar-riers ensures therapeutic success of the treatment, amongst lipid base nanocarriers, which received greater attention by the researchers worldwide.

Liposomes are spherical vesicles containing an internal aqueous core that stores hydrophilic drugs and is surrounded by phospholipid bilayer that stores hydrophobic drugs [32]. Examples of chemotherapeutic drugs in which liposomes are used as carrier to get better efficacy and reduced toxicities include doxorubicin (DOX) and cisplatin. Cardiotoxicity and neurotoxicity are the reported side effects that comorbid these drugs respectively [33, 34], In cancer therapy, DaunoXome and Doxil are two known clinically-approved marketed lipo-somal based delivery system for the treatment of either Ka-posi’s Sarcoma or both ovarian and recurrent breast cancer [35, 36]. A lyophilized liposome-based PTX (LEP-ETU) has also been developed by Zhang et al. to increase the drug’s solubility without affecting the particle size or precipitation of drug. An in vitro study of LEP-ETU has showed a <6% release of entrapped PTX, proving that the formulation is stable at physiologic temperature [37]. There are many other potentially effective liposomal formulations of chemothera-peutic drugs still undergoing pre-clinical and clinical trials.

Micelles are colloidal dispersions made from amphiphilic block copolymers. Compared to liposomes, they have a smaller size, which permits them to escape from circulation through the vascular damage present at tumor sites to target the tumor tissues. In addition, the poor lymphatic drainage at these sites which is also known as enhanced permeability and retention (EPR) effect contributes to the effectiveness of the entrapped cytotoxic agents [33]. There are a rising num-ber of micellar-based formulations currently in the different stages of clinical trials, such as, NK911, SP1049C, NK105, and NC6004 [33]. Zhu and partners designed nano-sized

278 Current Pharmaceutical Biotechnology, 2018, Vol. 19, No. 4 Pandey et al.

micelles that when present in water will produce a positively charged surface through the formation of cationic micelle with PDMAEMA-PCL-PDMAEMA triblock copolymer. Their aim is to successfully deliver VEGF siRNA and PTX chemotherapeutic drugs [38]. Recently, the addition of tar-geting ligand into these micellar-based formulations are in the rise and have successfully shown to be more cytotoxic particularly to the cancer cells. For example, ovarian carci-noma cells were more susceptible to the cytotoxic effects of micelles containing folate than the non-targeted micelles [39].

Dendrimers are highly branched macromolecules [40]. They possess host-guest entrapment properties through en-capsulation process, electrostatic interactions, and covalent conjugations [28, 38]. Poly(amidoamine) (PAMAM) and poly(propyleneimine) dendrimers have been widely studied as carriers for cancer drug delivery [41]. Sanyakamdhorn et al. suggested that the encapsulation process involves hydro-gen bonding between the cancer drugs and the -NH groups in the interior of PAMAM. The encapsulation of chemothera-peutics is also due to the hydrogen bonding and electrostatic interactions with dendrimers’ surface amino groups [40]. Han and partners introduced peptide HAIYPRH (T7)-conjugated PEG-modified PAMAM dendrimer (PAMAMPEG-T7) for the co-delivery of pDNA and DOX. Between individual DOX or pDNA delivery system and the co-delivery system, the latter initiated tumor cells apoptosis in vitro and sup-pressed tumor growth in vivo more effectively [38].

Polymer-drug conjugates have a biodegradable linker to covalently connect low water soluble drugs to water-soluble polymer, which enables it to accumulate at tumor sites via the EPR effect. PEGylated drugs such as Oncaspar and PEG intron have been marketed to use for the treatment of acute lymphoblastic leukemia and other cancers [42, 43]. Besides that, Trastuzumab emtansine which is a monoclonal anti-body-drug conjugate is also an approved delivery system used to treat breast cancer [37].

2.2. Advantages of Nanoemulsion from Others

Toxicological evaluation of most of the nanocarriers has not yet been completely revealed, hence preclinical and clin-ical studies are required to identify any underlying toxicity of these carriers. On the other hand, nanoemulsions are hetero-geneous dispersions of two-phase mixtures of insoluble liq-uids (water-in-oil/oil-in-water) stabilized by surfactants to prevent the dispersed phase and continuous phase from coa-lescing [44, 45]. Usually in nanoemulsion, the continuous phase is aqueous and the hydrophobic drug often is trans-ported in the oil phase of the emulsion with a mean droplet size of 50-200 nm (Fig. 1) [14]. Oils and surfactants used in nanoemulsions have acquired safety recognition through the various testing, and only the GRAS (generally recognized as safe) components are more widely and successfully utilized by the researchers [46]. Generally, nanoemulsions are more superior than the other conventional dosage forms in terms of specificity in delivering the drugs to the target site, greater bioavailability and stability, availability in different formula-tions and many others [14].

Nanoemulsions’ ability to protect chemically unstable compounds from oxidative degradation and degradation by

UV light are additionally advantageous for the drug stability [47]. A special feature nanoemulsions possess is the defense against certain bacteria, fungi and viruses. Accumulation of

these droplets at the epidermis and dermis of the wound al-lows them to directly distort the organisms [48]. Besides that, the size of therapeutic nanoemulsions enables the drop-lets to cross through pores and hair follicles in a manner without disrupting healthy tissues, therefore, they have a low report for skin irritation [47]. Comparing nanoemulsions with macroemulsions and coarse emulsions, the former has greater surface area and free energy as well as the absence of complications such as inherent creaming, sedimentation and coalescence [6]. Nanoemulsions and liposomes possess a few common properties when delivered topically such as diminished side effects, and enhanced physical stability.

However, liposomes are inferior to nanoemulsions in terms of the lesser cost of preparation [49]. In vaccine delivery, nanoemulsions are considered a better carrier as it is able to stay in the circulation for a longer period, and are highly taken up by antigen presenting cells. Shi et al. reported a study on the effectiveness of nanoemulsion vaccine in co-delivering immunostimulatory CpG and a gastric cancer-specific antigen MG7 against MG7-expressing cancer cell. The results showed that mice which were pre-immunized with nanoemulsion vaccine co-encapsulating MG7 and CpG had their tumor growth significantly inhibited [23]. In anoth-er example involving heterotropic and lung metastatic tumor

models, higher concentration of LBT was found in the tumor site when PEGylated LBT–OA–nanoemulsion was adminis-tered as compared to free LBT. The inhibitory effect and survival time of the LBT nanoemulsion was also greater in comparison to the free LBT [46]. These results clearly sug-gest that nanoemulsion could be a suitable carrier for vaccine delivery in the immunization against cancer and other patho-genic organisms. Additionally, in comparison to suspension to hydrophobic drug nanoemulsion have greater advantage as Tagne et al. demonstrated that nanoemulsion of tamoxifen (TAM) have higher anticancer properties towards breast can-cer as compared to TAM suspension. This is due to the

greater zeta potential and smaller particle size of the nanoemulsion of TAM that helps with the increased drug permeability [50]. Formulating lipophilic drugs in oil-in-water nanoemulsion are advantageous because of its self-assembled nature that is inherently sensitive to its surround-ings. On top of that, the oil phase of the nanoemulsion sys-tem helps to solubilize the lipophilic drug to be stored in it. Since the lipophilic drug’s solubility is increased, therefore lesser administration volumes are required to that of aqueous solution [51]. In this context, Chen et al., incorporation of ethyl oleate, Tween 80, or PEG400 formulations into nanoemulsions further increases the solubility of low water-

soluble drug like Resveratrol thereby increasing the drug loading [52]. An important feature of nanoemulsion is that it can protect the encapsulated drugs from enzymatic degrada-tion and hydrolysis as well as from the detection of macro-phages. An added advantage of oil-in-water nanoemulsion formulation is that the encapsulation of hydrophobic drug prevents the immediate contact with body fluids and tissues thereby minimizing tissue irritation caused by any pharma-cokinetic incompatibility.


3. TUMOR MICROENVIRONMENT

Tumor microenvironment (TME) refers to the complex tumor tissues which are composed of extracellular matrix (ECM), activated fibroblasts, immune cells, pericytes, adipo-cytes, epithelial cells, glial cells, vascular cells, lymphatic endothelial cells, and proteins [23, 53]. The components of the TME support the physiology, structure, and function as an environment that promotes the tumor to progress into a malignant phenotype especially the ECM which support the growth, migration, invasion, and metastasis of tumor [23,53]. The different type of cells of the TME have different cell-special markers which expressed on the cells surface and these markers can act as the target site for the drug delivery systems [23].

There are significant differences between tumor tissues and normal tissues from the following aspects: angiogenesis, vascular abnormalities, oxygenation, perfusion, pH, and metabolic states [54]. Angiogenesis is the process of the de-velopment of new blood vessels from pre-existing blood vessels. This process occurs normally during fetal develop-ment, tissue regeneration, wound healing and in the female reproductive cycle. However, angiogenesis also involved in the development of various diseases like cancer [54]. When the tumor tissue reaches over 2 mm3, the core of the tumor will expose to hypoxic condition. Hence, the tumor tissue will stimulate angiogenesis to ensure the presence of oxygen and nutrients for further growth [23, 53]. Moreover, it also helps the tumor tissues to remove waste products, delivers immune cells, macrophages, and humoral factors [55]. This indicates that tumor tissues depend on the angiogenesis for their active growing and this could be the potential target therapy for treating cancer. Based on this hypothesis, angio-genesis inhibitors are developed to inhibit this process. For examples, VEGF-neutralizing antibody: Bevacizumab (Avastin), Ramucirumab (Cyramza) [53-56] and VEGF sig-naling pathways blockers: Sorafenib (Nexavar), Sunitinib (Sutent), Pazopanib (Votrient) are the currently clinical available angiogenesis inhibitors for the treatment of various types of cancers [23, 54, 56]. These inhibitors prolong the survival rate of the responsive patients in terms of months but the toxicity, drug resistance and delivery problems re-main as the main challenges for cancer therapy. Nanoemul-sion delivery systems are current technology used to encap-sulate the angiogenesis inhibitors and this system helps in reducing toxicity and improving the therapeutic efficacy [23]. Dehelean et al. had shown that the betulinic acid

nanoemulsion can efficiently inhibit the angiogenesis pro-cess as this system increase the delivery efficiency [57].

Apart from that, the TME has pH of around 6 to 7, which is slightly acidic compared to healthy tissues and blood (pH 7.4). This difference provides a design internally controlled drug delivery system for cancer therapy. The drug in this system has been designed in order to stabilize at normal physiological pH however, rapidly destabilized in the acidic environment in the TME. The pH mediated cellular uptake of perfluorocarbon (PFC) nanoemulsions has studied by Pat-rick et al. in rat glioma cells with real-time pH measurement. They found out that intracellular pH changed from 6.7 to 5.5 over three hours’ uptake experiment and this indicated that the nanoemulsion migration from neutral cytosomes to acid-ic lysosomal compartments over this time period [58]. Nanoemulsion delivery system that used in the treatment for pH sensitive tumor have shown improvement in anticancer efficacy and reduced chemotherapy related toxicity [23].

4. MECHANISM FOR IMPROVED BIOAVAILABIL-ITY WITH NANOEMULSION

The conventional chemotherapeutic agents exert its ac-tion by killing rapidly proliferating cells as well as divisible normal cells. This leads to systemic toxicity(ies) which are unwanted and unacceptable [23]. As discussed earlier, nanoemulsion nanocarrier can deliver either small hydro-phobic drug molecules or other macromolecules like antigen-ic proteins and peptides. It can deliver locally or systemically to tumor resulting in potent humoral and cellular antigen-specific immune responses [59]. For instant, the delivery of MAGE-1 HSP70/SEA encapsulated within a nanoemulsion has shown an increase in the tumor-specific responses and protection when compared to the non-encapsulated delivery [60].

Moreover, nanoemulsion delivery system also increases the intratumoral accumulation of chemotherapeutics drugs which then reduce the therapeutic dose [23]. Cao et al. had proven that the co-encapsulated DOX and bromotetrandrine lipid nanoemulsion showed improved cytotoxicity due to increased intracellular uptake in DOX-resistance human breast cancer cells when compared to DOX lipid nanoemul-sion [61]. Melphalan incorporated in nanoemulsion had shown higher values of bioavailability in treatment of ovari-an cancer compared to the free drug as they enhance the re-tention time in the tumor [62].

Fig. (1). Molecular structure of entrapment of lipophilic agents in oil-in-water nanoemulsion.


4.1. Solubility Enhancement and Permeability Improve-ment

The unique structure of the nanoemulsion system is ad-vantageous with improved solubility of drugs, because it provides both, lipophilic and hydrophilic environments. This delivery system also increases mucosal permeation, prevents P-gp efflux, prevention of premature degradation of drugs, decreases liver by-pass and thus increased availability of drugs in systemic circulation [29]. Further, improvement of bioavailability of incorporated drugs in nanoemulsion can be explained by improved solubility within the gastro-intestinal fluid, and decreased rate of gastric emptying [63]. Huge in-crease in the interfacial area due to the formation of nano structured dispersed droplets, and integration of permeation enhancers (e.g., D-α-tocopheryl polyethylene glycol 1000 succinate, hydroxypropyl-β-cyclodextrin, Lipoid E 80, sodium taurocholate, etc.) also contributes towards enhancement of drug bioavailability. These permeation enhancers aid to open the tight cellular junctions temporarily, and thereby promote permeation of the drug molecule [63, 64].

Delivery of drugs through transdermal route need to cross the outermost horny epidermal layer, stratum corneum. Percutaneous absorption of drugs is important to cross the dense impermeable layer. The interesting fact is that this stratum corneum swells several folds in the water than in dry condition. Thus, when delivered nanoemulsion formulation, the dispersed phase act as reservoir for the drug whereas the continuous phase ensures wetting of the skin layer [65]. All these attractive properties allow nanoemulsion to explore as potential delivery tool through different routes of drug admin-istration via enhancement of solubility and permeability.

4.2. Lymphatic Transport

Due to formation of lipoproteins, several researchers have suggested facilitation of lymphatic transport of the lipophilic agents. Administration of nanoemulsion formulation into gas-tro-intestinal route allows formation of mixed micelles of the oil droplets with bile salts, and internalize into the enterocytes

through clathrin mediated enterocytosis with the help of aque-ous layer and mucin, and thus reach to the systemic circulation via portal veins or through the lymphatic system [66]. Corre-spondingly, other studies suggested that oil in water nanoemulsion will be better absorbed than the oil solution of corresponding lipophilic drugs [67]. Cho et al. had reported that dispersed oil droplets facilitate transportation of incorpo-rated drugs including long chain fatty acids by digestion of the lipids. Thereby, digestion process aids in solubilisation and transportation of the drugs to the enterocytes and facili-tate formation of chylomicrons within the enterocytes, which in turn facilitate transportation of lipophilic components into lymphatic channel. Therefore, the authors concluded that smaller droplet size in nanoemulsion facilitate absorption of lipophilic components into systemic circulation [68].

4.3. Passive Targeting

Since tumor tissues depend on angiogenesis for survival and metastasis, therefore tumor sites have poorly developed tumor vasculature. This leads to pericyte deficiency, abnor-mal basement membrane and fenestration that accounts for the increased in vascular permeability [53]. This causes raise in interstitial fluid pressure and unevenness of blood flow, oxygenation, nutrient, and distribution of drug in the TME, which lead to increase hypoxia and thus, facilitates metasta-sis. The tumor cells are lack of lymphatic system, which leads to increase in the retention time of drug as their growth compresses the lymph vessels especially in the central por-tion of the tumor and causing collapse. This leads to the poor lymphatic drainage from tumor cells and causes delays in the clearance of macromolecules, which accumulated in the solid tumor tissues. The combination of increase vascular permea-bility and poor lymphatic drainage is known as the EPR effect. This effect serves to deliver several nanotechnological deliv-ery effectively to the tumor tissues (Fig. 2) [23]. However, EPR effect can be achieved via intravenous delivery of the nanoemulsion, where the nanoemulsions accumulate within the tumor microenvironment by this effect [53].

The EPR effect is mainly observed for biocompatible

Fig. (2). Nanoemulsion–based drug delivery exploiting tumor microenvironment by passive targeting mechanism.


macromolecules such as macromolecular drugs and lipids. The mechanism of EPR effect for macromolecules are reten-tion whereas for low molecular weight is the returning to blood circulation by diffusion [29]. Generally, the ideal size of nanoemulsion is to control within the diameter range of 20-100 nm in order to ensure the accumulation of the drugs in tumor tissues but not penetrate to normal vessel walls to decrease side effects towards normal cells (Fig. 2) [14]. Their small size helps in avoiding them from mononuclear phagocytic system (MPS) in the liver but their size is also large enough for them to preclude fast renal clearance. Hence, this indicates that the particle with this size are able to circulate in the blood for longer period. For increasing the circulation half–life and therapeutic effect, the surface of the nanoemulsion can be modified with the hydrophilic poly-mers, like polyethylene glycol (PEG), poloxamer, etc. It can suppress the blood protein adsorption and recognition by MPS cells, thereby facilitate EPR [23].

Furthermore, other researches revealed that the positively charged particles are more easily taken up by tumor cells and retained for a longer time as compared to negatively charged or neutral particles. This is because the surface of tumor cells is translocated with a negatively charged residue which is known as phosphatidyl serine [23]. The encapsulated dauno-rubicin with dextran and chitosan directly on nanoemulsion liquid core formed positively charged particles and localized delivery showed improved antitumor efficacy against colon MC38 cancer cells. This is due to the electrostatic interac-tions between the positively charged nanocarrier with the negative charged cancer cells [69].

However, passive targeting also has various limitations like inability to actively distinguish between normal tissues from tumor tissues. This is because the passive targeting is not feasible in all tumors as different tumor types have dif-ferent degree of tumor vascularization and fenestration of blood vessels [23].

4.4. Active Targeting

Attaching various ligands on the surface of the nanoemulsion can help to recognize active target within the tumor and/or affected organ, tissue, cells or intracellular or-ganelles and this mechanism is known as active targeting [23]. The ligands commonly used are monoclonal antibodies or antibody fragments, antigen binding fragments, and single chain variable fragments [70]. The active targeting delivers the drug to the tumor site by binding to the receptors or substrates that express on the target cancer cells such as engineered anti-bodies, folic acid, transferrin, enzymes like hyaluronic acid (HA) and aptamer which is a short DNA sequence (Fig. 3) [23, 70, 71]. However, this mechanism needs the exclusive expression of receptors on the target cancer cells and the expression should be homogenous across all targeted cells. The active targeting mechanism increases the cytotoxicity to tumor tissues and reduce the delivery of toxic drugs to nor-mal tissues [23]. Like passive targeting mechanism, this ac-tive targeting is also limited to parenteral delivery of the adorned nanoemulsions [29]. Ganta et al. had shown that the folate-targeted nanoemulsion improved its cytotoxicity by decreasing 270-folds in the concentration of DTX needed for inhibiting growth of cells by 50% (IC50) when compared to

DTX alone. This proved that the folate-targeted nanoemul-sion can be designed to target the folate receptor-positive ovarian tumors [72]. The PTX loaded polyurethane nanocar-rier decorated with folic acid (PTX-PU-NP-FA) had shown about 90% of fraction of apoptotic cells in tumors and this indicates the effectiveness in therapeutic effect of folate-targeted nanoemulsion [73]. Afizal et al. had proven that the transferrin targeted-DTX lipid nanoemulsion reduce the sys-temic toxicity but improve the antitumor activity when com-pared to free drug [74].

Therefore, combination of surface charge modification and stimuli sensitivity like sensitivity towards pH, enzyme, magnetic field, temperature, ultrasound, and UV light can also be a part of active targeting [23]. Jiang et al. incorpo-rated the cationic polymer chitosan and target ligand biotin on the surface of PLGA nanocarrier. They evaluated the ef-fect of surface charge of nanoparticle along with targeting ligand on the cellular uptake and found in increased cellular uptake by the synergistic effects of electrostatic interaction and receptor-mediated internalization [75]. Hence, it can be concluded that the increased cellular uptake is not affected by the size of nanocarrier, besides this is able to facilitate the tumor cell adsorption and tissue retention of drug as the acid-ic TME increases its zeta potential.

5. OUTCOMES OF RECENT NANOEMULSION BASED CHEMOTHERAPY

Delivery of nanoemulsion can be approached by different routes of administration to obtain better efficacy and bioa-vailability with decreased toxicities of cytotoxic drugs. Such routes involve oral, parenteral, and transdermal. The follow-ing section will provide evidences of improved delivery of nanoemulsion in different delivery routes.

5.1. Delivery of Nanoemulsion Using Most Preferred Oral Route

In the recent years, the development of nanoemulsions-based delivery system via oral route has gained attentions in the treatment of cancer. Nanoemulsions aid in drug delivery system by protecting and delivering lipophilic drugs by coat-ing and preventing them from being damaged by several environmental factors like pH and hydrolytics enzymes [47]. Oral route administration become the most commonly used route for systemic delivery because it is convenient, cheap, easy to use, and preferentially preferred by patients. Howev-er, oral administration of anticancer drugs becomes a chal-lenge due to its low oral bioavailability, poor solubility, sta-bility, and high drug efflux through P-gp transporters in the lumen [14, 76]. This can overcome by introducing nanoemulsion delivery system in order to enhance solubility, stability, absorption, and bioavailability of drug. There is a wide variety of anticancer drug used to deliver using nanoemulsion delivery system to increase oral bioavailabil-ity. Pangeni et al. used oxaliplatin (OXA) in combination with 5-fluorouracil (5-FU) for the treatment of resectable and advanced colorectal cancer. Due to poor membrane permea-bility of OXA, deoxycholic acid derivative (DCK) is used as a permeation enhancer in order to improve oral bioavailabil-ity. The results of membrane permeability test in Caco-2 cell monolayer showed 4.80- and 4.30- fold increase in mem-


brane permeability of OXA/DCK and 5-FU in comparison to free OXA and 5-FU. Simultaneously, the oral bioavailability of OXA/DCK and 5-FU in the nanoemulsion system were 9.19- and 1.39- folds greater than those OXA and 5-FU, re-spectively. Thus, using of oral nanoemulsification technique the absorption of OXA/DCK and 5-FU has been increased, resulting in inhibition of growth of tumor in the colorectal cancer in mice in in vivo model [77].

Li et al. developed oil-in-water nanoemulsion system of berberine hydrochloride (BBH) to enhance its permeability, stability and oral bioavailability. In bioavailability study, the BBH nanoemulsion showed 440.40% relative bioavailability in rat as compared to unencapsulated BBH. In addition, the intestinal permeability of BBH increased when tested with Caco-2 cell monolayers. The efflux of BBH through P-gp transporters in the lumen also decreased which indicates that oil droplets of the nanoemulsion aids in improving absorp-tion of BBH [78]. Besides that, Zhang et al. used low-energy emulsification method to develop nanoemulsion for pterostilbene due to its low solubility and stability. Based on the solubility and stability test, the nanoemulsion delivery system enhanced the solubility and stability as well as in vitro release of pterostilbene also improved (96.5% in pH 3.6 buffer; 13.2% in pH 7.4 buffer) compared to pterostilbene suspension (<21.4% in pH 3.6 buffer; 2.6% in pH 7.4 buffer) [79].

Due to some undesirable side effects and poor oral bioa-vailable DTX, Verma et al. developed oral nanoemulsion delivery system of DTX to improve the chemotherapy. De-veloped nanoemulsion showed 2.83 times higher cellular uptake than control. According to the results, there is a strong cytotoxic activity against MCF-7 cancer cell line, which confirmed DTX to be more effective in this formula-tion. When single high dose of DTX nanoemulsions (520 mg/kg) is administered, there was no specific toxicity or ne-crosis in the liver and kidney tissues observed in mice, indi-cating it as safe for further action [19]. In another study by

Pandey et al., DTX loaded nanoemulsion was formulated with additional loading of P-gp inhibitor in order to increase the bioavailability of the drug. The formulation exhibited higher uptake in Caco-2 cells and inhibited P-gp transporter significantly. In MDA-MB-231 cells, it shows less IC50, arrested the cells in G2-M phase and showed more cell apop-tosis than marketed formulation (Taxotere®). Based on the bioavailability test, there was an increment in oral bioavaila-bility, resulting in higher in vivo anti-proliferative activity manifesting 19% more inhibition compared to Taxofere®

[80].

Similarly, hydrophobic drug- PTX always face challeng-es in achieving effective delivery due to its low solubility nature and high hemolytic toxicity. Thus, nanoemulsion is used to enhance the condition as well as to achieve safe and better delivery. Pawar et al. incorporated PTX into a vitamin E nanoemulsion using high-pressure homogenization. When tested in MCF-7 breast cancer cell line, PTX loaded nanoemulsion showed greater cytotoxicity in comparison with free PTX and marketed formulation (Taxol®). There was also significant improvement in efficacy of PTX loaded nanoemulsion in in vivo anticancer activity compared to pure PTX and Taxol® [81]. Similar results have also been accom-plished in our previous experiment on PTX nanoemulsion [14]. In another study, Ahmad et al. used solid-nanoemulsion pre-concentrate system to improve the bioa-vailability of PTX. Results appeared to show an increase in in vitro cumulative drug release as well as permeability coef-ficient through everted gut sac in compared to pure drug sus-pension and commercial intravenous product (Intaxel®). The spherical globule size of nanocarrier provides high mem-brane permeability. Solid nanoemulsion preconcentrate of PTX also showed strong inhibitory effect on proliferation of MCF-7 cells. Hence, solid nanoemulsion pre-concentrate can be used as an oral dosage form as it can enhance dissolution and oral bioavailability of PTX [82]. To sum up, nanoemul-sion and/or solid-nanoemulsion pre-concentrate system are

Fig. (3). Nanoemulsion-based drug delivery exploiting tumor microenvironment by active targeting mechanism.


successful in improving oral bioavailability of hydrophobic drugs. Ganta et al. evaluated on the efficacy of co-administration of PTX and CUR, an inhibitor of nuclear factor kappa B (NFkappaB) and P-gp in nanoemulsion for-mulation to SKOV3 tumor-bearing mice. The mice pre-treated with CUR showed a 4.1-fold increase in PTX plasma concentration, which suggest increased PTX cytotoxicity in ovarian adenocarcinoma [83].

Sunitinib is an anticancer drug where it works by inhibit-ing proliferation of tumor cells and angiogenesis. In one study, Nazari-Vanani et al. developed self-nanoemulsifying drug delivery system (SNEDDS) as a carrier for sunitinib. Sunitinib released from SNEDDS was found to be enhanced accompanied by controlled dissolution of the drug. Accord-ing to the cytotoxicity studies, the results showed an im-proved toxicity of sunitinib by SNEDDS when tested in 4T1 and MCF-7 cell lines. In bioavailability study, the maximum plasma concentration and the mean under the plasma con-centration-time curve had increased by 1.45- and 1.24-times respectively, when compared to the drug suspension [84]. Tamoxifen (TAM) is also another lipid-soluble drug with low aqueous solubility; hence, Tagne et al. prepared a water-soluble nanoemulsion of TAM. When compared between nanoemulsion of TAM and pure TAM, nanoemulsion can inhibit the proliferation of tumor cells 20-fold greater as well as increased cell apoptosis 4- folds greater in the HTB-20 breast cancer cell line. In conclusion, the nanoemulsion of TAM increases anticancer properties of TAM in treatment of breast cancer [50].

Curcumin (CUR) from Curcuma longa has low aqueous solubility and low oral bioavailability. Therefore, in order to increase the oral absorption of CUR, Guan et al. prepared CUR nanoemulsion to target prostate cancer. The results showed that CUR nanoemulsion increased cytotoxicity and cell uptake as well as exhibited prolonged biological activity, showed better therapeutic efficacy compared to pure CUR. In in situ single-pass perfusion studies, CUR nanoemulsion has higher effective permeability coefficient and absorption rate constant than free CUR. Therefore, this study proved that CUR nanoemulsion is useful as an effective drug deliv-ery system to improve oral bioavailability and anticancer effect of CUR [85]. In another study, Sun et al. developed functional nanoemulsion-hybrid lipid nanocarriers containing diferuloylmethane (DNHLNs) to treat lung adenocarcinoma. The absorptive constants and penetrability of DNHLNs in four gastrointestinal sections increased by 1.43-3.23 times and 3.10-7.76 times compared to free diferuloylmethane (DIF), respectively. Thus, the relative oral bioavailability of DNHLNs to free DIF was 855.02% and it has stronger inhib-itory effects on viability of lung adenocarcinoma A549 cells than free DIF [86].

Fofaria et al. have developed two nanoemulsion formula-tions of piplartine (PL) for oral delivery and then assess its toxicity, pharmacokinetics and therapeutic efficacy. Both nanoemulsions improved dissolution, cellular permeability and cytotoxic effects in comparison with plain PL. Upon long-term administration through oral route, the developed formulations did not show toxicity when tested in mice. Pharmacokinetics study of PL was conducted, which fol-lowed two-compartment model following intravenous ad-

ministration. PL loaded nanoemulsions showed 1.5- fold raise in oral bioavailability as well as increased in anti-tumor activity and hence suppressed melanoma tumor growth in experimental mice [87].

Genistein (Gen) has anticancer activities in oral cavity and oropharyngeal cancer. However, its usage is limited by low aqueous solubility and extensive metabolism, causing it to have low oral bioavailability and pharmacokinetics pro-files. Therefore, Gavin et al. developed nanoemulsion loaded with proapoptotic lipophilic Gen as a mucoadhesive buccal tablet to target proliferating oropharyngeal cancer. Chitosan was added as a layering to overcoat Gen-containing nanoemulsion in order to enhance mucoadhesion properties. The chitosan polyelectrolyte solution overcoat rendered nanoemulsion droplets cationic, by acting as a mucoadhesive nanoemulsion layer. Biocompatibility screening of prototype chitosan-layered nanoemulsions showed better anticancer activity against oropharyngeal carcinomas [88]. Above dis-cussions on oral delivery of nanoemulsion suggest that nanoemulsion can improve solubility of poorly water soluble drugs by dissolving it in the oil core and can improve oral bioavailability by delivering the drug entrapping within the oil core.

5.2. Parenteral Approach to Deliver Nanoemulsion for Cancer Therapy

Nanoemulsion is an ideal for loading active pharmaceuti-cal ingredients for parenteral drug delivery as they have the potential to achieve targeted drug delivery through the addi-tion of specific ligands. We have seen that nanoemulsion can increase the solubility of hydrophobic drugs, and provide protection from enzymatic degradation and hydrolysis. Fur-thermore, their small, uniform droplet size provides a large surface distribution, leading to an increase in API concentra-tion in the human body [53, 89]. An extensive research has been performed on nanoemulsion for cancer chemotherapy. A study conducted by Chen et al. to compare the efficiency of LBT when formulated with oleic acid (OA) as a nanoemulsion (LBT-OA-NE) and a liposome (LBT-OA-Lipo) for lung cancer therapy [12]. The formulations were also investigated in the presence of PEGylated lecithin; PEGylated nanoemulsion (LBT-OA-PEG-NE) and PEGylat-ed Lipo (LBT-OA-PEG-Lipo). A therapeutic adjuvant, nRGD was also used in PEGylated Lipo (LBT-OA-PEG-Lipo-nRGD). The study demonstrated that LBT-OA-PEG-Lipo had the highest cytotoxicity actions towards cancer cells. OA, in the presence of sodium bicarbonate, forms an ion-pair complex with enhanced lipid solubility, as the am-monium group on the LBT ionizes the carboxyl group on OA. This allows the nanoemulsion to entrap larger amounts of LBT [12, 90]. However, liposomes were shown to entrap more LBT-OA compared to NE, as shown by the oxygen content of LBT-OA-Lipo (31.10%) and LBT-OA-NE (25.47%). Further, PEGylated lecithin acts as a protective measure for drug carriers, reducing recognizing them as for-eign bodies by MPS. This decreased rate of removal of the compound from the systemic circulation [12]. The result at the 8th hour had depicted the lowest cumulative amount of LBT release (56.2%) from LBT-OA-PEG-Lipo compared to LBT-OA-Lipo (61.3%), LBT-OA-PEG-NE (77.8%), and LBT-OA-NE (86.5%). Lastly, the addition of nRGD further en-


hances the cytotoxicity effect of LBT-OA-PEG-Lipo. nRGD acts on integrin receptors and neuropilin-1, improving the build-up of the drug in tumors [91].

Natesan et al. developed a nanoemulsion formulation of CPT, by stabilizing with chitosan [92]. The resulting stabi-lized nanoemulsion produced demonstrated a uniform drop-let size (46-54 nm vs. 39-58 nm), a prolonged period of drug release (61.65% vs. 58.87%) and lower haemolytic activity (16.4 ± 1.4% vs. 17.6 ± 1.2%). The stabilized nanoemulsion also showed higher cytotoxicity (285 ± 11ng/ml vs. 178 ± 4.3 ng/ml) towards human breast cancer cells (MCF-7). When administered intravenously to BALB/c mice with 4T1-breast tumor, the stabilized nanoemulsion showed im-proved levels of passive targeting and bio-distribution, at 2495.22 ± 174.66 ng/gm compared to non-stabilized nanoemulsion (1677.58 ± 134.21 ng/gm). This occurs as the stabilized nanoemulsion experience and increase in circula-tion time, improving the uptake of CPT into cancer cells due to EPR [51]. Chitosan, having a pKa value of about 6.5, will only swell and enlarge in the acidic tumor environment, thereby accelerating the rate of CPT release [93]. This shows that the stabilized nanoemulsion improved the solubility and targeting capacity of CPT, thereby improving its clinical use for breast cancer.

When PTX was co-encapsulated with baicalein (BA) in nanoemulsion, a reduction in PTX resistance was observed, as BA possibly suppresses the activity of P-gp and induce oxidative stress. The nanoemulsion exhibited increased cyto-toxicity towards MCF-7/Tax cells compared to free PTX due to the combined effect of PTX and BA. It is also shown that the cellular uptake of the nanoemulsion was higher on MCF-7/ Tax cells compared to free PTX due to nanoemulsion-mediated endocytosis. The observed increase in uptake could be due to the inhibition of P-gp by BA. A significant in-crease in intracellular reactive oxygen species (ROS) was also observed in MCF-7/Tax cells when treated with the nanoemulsion, as BA increases the production of intracellu-lar ROS. This overproduction of intracellular ROS contrib-utes towards the synergism of PTX and BA. The administra-tion of the nanoemulsion also greatly reduces the intracellu-lar glutathione levels and elevates caspase-3 activity, which attributed to increased apoptosis (Fig. 4) [94]. The results of the study suggest that the PTX/BA nanoemulsion could function as a reversal agent for tackling drug resistance. Be-sides that, PTX is having low water solubility that restricts its use in treatment. Kim et al. formulated a novel nanoemul-sion, PTX-loaded hyaluronan solid nanoemulsion (PTX-HSNs) to investigate on the efficacy by enhancing tumor targeting. Cytotoxic effect of PTX-HSN is enhanced due to prolonged level of PTX in blood leading to PTX accumula-tion in ovarian cancerous cells, thereby, suppresses tumor growth [95].

The non-steroidal anti-inflammatory drug, ketoprofen (KP) when developed as a nanoemulsion showed higher pho-to-stability and increased solubility. The nanoemulsion con-sists of KP and pullulan (as a stabilizer) encapsulated in pomegranate seed oil (PSO), protected against photodegrada-tion. This is due to the ability of PSO to confine KP in oil droplets, resulting in the dispersion of light, hence increasing photo-stability. When the nanoemulsion was incubated with

C6 cells, demonstrated increased anti-tumor activity by in-hibiting 40% of cell growth, which is significantly more than blank nanoemulsion. The increased activity can be attributed to the smaller size of the nanoemulsion, leading to an in-creased contact area with the C6 cells, which allows an in-crease in the inflow of KP. Therefore, the KP and pullulan nanoemulsion encapsulated with PSO has shown to be fa-vorable for the treatment of glioma [96].

In 2016, Monge-Fuentes et al. investigated the potential of acai oil as a nanoemulsion (NanoA) for the photodynamic therapy (PTD) of melanoma [97]. The study utilized acai oil as a photosensitizer (PS) to induce the death of melanoma cells. The results showed an 85% melanoma cell death and a decrease in tumor size by 82% in tumor bearing experi-mental mice as compared to the control. It has been ex-plained that the presence of polyphenols in acai oil generates ROS and producing irreversible photo-damage to melanoma cells. Small size of the acai oil droplets enables increased permeability into tissues and subsequently this increases cellular uptake [98].

Based on a study conducted by Ahmad et al. the encapsu-lation of omega-3 fatty acid conjugated with taxoid prodrug (NE-DHA-SBT-1214), a hydrophobic drug to treat prostate cancer, in nanoemulsion shows increased cytotoxic effect in nanoemulsion compared with aqeous solution of DHA-SBT-1214 in vitro in human prostate cancer cell line, PPT2 cells [99]. The increase in effect is correlated with pharmacokinet-ic and biodistribution which is found to be caused by the reduction in particle size rather than the characteristic of the encapsulated drug. Besides that, tumor growth is suppressed extensively when NE-DHA-SBT-1213 is administrated in-travenously into NOD/SCID mice with PPT2 tumor xeno-grafts weekly when compared with Abraxane as well as pla-cebo nanoemulsion formulation [99]. On the other hand, PEG-modified nanomeulsion improved the duration of drug present in the circulation. Consequently, this allows accumu-lation of the drug at the tumor site due to EPR effect [100]. Therefore, nanoemulsion based delivery system is having higher efficacy in treating prostate cancer by enhancing su-perior regression and inhibition of tumor growth.

The compound α-tocopherol succinate (α-TOS), derived from Vitamin E and succinic acid contains anti-tumor prop-erties but has low bioavailability. Gao et al. has shown that when α-TOS is formulated as a nanoemulsion (α-TOS-NE), the bioavailability increases [101]. This is seen due to higher AUC0→∞ of α-TOS-NE compared to free α-TOS. The bioa-vailability was further improved when administered intrave-nously. The increased bioavailability is reflected by the pres-ence of small, uniform size of the nanoemulsion, and the capability of the nanoemulsion to deliver α-TOS to serum lipoproteins, the binding protein responsible for the transport of α-TOS into tumor tissues [102]. The α-TOS-NE also demonstrated higher cytotoxicity towards tumor cells com-pared to free α-TOS. As the method of cell apoptosis induc-tion is mediated by the mitochondria, when the mitochondria is damaged, depolarization occurs, lowering the mitochon-drial membrane potential (ΔΨ) [103]. Simultaneously, a lower ΔΨ was seen when α-TOS-NE was administered.

Similarly, Loureiro et al. showed that carbon monoxide releasing molecule-2 (CORM-2), when formulated as a


nanoemulsion tagged with folic acid showed higher anti-tumor activity and prolonged survival lymphatic cancer induced ex-perimental animal [104]. CORM-2 can induce apoptosis and block the proliferation of tumors. The increased anti-tumor activity of CORM-2 is due to the increased uptake of the nanoemulsion into the tumor bearing cells, as folic acid on the nanoemulsion recognizes the folate receptor present on the cells. Besides that, the increased uptake increases the ability of CORM-2 to induce the anti-Warburg effect, pro-longing the survival of mice with A20 lymphoma tumors. The presence of carbon monoxide compels cancer cells to

use more oxygen, leading to cellular exhaustion and death [105].

Nanoemulsions have been shown to be promising alterna-tives to conventional chemotherapy. The increasing amount of studies being carried out have shown an overall increase in anti-tumor activity, extended drug release and circulation, and could also be the key in tackling MDR.

5.3. Transdermal Delivery of Nanoemulsion in Cancer Therapy

Researches have now focused more on areas of transder-mal delivery of nanoemulsion in chemotherapy as it is well established and accepted as alternative route of administra-tion. Taking in consideration of the bioavailability of drug via oral route, the first pass metabolism and gastrointestinal P-gp efflux reduces the amount of drug in systemic circula-tion and thereby lacking its desired goal. Patient receiving chemotherapy has substantial risk of nausea and vomiting, making them feeling extreme discomfort and inconvenience. Hence, transdermal application can help increase tolerability towards GI irritation. Introduction of drug delivery through the skin is appreciably important, as it can possibly avoid first pass metabolism and to alleviate the discomfort when injected. As compared to other route, transdermal application

is beneficial for long-term treatment of chronic pain as the skin provides a larger surface area for absorption [106].

The current marketed formulation of 5-FU is in topical and injectable route. This is because oral administration ex-hibits serious adverse effect and low bioavailability. Howev-er, the permeability through lipophilic human stratum corneum has risen issue for dermal/ transdermal administra-tion due to the hydrophilic characteristics of 5-FU. There-fore, many trial and error were carried out to find the suitable carriers of hydrophilic drugs [11]. Recent studies show the dispersion of oil based nanocarriers like nanoemulsions and microemulsions are rather stable for transdermal/topical de-livery of many lipophilic drugs compared to other prepara-tion compound.

A study conducted by Shakeel et al. is to develop w/o nanoemulsions of hydrophilic drug 5-FU for topical chemo-prevention of skin cancer using low HLB surfactants [11]. Lauroglycol-90 is used as an oil phase while Transcutol-HP and IPA are selected as the surfactant and co-surfactant due to low HLB value the favors the formation of w/o nanoemul-sions [107]. The permeation data analysis performed con-

cluded that the formulated nanoemulsions were extensively superior when compared to the controlled aqueous solution of 5-FU [11]. In vitro cytotoxicity study on SK-MEL-5 mel-anoma cell line was conducted to compare the therapeutic effect of the formulated nanoemulsion. As expected, mela-noma cells were resistant toward the free 5-FU solution due to the absence of cell inhibition. However, free 5-FU shows 5.400.32% of cytotoxic effect at molar concentration of 120 m. With the same concentration of 5-FU in nanoemulsion, the cytotoxicity increases by approximately 11 folds which indicates the potency and efficacy of the nanoemulsion in chemotherapy against skin cancer. Based on the obtaining

results, the nanoemulsion formulation is more effective in chemopreventive of skin cancer than free 5-FU [11].

Fig. (4). The effect of PTX and BA when administered in combination.


To evaluate the effectiveness of Tocomin nanoemulsion as an anti-proliferative agent, a time-dependent profile was plotted against both human keratinocyte cancer cells, A431 and SCC-4. A positive result was obtained for both controls while Tocomin hybrid nanoemulsion showed a prominent cell inhibition effect over a period of incubation (up to 96 hours). Cell inhibition was superior when using Tocomin hybrid nanoemulsion (p≤0.05) and the IC50 values in A431 and SCC-4 were 42.6±3.8 mM and 47.3±3.2 mM, respec-tively. Hence, with all the data obtained, the hybrid-nanoemulsified delivery system has substantiated a great potential therapeutic benefits for such topical delivery [20].

The following study is regarding the use of carbopol-

based nanoemulsion gel of apigenin for UV-induced skin

carcinoma. Apigenin is a naturally occurring plant belonged

to the flavone class. It selectively inhibits the cell growth, induces apoptosis in cancer cells, and most importantly, im-

pede the invasion process [108]. In the cytotoxicity experi-

ment, MTT assay was carried out on HaCaT cells and A431

cells. After that, 25µL of apigenin, plain drug loaded gel and

apigenin-loaded nanoemulsion gel are incubated for 24

hours. The ex-vivo skin permeation test analysis reveals that

the amount of apigenin permeated through skin is from

nanaemulsion gel was at value of 6.680.46 gch-2 h-1, signifi-

cantly higher than the pure apigenin and plain drug loaded gel

5.431.02 gch-2 h-1 and 5.600.63 gch-2 h-1 respectively

[109].

Based on a research conducted by Pathan et al., trans-dermal permeation and bioavailability of TAM increased remarkably in vitro and in vivo, respectively. Increased per-meation might occur due to low droplet size and viscosity which facilitate percutaneous TAM uptake while increased bioavailability is due to increased skin permeation and by-pass first pass metabolism [110]. Nanoemulsion enhance cytotoxicity of TAM by avoiding first pass metabolism and increase membrane permeation.

Another anticancer drug, caffeine in nanoemulsion, has caught Shakeel and Ramadan’s research attention. The hy-pothesis developed in this study is efficacy of transdermal application of nanoemulsion of caffeine in preventing ultra-violet light induced skin cancer. The investigation performed through in vitro studies on Franz diffusion using animal rat skin as permeation membrane. A histopathological examina-tion of a normal skin versus nanoemulsion treated skin spec-imens were evaluated and the photomicrograph indicates nanoemulsion is safe for transdermal delivery of caffeine as there is no signs of inflammation or edema on the stratum corneum [111].

Neuroblastoma is a cancer commonly found in infants and young children that affects the immaturing or developing of cells [112]. According to the reported neuroblatoma cell culture studies, anti-oxidant synergy formulation can induce differentiation and buffer neuronal degeneration and oxida-tive stress in cultured cortical neurons and in central nervous system tissue of apolipoprotein E-deficient mice. The main goal of the study by Kuo et al. was to investigate the com-parative efficacy between subcutaneous injection and trans-dermal application of a nanoemulsion preparation of ASF in reducing tumor growth rate using a neuroblastoma xenograft

mouse model. The data proposed that ASF suspension is fairly ineffective when compared to nanoemulsion in the treatment of neuroblastoma mouse. However, the conclusive result shows that both subcutaneous and transdermal route of nanoemulsion are as effective with an average reduction of 65% in tumor growth rate in this neuroblastoma mouse mod-el [113].

Therefore, the delivery of chemotherapeutic agents through skin via nanoemulsion could be advantageous for local as well as systemic delivery of drugs and further effec-tively treat the cancers with increased safety profile. In summary, nanoemulsion is employed to overcome physio-logical and anatomical barriers as well as engineered to pro-long anti-cancer drug in blood circulation and improves tar-get binding ability. As a result, the cytotoxic effect of poorly soluble anti-cancer drugs is improved by enhancing solubili-ty of drugs, providing physiochemical improvement and pro-tection against enzymatic degradation and P-gp efflux, thereby facilitate cellular uptake and promoting controlled-released chemotherapy. Various nanoemulsion approaches against different cancers have been summarized in Table 1.

CONCLUSION AND FUTURE PERSPECTIVES

Conventional cytotoxic agents are often hydrophobic in nature, which contributes to low aqueous solubility and seri-ous adverse effects, thereby, reducing its use as well as its efficacy. Therefore, utilization of nanotechnology in cancer treatment is significantly important. Among various types of nanocarriers, nanoemulsion is prominent due to its capabili-ties in improving stability of unstable chemicals by protect-ing them against oxidative, UV light degradation, distorting organisms such as bacteria, fungi and viruses directly, reduc-ing incidence of skin irritations and adverse effects as well as prolonging the agents in the body by controlling drug-release pattern. There are several routes of administrating cytotoxic agents, which include oral, parental, and transdermal. The incorporation of nanoemulsion formulation possess several advantages in drug formulation. Enhancement of solubility further pharmacokinetic and pharmacodynamics properties of poorly water soluble drugs by means of nanoemulsion formulation through different routes of administration, tar-geting properties in chemotherapy, desirable release profile, drug uptake control, avoidance of drug resistance, prolonged efficacy with improved safety profile make the nanoemul-sion unique in recent formulation development field. Availa-bility several of preparation methods, appreciable thermody-namic stability and accessibility diversified safe oil, surfac-tants, co-surfactants and combinations for nanoemulsion make it more flexible with wide valued application. As a result, the efficacy of the chemotherapeutic agents’ increases via active and passive targeting of the nanocarrier to the site of action, which further provide promising decrease in sys-temic toxicity. In conclusion, nanoemulsion is a good candi-date in enhancing drug delivery of cytotoxic agents, thereby, improving the outcomes of cancer treatment by increasing life span of the patient, and quality of life.

Nanotechnology is a potential drug-delivery system to be employed in our daily life especially in healthcare setting [46]. Cost effective well-designed targeted nanoemulsion with improved safety profile are developing to address several


Table 1. Representation of nanoemulsion based approaches for parenteral, oral and transdermal treatment of various cancers.

Route of Ad-

ministration Drug Name

Method Used for

Preparation Cancer Type

Targeting

Ligand Cell Line/Animal Outcome of the Study Refs.

Parenteral

LBT Homogenization

Lung cancer

nRGD and

PEG

LLC cells, A549

cells and B16 cells

Increased LBT entrapment capacity

with extended drug release and

circulation time. Nanoemulsion

showed enhanced anti-tumour effect

on cells.

[12]

CPT Sonication Breast cancer - MCF-7 and 4T1

cell lines

Stablized nanoemulsion showed

uniform droplet size and extended

drug release with lower haemolytic

activity and higher cytotoxicity along

with higher passive targeting.

[92]

PTX and

baicalein

(BA)

High-pressure

homogenization

Breast cancer - MCF-7 and

MCF-7/Tax

Loaded nanoemulsion enhanced

cellular uptake, cytotoxicity and

apoptosis due to inhibition of P-glyco-

protein and increased oxidative stress.

[94]

KP Solvent diffusion Brain cancer - C6 and 3T3 cells Nanoemulsion increased drug photo-

stability as well as anti-tumour effect.

[96]

Acai oil - Skin cancer - NIH/3T3 normal

cells and B16F10

melanoma cell

lines, C57BL/6

mice

Nanoemulsion of Acai oil killed 85%

of melanoma cells, while maintaining

high viability in normal cells. It also

showed 82% reduction in tumor

growth.

[97]

α-TOS - Breast cancer RGD

peptide

MCF-7 cells, rat Nanoemulsion of α-TOS increased

cytotoxicity and enhanced bioavaila-

bility compared to free drug.

[114]

CORM-2 - lymphatic cancer Folic acid A-20 cell line,

BALB/c mice

Nanoemulsion increased uptake of

(CORM-2) into the tumour bearing

cells. Besides that, the increased

uptake increases the ability of

CORM-2 to induce the anti-Warburg

effect, prolonging the survival of

mice with A20 lymphoma tumours.

[104]

Oral OXA and 5-

FU

Ion-pairing com-

plex

Colorectal cancer - Caco-2 cell, mice The permeability of OXA and 5-FU

increased 4-5 folds, which is higher

than free OXA and 5-FU. Nanoemul-

sion also enhanced cytotoxicity

compared to free drug.

[77]

BBH Oil-in-water

nanoemulsion

Cancer (anti-

tumor)

- Caco-2 cell mono-

layer, rat

The BBH nanoemulsion showed

440.40% relative bioavailability

which enhanced absorption of BBH.

The intestinal permeability of BBH

increased while there is a decrease in

BBH efflux through P-glycoprotein.

[78]

Pterostilbene Low-energy emulsi-

fication method

Cancer - - The nanoemulsion delivery enhanced

the solubility, stability and in vitro

release of pterostilbene.

[79]

DTX Hot homogeniza-

tion followed by

ultra-sonication

Breast cancer - MCF-7 cell line Nanoemulsion of docetaxel is stable,

effective and safe for use as the

nanoemulsion exhibited higher cell

uptake, strong cytotoxicity activity

against MCF-7 cancer cell and no

any toxicity found in liver or kidney

tissues of mice.

[19].

DTX - Breast cancer - Caco-2 cells,

MDA-MB-231 cell

lines

The formulation showed more cell

apoptosis and increase oral bioavail-

ability, hence anti-proliferative

activity was enhanced, manifesting

19% more inhibition compared to

Taxofere.

[80]

(Table 1) Contd….


Route of Ad-

ministration Drug Name

Method Used for

Preparation Cancer Type

Targeting

Ligand Cell Line/Animal Outcome of the Study Refs.

DTX Emulsification

method

Breast cancer - MDA-MB-231 cell

lines

Docetaxel loaded chitosan nanoparti-

cles exhibited 65-76% of drug en-

trapment and 8-12% loading capacity

in which drug released about 68-83%

and also an increase of 20% in cell

growth inhibition in breast cancer

cell line.

[115]

PTX Emulsification

method

Breast cancer

(particular)

- MDA-MB-231 cell

lines

IC50 value of PTX-CS-NP-10 for

anticancer activity was 1.6 folds less

than pure drug while haemolytic

toxicity was 4 folds less than naive

drug. PTX-CS-NP-10 treatment

showed enhancement in overall

toxicity and anticancer efficacy of

PTX.

[116]

PTX High pressure

homogenization

Metastatic breast

cancer

- MCF-7 cell line PTX loaded nanoemulsion showed

greater cytotoxicity as well as im-

proved efficacy in anticancer activity

in comparison with free PTX and

marketed formulation (Taxol).

[81]

PTX - Breast cancer,

ovarian carcino-

ma, non-small cell

lung cancer, and

AIDS-related

Kaposi’s sarcoma

- Animal tumor cell

lines, rabbit

EmPAC exhibited higher anti-tumor

efficacy and better safety than Taxol.

[117]

PTX Modified solvent

injection method

Breast cancer,

ovarian cancer,

head/neck cancer,

small and non-

small cell lung

cancers.

- Male Swiss albino

mice

PTX-SLNs showed 10- and 2- folds

higher improvement in oral bioavail-

ability of PTX compared to free PTX

solution.

[118]

PTX Fusion method Breast cancer,

ovarian cancer,

head/neck cancer,

small and non-

small cell lung

cancers.

- MCF-7 cell line Solid nanoemulsion preconcentrate

of paclitaxel exhibited strong inhibi-

tory effect on proliferation of MCF-7

cells.

[82]

Sunitinib Self-emulsification Breast cancer - 4T1 and MCF-7

cell lines

Cytotoxicity studies showed toxicity

enhancement in sunitinib by

SNEDDS. In bioavailability study,

maximum plasma concentration and

mean under the curve were increased

1.45- and 1.24- times respectively

compared to a drug suspension.

[84]

TAM Water-soluble

nanoemulsion

Breast cancer - HTB-20 cell line. Nanoemulsion of tamoxifen can

inhibit cell proliferation 20-fold

greater as well as increased cell

apoptosis 4- folds greater in compari-

son with pure tamoxifen.

[50]

CUR Self-

microemulsifying

method

Prostate cancer - PC-3 cells Curcumin nanoemulsions increased

the cytotoxicity as well as exhibited

prolonged biological activity and

showed better therapeutic efficacy.

Cur nanoemulsion also has higher

effective permeability coefficient and

absorption rate constant than free

curcumin.

[85]

(Table 1) Contd….

Route of Ad- Drug Name Method Used for Cancer Type Targeting Cell Line/Animal Outcome of the Study Refs.


ministration Preparation Ligand

Diferu-

loylmethane

(CUR)

Thin film-

sonication disper-

sion technology

Lung adenocarci-

noma

- A549 cells The absorptive constants and perme-

abilities of DNHLNs increased by

1.43-3.23 times and 3.10-7.76 times

compared to diferuloylmethane

(DIF). DNHLNs enhanced the ab-

sorption and bioavailability of DIF

and also had stronger inhibitory

effects.

[86]

Piplartine

(PL)

Self-emulsification

and homogeniza-

tion-sonication

method

Melanoma tumor - Mice PL loaded nanoemulsions showed

1.5- fold increase in oral bioavailabil-

ity and increased anti-tumor efficacy.

[87]

Genistein

(Gen)

Coarse homogeni-

zation followed by

low-amplitude

ultrasonication

Oral cavity and

oropharyngeal

cancer

- Oral carcinoma cell

line

Cationic Genistein-loaded nanoemul-

sions have anticancer activity against

oropharyngeal carcinomas.

[88]

Transdermal

5-FU oil phase titration

method

Skin cancer - MEL-5 cancer

cells lines

Nanoemulasion of 5-FU was found to

be physical stable with enhanced skin

penetration and more efficacious then

free drug.

[11]

Tocotrienols Homogenization Skin cancer Propyl-

eneglycol

human cutaneous

carcinoma cells

Nano emulsion of tocotrienols

demonstrated significantly stronger

cytotoxic profiles along with low

IC50 value compared to free drug.

[20]

Apigenin High speed homog-

enization

UV induce skin

cancer

- HaCaT Cells and

A431 cells

Nanoemulsion showed high penetra-

bility through goatskin and high

toxicity on A341cells, However less

toxicity toward HaCaT cells.

[109]

Caffeine Oil phase titration

method

Skin cancer - - Significant increase in permeability

parameters was observed

in nanoemulsion formulations as

compared to aqueous solution of

caffeine.

[111]

formulation issues in chemotherapy through different route of administration. Moreover, there are still lack of research in this field such as the characteristic of the system and its establishment of clinical benefits in human. Understanding of detailed mechanism, which make nanoemulsion targeted and more efficient chemotherapy compared to conventional chemotherapy is in demand. Further investigations are in need for detailed pre-formulation interaction studies, exclu-sive studies on preparation method to make more stable nanoemulsion, influence parameters behind targeted nanoemulsion as well as drug uptake through different routes of administration and finally in cancer cells, and the reason behind improved safety profile should be explored in search of mechanistic details. These issues should be addressed and evaluated particularly safety assessment prior to marketing to prevent unforeseen complications.

CONSENT FOR PUBLICATION

Not applicable.

CONFLICT OF INTEREST

The authors declare no conflict of interest, financial or otherwise.

ACKNOWLEDGEMENTS

Dr. Pandey, Dr. Choudhury, and Dr. Bhattamisra would like to acknowledge School of Pharmacy, International Med-ical University, Malaysia, and Dr. Gorain would like to acknowledge Faculty of Pharmacy, Lincoln University Col-lege, Malaysia for providing resources and support in com-pleting this work.

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