INTRODUCTION:

Phytoconstituents are gaining popularity as ingredients in cosmetic formulations as they can protect the skin against exogenous and endogenous harmful agents and can help remedy many skin conditions. Exposure of skin to sunlight and other atmospheric conditions causes the production of reactive oxygen species, which can react with DNA, proteins, and fatty acids, causing oxidative damage and impairment of antioxidant system. Such injuries damage regulation pathways of skin and lead to photoaging and skin cancer development.

They are chemical compounds that occur naturally in plants. some are responsible for colour and other organoleptic properties.

The term is generally refer to biologically significant chemicals, but not Since ancient times, herbal plants have been utilized to treat distinctive ailments because of their availability, accessibility, inherited practice, economic feasibility, and perceived efficacy. Ayurveda is the oldest health care system and describes a large number of medicinal plants with their curative properties. The research and development push is focused on development of new creative and innovative delivery systems for plant based drugs. Phytoconstituents obtained from plants generally possess an inherent drawback of limited oral bio availability and instability owing to their hydrophilic nature. These water solvent phytoconstituents (e.g., tannins, flavonoids) have a poor lipophilicity and large atomic size, which prevents their entrance through the cell membrane[1].

Advantage of phytoconstituents:

1. Marked enhancement of bioavailablity.

2. Valuable components of the herbal of extracts are protected from destruction by digestive secretions and gut bacteria.

3. No compromise of nutrient safety.

Types of phytoconstituents:

1. Phenolics:

Phenolics are plant metabolites widely spread throughout the plant kingdom. Recent interest in phenolic stems from their potential protective role, through ingestion of fruits and vegetables, against oxidative damage diseases (coronary heart disease, stroke, and cancers). Phenolic compounds are essential for the growth and reproduction of plants, and are produced as a response for defending injured plants against pathogens. Phenolic acid compounds are universally distributed in plants. They have been the subject of a great number of chemical, biological, agricultural, and medical studies. They form a varied group that includes the widely distributed hydroxybenzoic and hydroxycinnamic acids. Plant phenolic compounds are diverse in structure but are characterized by hydroxylated aromatic rings (e.g. flavan‐3‐ols). They are categorized as secondary metabolites. Many plant phenolic compounds are polymerised into larger molecules such as the proanthocyanidins and lignins. Furthermore, phenolic acids may occur in food plants as esters or glycosides conjugated with other natural compounds such as flavonoids, alcohols, hydroxyfatty acids, sterols, and glucosides [2].

2. Alkaloids:

Alkaloids are traditionally defined as basic, nitrogen‐containing organic constituents that occur mainly in plants. The nitrogen in the alkaloid molecule is derived from amino acid metabolism. Since the amino acid skeleton is often largely retained in the alkaloid structure, alkaloids originating from the same amino acid show similar structural features. Alkaloids often have pronounced bioactivities and are therefore thought to play an important role in the interaction of plants with their environment. Alkaloids and extracts of alkaloid‐containing plants have been used throughout human history as remedies, poisons and psychoactive drugs [3] Many alkaloids, though poisons, have physiological effects that render them valuable as medicines. Other common alkaloids include quinine, caffeine, nicotine, strychnine, serotonin, and LSD. Aconitine is the alkaloid of aconite. Cinchonine and quinine are derived from cinchona, coniine is found in poison hemlock, and reserpine is an extract of rauwolfia roots. Emetine is an alkaloid of ipecac [4].

3. Saponins:

Saponins are phytochemicals found in most vegetables, beans and herbs. The best known sources of saponins are peas, soybeans, and some herbs with names indicating foaming properties such as soapwort, saoproot, soapbark and soapberry. Commercial saponins are extracted mainly from Yucca schidigera and Quillaja saponaria. Saponins are glucosides with foaming characteristics. They consist of a polycyclic aglycones attached to one or more sugar side chains. The foaming ability of saponins is caused by the combination of a hydrophobic (fat‐soluble) sapogenin and a hydrophilic (water‐soluble) sugar part. Saponins have a bitter taste. Some saponins are toxic and are known as sapotoxin. Saponins have many health benefits [5].

4. Glycosides:

Glycosides are compounds containing a carbohydrate and a non-carbohydrate residue in the same molecule. The carbohydrate residue is attached by an acetal linkage at carbon atom 1 to a non carbohydrate residue or aglycone. The non sugar component is known as the aglycone. The sugar component is called the glycone [6].

Figure 1: Various phytoconstituents in anticancer

Phytoconstituents having anticancer activity:

1. Apigenin:

Apigeninis a member of the flavone subclass of flavonoids present in fruits and vegetables and is considered to have various biological activities such as being anti-inflammatory, anticancer and it also has free-radical scavenging properties [7] Apart from having anticancer activity it may also stimulate adult neurogenesis.

Mechanism of Action:

Apigenin can effectively inhibit proliferation in various breast cancer lines MDA-MB-453.[8] Several mechanisms have been proposed to explain the inhibition of cancer cell growth by apigenin; these include the arrest of the cell cycle, the induction of apoptosis and the modulation of signal transduction [8 9]. It has been suggested that apigenin- induced apoptosis results from the depletion of ErbB2 following the dissociation of a complex containing ErbB2 and GRP94 [10].

2. Curcumin:

Curcumin is a diarylheptanoid belonging to the group of curcuminoids, which are natural phenols responsible for turmeric’s yellow color. It is a tautomeric compound existing in enolic form in organic solvents, such as a keto form in water [11]. Curcumin was first isolated in 1815 and its chemical structure was determined by Roughley and Whiting in 1973. [12] Curcumin has effect on gastrointestinal system, anemia, diabetes, hepatitis, skin diseases, inflammation, urinary diseases, cough, liver disorders, carcinogenesis, etc.

Mechanism of Action:

Curcumin acts as a potent anticarcinogenic compound. Induction of apoptosis plays an important role in its anticarcinogenic effect. It induces apoptosis and inhibits cell-cycle progression, both of which are instrumental in preventing carcinogenic cell growth in rat aortic smooth muscle cells[13]. Curcumin induces apoptotic cell death by DNA- damage in human cancer cell lines, TK-10, MCF-7 and UACC-62 by acting as topoisomerase II poison [14].

However, curcumin affects different cell lines differently, whereas leukemia, breast, colon, hepatocellular and ovarian carcinoma cells undergo apoptosis in the presence of curcumin, lung, prostate, kidney, cervix and CNS malignancies and melanoma cells show resistance to cytotoxic effect of curcumin. Curcumin also inhibits proliferation of rat thymocytes. These strongly imply that cell growth and cell death share a common pathway at some point and that curcumin affects a common step, presumably involving modulation of AP-1 transcription factor [15].

3. Indole- 3- Carbinol (I3C):

Indole-3-Carbinol is produced by members of the family Cruceferae and particularly members of the genus Brassica. Glucoinolate glucobrassicin breakdowns to produce Indole-3-Carbinol [16].

Mechanism of Action:

I3C has been shown to suppress the proliferation of a wide variety of cells, including breast cancer cell [17], colon cancer cells [18]. Prostate cancer cells and endometrial cancer cells. DIM (3, 3’-Diindolymethane derived from the digestion of I3C) inhibits DNA synthesis and cell proliferation in both ER positive (MCF-7) and ER-deficient (MDA-MB-231) human breast cells. Bonnesen and his colleagues found that I3C can both stimulate apoptosis and confer protection against DNA damage in human colon cell lines. The naturally occurring DIM, ascorbigen (ASG), I3C and ICZ stimulate apoptosis in human colon adenocarcinoma LS-174 and CaCO₂ cells. These phytochemicals may prevent colon tumorigenesis by both stimulating apoptosis and enhancing intracellular defenses against genotoxic agents.

4. Fisetin:

Fisetin is a plant polyphenol from the flavonoid group. It can be found mainly in fruits, vegetables, nuts and wine and displays a variety of biological effects including antioxidant and anti-inflammatory [18]. It serves coloring agent in fruits and vegetables like strawberries, apple, persimmons, onion and cucumber.

Mechanism of Action:

Fisetin has been shown to exhibit anticancer activities in various types of tumor cells, with the capability to induce cell cycle arrest and apoptosis [19,20]. The cytotoxic and apoptotic effects induced by fisetin in human breast cancer MCF-7 and MDA-MB-231 cells exhibit a robust anticancer activity in caspase-3 deficient MCF-7 cells and fisetin induced apoptosis did not display typical features of apoptosis such as DNA fragmentation and PS externalization but instead triggered plasma membrane rupture, mitochondrial depolarization, activation of caspase-7, -8 and -9 and PARP cleavage in MCF-7 cells, which can be intensively blocked by caspase inhibition [21].

Cancer:

The term cancer refers to a group of diseases which share similar characteristics. Cancer can affect all living cells in the body, at all ages and in both genders. The causation is multifactorial and the disease process differs at different sites. Tobacco is the single most important identified risk factor for cancer. A host of other environmental exposures, certain infections as well as genetic predisposition play an important role in carcinogenesis [22]. Cancer starts when a cell is somehow altered so that it multiplies out of control.

The cancer phenomenon is described by uncontrolled proliferation and dedifferentiation of a normal cell. Sequential genetic alterations which produce genetic instabilities accumulate in the cell and a normal cell transforms into a malignant cell.

These alterations include mutations in DNA repair genes, tumor suppressor genes, oncogenes and genes involve in cell growth & differentiation. These modifications are not just abrupt transitions but may take several years. Both external (e.g., radiations, smoking, pollution and infectious organisms) and internal factors (e.g., genetic mutations, immune conditions, and hormones) can cause cancer. Various types of cancer forms exist in human and the lung, breast and colorectal cancer being the most common forms.Among these the lung cancer is reported the most in men and the breast cancer in women [24].

History of Cancer:

Cancer is the second leading cause of death in the world after cardiovascular diseases. Half of men and one third of women in the United States will develop cancer during their lifetimes. Today, millions of cancer people extend their life due to early identification and treatment. Cancer is not a new disease and has afflicted people throughout the world. The word cancer came from a Greek words karkinos to describe carcinoma tumors by a physician Hippocrates (460-370 B.C), but he was not the first to discover this disease.[25] Cancer is a major public health problem in the United States and other developed countries. Currently, one in four deaths in the United States is due to cancer [26].

Types of cancer

Figure 2: Types of cancer

1. Carcinoma:

That starts in cells that make up the skin or the tissue lining organs, such us the liver or kidney. We performed mutational analysis of the PIK3CA gene by polymerase chain reaction-single-strand conformation polymorphism assay in 668 cases of common human cancers, including hepatocellular carcinomas, acute leukemias, gastric carcinomas, breast carcinomas, and non-small-cell lung cancers [27]. Carcinoma-the most commonly diagnose cancer-originate in the skin, lungs, breast, panccreas and other organs and gland.

2. Sarcoma:

It can affect different types of tissue. Rare type of sarcoma that is likely to be confused with a variety of benign and malignant conditions, especially a granulomatous process, a synovial sarcoma, or an ulcerating squamous cell carcinoma [28]. Sarcoma aries in bone, muscle, fat, blood vessels, cartilage or other soft or connective tissue of the body.\

3. Melanoma:

Melanoma is cancer that arises in the cells that make the pigment in skin. Melanoma accounts for only 4 percent of all dermatologic cancers, it is responsible for 80 percent of deaths from skin cancer; only 14 percent of patients with metastatic melanoma survive for five years [29].

4. Lymphoma:

Lymphomas are cancer of lymphocyte Lymphoma involving the testis at the time of diagnosis, or primary testicular lymphoma, is a rare disease. Lymphoma is cancer that begins in infection-fighting cells of the immune system, called lymphocytes. These cells are in the lymph nodes, spleen, thymus, bone marrow, and other parts of the body. When you have lymphoma, lymphocytes change and grow out of control [30].

5. Leukemia:

Leukemia is a cancer of the blood or bone marrow. Bone marrow produces blood cells. Leukemia is cancer of the body's blood-forming tissues, including the bone marrow and the lymphatic system. Many types of leukemia exist. Some forms of leukemia are more common in children.

Common types of cancer:

The most common type of cancer are in male lung cancer, prostate cancer, colorectal cancer, stomach cancer and in females breast cancer, colorectal cancer, lung cancer, cervical cancer.

1. Lung cancer:

Lung cancer starts in the cells of the lung. A cancerous (malignant) tumour is a group of cancer cells that can grow into and destroy nearby tissue. It can also spread (metastasize) to other parts of the body. When cancer starts in lung cells, it is called primary lung cancer. Lung cancer caused by chronic exposure to tobacco smoke. This epidemic of lung cancer deaths is now receding in some nations where tobacco control has reduced smoking, but it is rapidly rising in others [31].

It is also the leading cause of cancer death among men and the second leading cause of cancer death among women worldwide [32].

2. Prostate cancer:

Prostate cancer begins when cells in the prostate gland start to grow out of control. The prostate is a gland found only in males. It makes some of the fluid that is part of semen. Prostate cancer is a major health issue in men; the incidence mainly dependent on age Prostate cancer remains the second most commonly diagnosed cancer in men, with an estimated 1.1 million diagnoses worldwide [33].

3. Colorectal cancer:

Colorectal cancer is the third most common cancer and the third leading cause of cancer death in men and women in the United States, in part because of historical changes in risk factors (eg, decreased smoking and red meat consumption and increased use of aspirin), the introduction and dissemination of early detection tests, and improvements in treatment [34].

4. Stomach cancer:

Stomach cancer is a leading cause of cancer death, especially in developing countries [35]. Stomach cancer is still the fourth most common cancer and the second most common cause of cancer death in the world. The best established risk factors for stomach cancer are Helicobacter pylori infection, the by far strongest established risk factor for distal stomach cancer, and male sex, a family history of stomach cancer, and smoking. While some factors related to diet and food preservation, such as high intake of salt-preserved foods and dietary nitrite or low intake of fruit and vegetables, are likely to increase the risk of stomach cancer, the quantitative impact of many dietary factors remains uncertain, partly due to limitations of exposure assessment and control for confounding factors [36]. Stomach cancer, also called gastric cancer, starts in the stomach.

5. Breast cancer:

Breast cancer develops from breast tissue. Signs of breast cancer may include a lump in the breast, a change in breast shape, dimpling of the skin, and fluid coming from the nipple, a newly-inverted nipple, or a red or scaly patch of skin. Breast cancer is the most common cancer diagnosed among US women, accounting for nearly one in three cancers. It is also the second leading cause of cancer death among women after lung cancer [37]. Breast cancer is the commonest cause of cancer death in women worldwide [38].

6. Cervical cancer:

Cervical cancer is cancer of the cervix. The cervix is the lower, narrow opening of the uterus. It leads from your uterus to your vagina. Your cervix looks kind of like a donut if you look at it through your vagina. Human papiloma virus (HPV), with double stranded DNA is the cause of sexually transmitted disease and also has been linked strongly with cervical cancer [39].

Causes of cancer

1. Smoking

2. Obesity and weight

3. Sun and UV

4. Alcohol

5. Diet and healthy eating

6. Physical activity

7. Infections(such as HPV)

8. Air pollution and radon gas [40].

Conventional dosage form available for cancer:

With fully integrated development and manufacturing services for solid dosage forms liquids, creams and both sterile and non-sterile ointments, our experts develop and manufacture drug products with success. There is various conventional dosage form available in the market as shown in the Table1.

Table 1: Conventional dosage forms are available for cancer.

S. No.	Brand name	Active ingredient	Dosage form	Reference
1	Abraxane	Nab-paclitaxel	Intravenous powder for injection	[41]
2	Adriamycin	Doxomubicin	injection	[42]
3	Carboplatin	Paraplatin	injection	[43]
4	Cytoxon	Cyclophosphamide	By mouth in tablet form injection in to vein	[44]
5	Daunorubicin	Cerubidine	Injection in to vein	[45]
6	Doxil	Doxomubicin	Injection in vein	[46]
7	Ellence	Epirubicin	intravenous	[47]

Novel drug delivery systems (NDDS):

Various drug delivery systems have been developed and some of them under development with an aim to minimize drug degradation or loss, to prevent harmful side effects and to improve drug bioavailability and also to favors and facilitate the accumulation of the drug in the required bio- zone (site). There are no. Of novel carries which have been established and documented to be useful for controlled and targeted drug delivery. It is important to critically evaluate different terms used under the different broad categories of novel drug delivery system [48,71-73].

· Sustained- or controlled- drug delivery systems provide drug action at a pre determined rate by providing a prolonged or constant (Zero-order) release respectively, at the therapeutically effective levels in the circulation [74-76].

· Localized drug delivery devices provide drug action through spatial or temporal control of drug release (usually rate- limiting) in the vicinity of the target [77-79]. There are various aims of Novel drug delivery system as shown in Figure 3 [80].

Fig3: Aims for new drug delivery system

There are different types of drug delivery vehicles, such as polymeric micelles, liposomes, lipoprotein-based drug carriers, nano-particle drug carriers, dendrimers, etc.

1. Liposome

2. Phytosome

3. Nanoemulsion

4. Microsphere

5. Ethosomes

6. Transferosomes

7. Microbubbles

8. Carbon nanotubes

1. Liposome:

This is most common vehicle currently used for targeted drug delivery [28]. They are are non-toxic, non-hemolytic, biocompatible and biodegradable and non-immunogenic.They are specially designed to avoid clearance mechanisms like reticuloendothelial system (RES), renal clearance, chemical or enzymatic inactivation, etc.) [49] Lipid-based, ligand-coated nanocarriers can store their goods in the hydrophobic shell or the hydrophilic interior depending on the nature of the drug/contrast agent being carried [50]. But difficulty with liposomes in vivo is their immediate uptake and clearance by the RES system and their relatively low stability in vitro. Polyethylene glycol (PEG) can be added to the surface of the liposome to overcome this problem [51].

2. Polymeric micelles:

Drug delivery using micellar solutions of amphiphiles is an effective way of delivering drugs to their targets. Due to the hydrophobic environment of the core of micelles, water insoluble drugs can easily be solubilized and thus loaded for delivery at the required targets. Targeted drug delivery systems are developed to produce minimum drug degradation and loss, prevent harmful side effects, increase drug bioavailability and enhance the amount of drugs at the required zone of interest. A variety of drugcarriers such as soluble polymers, insoluble natural and synthetic polymers, micro particles, cells, cell ghosts, lipoproteins, liposomes, and amphiphilic polymers based micellar systems are extensively used [52-53]. As the threshold of renal clearance of nanoparticles is ̴ 5.5 nm and the size of polymeric micelles is above the threshold for filtration by kidneys, so, polymeric micelles have maximum drug loading capacity and ability to carry many drugs with prolonged circulation times [54-55]

Fig4: Liposome for drug delivery system

3. Lipoprotein based drug carriers:

Lipoproteins also have a strong potential to serve as drug-delivery vehicles due to their small size, long residence time in the circulation and high-drug payload. Consequently, lipoproteins and synthetic/reconstituted lipoprotein preparations have been evaluated with increasing interest towards clinical applications, particularly for cancer diagnostics/imaging and chemotherapy. Lipoprotein-based nanoparticles have the potential to overcome these limitations and have already proven to be a superior drug-delivery platform for cancer theranostics due to their extremely small size, lack of immunogenic response and selective targeting [56, 57, 58]. Recently, the repositioning of a drug, valrubicin, via enhancing its solubility and selective targeting by incorporation into reconstituted HDL (rHDL) nanoparticles has been demonstrated [59] Lipoproteins are endogenous carriers of lipids and lipophilic compounds [60]

Figure 6: Structure of Lipoprotien

4. Dendrimers:

Dendrimers are the emerging polymeric architectures that are known for their defined structures, versatility in drug delivery and high functionality whose properties resemble with biomolecules [61-63]. These nanostructured macromolecules have shown their potential abilities in entrapping and/or conjugating the high molecular weight hydrophilic/hydrophobic entities by host-guest interactions and covalent bonding (prodrug approach) respectively. The introduction of highly branched, well-defined molecular architectural polymers, i.e. Dendrimers, firstly in 1978 by Vogtle has provided a novel and one of the efficient nanotechnology platforms for drug delivery [64-66]. Dendrimers are three-dimensional, immensely branched, well-organized nanoscopic macromolecules (typically 5000-500, 000 g/mol), possess low polydispersity index and have displayed an essential role in the emerging field of nanomedicine [67-70].

Fig 7: Hyper branched molecules for dendrimers

ACKNOWLEDGEMENT:

Authors want to acknowledge Dr. A. K. Jha. Principal of Shri Shankaracharya Technical Campus, SSGI, Faculty of Pharmaceutical Sciences, Bhilai, Chhattisgarh for providing facilities to compete work in stipulated period of time.

CONCLUSION:

There are sufficient number of phytoconstituents, which could be an important part of novel formulation. The modern prospect of plant constitute delivery development is extremly encouraging. There is incredible capability of herbal delivery to be a safe, effective, conventient and economic treatment. In any case, herbal formulation development studies are usually exploratory to date and need active expansion. It is widely expected that utilization of herbal drug delivery will make novel therapeutics, changing the prospect of phyto-pharmaceutical industries. Development of phyto-constituent delivery can help in achieving constituent quality, bioavailability and therapeutic effects of herbal drugs and product. It will be evolving very soon for the benefit of humanity at large.

REFERENCES:

1. Sharma V, Gupta M, Chauhan DN, Chauhan NS, Goyal RK, Shah K. Novel Drug Delivery Systems for Phytoconstituents: Current and Future Prospects. Novel Drug Delivery Systems for Phytoconstituents. 2019 Jul 23:

2. Tamilselvi N, Krishnamoorthy P, Dhamotharan R, Arumugam P, Sagadevan E. Analysis of total phenols, total tannins and screening of phytocomponents in Indigofera aspalathoides (Shivanar Vembu) Vahl EX DC. Journal of Chemical and Pharmaceutical Research. 2012;4(6):3259-62.

3. Csupor D, Wenzig EM, Zupkó I, Wölkart K, Hohmann J, Bauer R. Qualitative and quantitative analysis of aconitine-type and lipo-alkaloids of Aconitum carmichaelii roots. Journal of Chromatography A. 2009 Mar 13;1216(11):2079-86.

4. Chan C, Zheng S, Zhou B, Guo J, Heid RM, Wright BJ, Danishefsky SJ. The solution to a deep stereochemical conundrum: Studies toward the tetrahydroisoquinoline alkaloids. Angewandte Chemie International Edition. 2006 Mar 6;45(11):1749-54.

5. Wolfenden R, Lu X, Young G. Spontaneous hydrolysis of glycosides. Journal of the American Chemical Society. 1998 Jul 15;120(27):6814-5.

6. Varma N. Phytoconstituents and their mode of extractions: An overview. Res. J. Chem. Environ. Sci. 2016;4(2):8-15.

7. Singh JP, Selvendrian K, Banu SM, Padmavathi R and Salethisekaran D: Protective role of Apigenin on the status of lipid peroxidation and antioxidant defense against heptocarcinogenesis in Wister albino rats. Phytomedicine 2014; 11: 309-314.

8. Yin F, Giuliano AE, Law RE and Van Harle AJ: Apigenin inhibit growth and induces G21M arrest by modulating cyclin-CDK regulators and ERK MAP kinase activation in breast carcinoma cells. Anticancer Res 2011; 21: 413-420.

9. Patel D, Shukla S and Gupta S: Apigenin and cancer chemoprevention: progress, potential and promise (Review). Int J Onco 2007; 30: 233-245.

10. Lin JK, Chen YC, Husang YT and Lin-Shian SY: J: Suppression of protein kinease C and nuclear oncogene expression as possible molecular mechanism of cancer chemoprevention by apigenin and curcumin. Cell Biochem 1997; (Suppl)28-29: 39-48.

11. Choi EJ and Kin GW: 5-Fluorouracil combined with apigenin enhances anticancer activity through induction of apoptosis in human breast cancer MDA-MB-453 cells. Oncology Reports 2009; 22: 1533-1537.

12. Ammon HPT and Wahl MA: Pharmacology of Curcuma longa. Planta Med 1991; 57: 1-7

13. Vopel G, Gaisbaver M and Winker W: Phytotherapie in der Prexis: Deutscher Arzte-verlay 1990; 74.

14. Chen HW and Huang HC: Effect of curcumin on cell cycle progression and apoptosis in vascular smooth cells. Br J Pharma col 1998; 124: 1029-1040.

15. Martin-Cordero C, Loper-Lazaro M, Galvez M and Ayuso MJ: Curcumin as a DNA topoisomerase II poison. J Enzyme Inhib. Med Chem 2003; 18: 505-509.

16. Khar A, Ali AM, Pardhasaradhi BV, Varalakshmi CH, Anjum R and Kumari AL: Induction of stress response renders human tumor cell lines resistant to curcumin mediated apoptosis: role of reactive oxygen intermediates. Cell Stress Chaperones 2001; 6: 368-376.

17. Chattopadhyay I, Biswas K, Bandyopadhyay U and Banerjee RK: Turmeric and Curcumin: Biological actions and medicinal applications. Current Science 2004; 87(1): 44-53.

18. Broadbent TA and Broadbent HS: The chemistry and pharmacology of indole-3-carbinol (indole-3-methanol) and 3-(methoxymethyl) indole [part II]. Curr Med Chem 1998; 5: 469-491.

19. Hong C, Firestone GL and Bjeldanes LF: BCl-2 family –mediated apoptotic effects of 3, 3’-diindelymethane (DIM) in human breast cancer cells. Biochem Pharmacol 2002; 63: 1085-1097.

20. Bonnesan C, Eggleston IM and Hayes JD: Dietary indoles and isothiocynates that are generated from cruciferous vegetables can both stimulate apoptosis and confer protection against DNA damage in human colon cell lines. Cancer Res 2001; 61: 6120-6130.

21. Chinni SR, Li Y, Upadhyay S, Koppolu PK and Sarkar FH: Indole -3- carbinol (I3C) induced cell growth inhibition, G1 cell cycle arrest and apoptosis in prostate cancer cells. Oncogene 2001; 20: 2927-2936.

22. Aggarwal BB and Ichikawa H: Molecular Targets and Anticancer Potential of Indole-3-carbinol and its derivative. Cell Cycle 2005; 4(9): 1201-1215.

23. Arai Y, Wantnable S, Kimira M, Shimoi K, Mochizuki R and Kinae N: Dietary intakes of flavanols, flavones and isoflavones by Japanese woman and inverse correlation between quercetin intake and plasma LDL cholesterol concentration. Nutr 2000; 130: 2243-2250.

24. Higa S, Hirano T and Kotani MJ: Allergy Fisetin a flavanol inhibits TH2-type cytokine production by activated human basophils. Clin Immunol 2003; 111: 1299-1306.

25. Khan N, Afaq F, Sayed DN and Mukhtal H: Fisetin, a novel dietary flavonoid, causes apoptosis and cell cycle arrest in human prostate cancer LMCaP cells. Carcinogenesis 2008; 29: 1049-1056.

26. Pei-Ming Y, Ho-heing T, Chin-ween P, Wen-shu C and Shu-Jun C: Dietary flavonoid fisetin targets caspase-3-deficient human breast cancer MCF-7 cells by induction of caspase-7- associated apoptosis and inhibition of autophagy. International Journal of Oncology 2012; 40: 469-478.

27. Nair MK, Varghese C, Swaminathan R. Cancer: Current scenario, intervention strategies and projections for 2015. NCHM Background papers-Burden of Disease in India. 2005:219-5.

28. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2019. CA: a cancer journal for clinicians. 2019 Jan;69(1):7-34.

29. Singh S, Sharma B, Kanwar SS, Kumar A. Lead phytochemicals for anticancer drug development. Frontiers in Plant Science. 2016 Nov 8;7: 1667.

30. Singh S, Sharma B, Kanwar SS, Kumar A. Lead phytochemicals for anticancer drug development. Frontiers in Plant Science. 2016 Nov 8;7: 1667.

31. Jemal A, Siegel R, Ward E, Murray T, Xu J, Thun MJ. Cancer statistics, 2007. CA: A Cancer Journal for Clinicians. 2007 Jan;57(1):43-66.

32. Lee JW, Soung YH, Kim SY, Lee HW, Park WS, Nam SW, Kim SH, Lee JY, Yoo NJ, Lee SH. PIK3CA gene is frequently mutated in breast carcinomas and hepatocellular carcinomas. Oncogene. 2005 Feb;24(8):1477.

33. Enzinger FM. Epithelioid sarcoma. A sarcoma simulating a granuloma or a carcinoma. Cancer. 1970 Nov;26(5):1029-41.

34. Miller AJ, Mihm Jr MC. Melanoma. New England Journal of Medicine. 2006 Jul 6;355(1):51-65

35. Gundrum JD, Mathiason MA, Moore DB, Go RS. Primary testicular diffuse large B-cell lymphoma: a population-based study on the incidence, natural history, and survival comparison with primary nodal counterpart before and after the introduction of rituximab. Journal of Clinical Oncology. 2009 Sep 21;27(31):5227-32.

36. Saraf S, Kaur CD. Phytoconstituents as photoprotective novel cosmetic formulations. Pharmacognosy reviews. 2010 Jan;4(7):1.

37. Torre LA, Siegel RL, Jemal A. Lung cancer statistics. Lung cancer and Personalized Medicine. 2016:1-9.

38. Mottet N, Bellmunt J, Briers E, Bolla M, Bourke L, Cornford P, De Santis M, Henry AM, Joniau S, Lam TB, Mason MD. EAU-ESTRO-ESUR-SIOG Guidelines on.

39. Siegel R, DeSantis C, Jemal A. Colorectal cancer statistics, 2014. CA: A Cancer Journal for Clinicians. 2014 Mar;64(2):104-17.

40. Arnold M, Moore SP, Hassler S, Ellison-Loschmann L, Forman D, Bray F. The burden of stomach cancer in indigenous populations: a systematic review and global assessment. Gut. 2014 Jan 1;63(1):64-71.

41. Brenner H, Rothenbacher D, Arndt V. Epidemiology of stomach cancer. Cancer Epidemiology. 2009:467-77.

42. DeSantis CE, Fedewa SA, Goding Sauer A, Kramer JL, Smith RA, Jemal A. Breast cancer statistics, 2015: Convergence of incidence rates between black and white women. CA: A Cancer journal For Clinicians. 2016 Jan;66(1):31-42.

43. Key TJ, Verkasalo PK, Banks E. Epidemiology of breast cancer. The Lancet Oncology. 2001 Mar 1;2(3):133-40.

44. Mortazavi S, Zali M, Raoufi M, Nadji M, Kowsarian P, Nowroozi A. The prevalence of human papillomavirus in cervical cancer in Iran. Asian Pac J Cancer Prev. 2002;3(1):69-72.

45. Bernstein C, Prasad AR, Nfonsam V, Bernstein H. DNA damage, DNA repair and cancer. New Research Directions in DNA Repair. 2013 May 22.

46. Miele E, Spinelli GP, Miele E, Tomao F, Tomao S. Albumin-bound formulation of paclitaxel (Abraxane® ABI-007) in the treatment of breast cancer. International Journal of Nanomedicine. 2009;4:99.

47. Keizer HG, Pinedo HM, Schuurhuis GJ, Joenje H. Doxorubicin (adriamycin): a critical review of free radical-dependent mechanisms of cytotoxicity. Pharmacology & Therapeutics. 1990 Jan 1;47(2):219-31.

48. Marani TM, Trich MB, Armstrong KS, Ness PM, Smith J, Minniti C, Sandler SG. Carboplatin‐induced immune hemolytic anemia. Transfusion. 1996 Nov 12;36(11‐12):1016-8.

49. Desprez JD, Kiehn CL. The effects of cytoxan (cyclophosphamide) on wound healing. Plastic and Reconstructive Surgery. 1960 Sep 1;26(3):301-8.

50. Dzięgiel P, Suder E, Surowiak P, Jethon Z, Rabczyński J, Januszewska L, Sopel M, Zabel M. Role of exogenous melatonin in reducing the nephrotoxic effect of daunorubicin and doxorubicin in the rat. Journal of Pineal Research. 2002 Sep;33(2):95-100.

51. Lyass O, Uziely B, Ben‐Yosef R, Tzemach D, Heshing NI, Lotem M, Brufman G, Gabizon A. Correlation of toxicity with pharmacokinetics of pegylated liposomal doxorubicin (Doxil) in metastatic breast carcinoma. Cancer: Interdisciplinary International Journal of the American Cancer Society. 2000 Sep 1;89(5):1037-47.

52. Effexor XR. Evidence Supporting Use of Ellence®. AWHONN Lifelines.;7(1).

53. Khan MG. Topic-the novel drug delivery system. World of Pharmacy and Pharmaceutical Science ISSN2278 – 4357.

54. Seidman A, Hudis C, Pierri MK, Shak S, Paton V, Ashby M, Murphy M, Stewart SJ, Keefe D. Cardiac dysfunction in the trastuzumab clinical trials experience. Journal of Clinical Oncology. 2002 Mar 1;20(5):1215-21.

55. Reddy PB, Gupta J, Sushma P. Recent Trends in Smart Drug Delivery. Life Sciences International Research Journal, ISSN.:2347-8691.

56. Pili R, Rosenthal MA, Mainwaring PN, Van Hazel G, Srinivas S, Dreicer R, Goel S, Leach J, Wong S, Clingan P. Phase II study on the addition of ASA404 (vadimezan; 5, 6-dimethylxanthenone-4-acetic acid) to docetaxel in CRMPC. Clinical Cancer Research. 2010 May 15;16(10):2906-14.

57. Scott RC, Crabbe D, Krynska B, Ansari R, Kiani MF. Aiming for the heart: targeted delivery of drugs to diseased cardiac tissue. Expert Opinion on Drug Delivery. 2008 Apr 1;5(4):459-70.

58. Couvreur P, Puisieux F. Nano-and microparticles for the delivery of polypeptides and proteins. Advanced Drug Delivery Reviews. 1993 May 1;10(2-3):141-62.

59. Lasic DD. Doxorubicin in sterically stabilized liposomes. Nature. 1996 Apr; 380(6574):561.

60. Ueyama T, Kawashima S, Sakoda T, Rikitake Y, Ishida T, Kawai M, Yamashita T, Ishido S, Hotta H, Yokoyama M. Requirement of activation of the extracellular signal-regulated kinase cascade in myocardial cell hypertrophy. Journal of Molecular and Cellular Cardiology. 2000 Jun

61. Choi HS, Liu W, Misra P, Tanaka E, Zimmer JP, Ipe BI, Bawendi MG, Frangioni JV. Renal clearance of quantum dots. Nature Biotechnology. 2007 Oct;25(10):1165.1;32(6):947-60.

62. Aliabadi HM, Lavasanifar A. Polymeric micelles for drug delivery. Expert Opinion on Drug Delivery. 2006 Jan 1;3(1):139-62.

63. Kwon GS, Forrest ML. Amphiphilic block copolymer micelles for nanoscale drug delivery. Drug Development Research. 2006 Jan;67(1):15-22.

64. Kataoka K, Matsumoto T, Yokoyama M, Okano T, Sakurai Y, Fukushima S, Okamoto K, Kwon GS. Doxorubicin-loaded poly (ethylene glycol)–poly (β-benzyl-l-aspartate) copolymer micelles: their Pharmaceutical Characteristics and Biological Significance. Journal of Controlled Release.

65. Ng KK, Lovell JF, Zheng G. Lipoprotein-inspired nanoparticles for cancer theranostics. Accounts of Chemical Research. 2011 May 10;44(10):1105-13.2000 Feb 14;64(1-3):143-53.

66. 4o. Shahzad MM, Mangala LS, Han HD, Lu C, Bottsford-Miller J, Nishimura M, Mora EM, Lee JW, Stone RL, Pecot CV, Thanapprapasr D. Targeted delivery of small interfering RNA using reconstituted high-density lipoprotein nanoparticles. Neoplasia (New York, NY). 2011 Apr;13(4):309.

67. McConathy WJ, Nair MP, Paranjape S, Mooberry L, Lacko AG. Evaluation of snthetic/reconstituted high-density lipoproteins as delivery vehicles for paclitaxel. Anti-Cancer Drugs. 2008 Feb 1;19(2):183-8.

68. Sabnis N, Nair M, Israel M, McConathy WJ, Lacko AG. Enhanced solubility and functionality of valrubicin (AD-32) against cancer cells upon encapsulation into biocompatible nanoparticles. International journal of nanomedicine. 2012;7:975.

69. Gotto Jr AM, Pownall HJ, Havel RJ. [1] Introduction to the plasma lipoproteins. Methods in Enzymology. 1986 Jan 1;128:3-41.

70. Madaan K, Kumar S, Poonia N, Lather V, Pandita D. Dendrimers in drug delivery and targeting: Drug-dendrimer interactions and toxicity issues. Journal of Pharmacy & Bioallied Sciences. 2014 Jul;6(3):139.

71. Sharma H, Dapurkar VK, Rai G, Sahu GK. Microemulsions for the Topical Administration of 5-Fluorouracil: Preparation and Evaluation. Research Journal of Pharmacy and Technology. 2012 Aug 1;5(8):5.

72. Tripathi S, Sahu UK, Meshram J, Kumari R, Tripathi DK, Alexander A, Sharma H, Sahu GK. Formulation and characterization of Virgin Coconut Oil Emulsion (VCOE) for treatment of Alzheimer's disease. Research Journal of Pharmaceutical Dosage Forms and Technology. 2018 Apr 1;10(2):49-54.

73. Sahu P, Mishra S, Sahu GK, Sharma H, Kaur CD. Formulation and Characterization of Resorcinol Gel. Research Journal of Pharmaceutical Dosage Forms and Technology. 2019 Sep 30;11(3):159-63.

74. Sahu K, Pathak R, Agrawal N, Banjare P, Sharma H, Sahu G. A Review of the Novel Drug Delivery System used in the Treatment of Cancer. Research Journal of Pharmaceutical Dosage Forms and Technology. 2019 Sep 30;11(3):199-205.

75. Mandavi N, Ansari N, Bharti R, Kader N, Sahu GK, Sharma H. Microemulsion: A Potential Novel Drug Delivery System. Research Journal of Pharmaceutical Dosage Forms and Technology. 2018;10(4):266-71.

76. Kader N, Ansari N, Bharti R, Mandavi N, Sahu GK, Jha AK, Sharma H. Novel Approaches for Colloidal Drug Delivery System: Nanoemulsion. Research Journal of Pharmaceutical Dosage Forms and Technology. 2018;10(4):253-8.

77. Sharma H, Sahu U, Kumar G, Kaur CD. A Spectrum of Skin Cancer in Kashmir Valley of India: Kangri Cancer. Journal of Atoms and Molecules. 2019;9(1):1196-205.

78. Yesmin R, Karmakar PC, Ali H, Biswas KK. Membrane stabilizing and thrombolytic activities of methanolic extract of Trichosanthes dioica Roxb. Shoot. Journal of Pharmacognosy and Phytochemistry. 2017;6(5):2500-2.

79. Islam M, Hoshen MA, Ayshasiddeka FI, Yeasmin T. Antimicrobial, membrane stabilizing and thrombolytic activities of ethanolic extract of Curcuma zedoaria Rosc. Rhizome. Journal of Pharmacognosy and Phytochemistry. 2017;6(5):38-41.

80. Sahu P, Mishra S, Sahu GK, Sharma H, Kaur CD. Formulation and Characterization of Resorcinol Peel. Research Journal of Pharmacy and Technology. 2019 Sep 30;11(3):159-63.

Received on 08.04.2020 Modified on 10.05.2020

Res. J. Pharma. Dosage Forms and Tech.2020; 12(3):169-177.

DOI: 10.5958/0975-4377.2020.00029.4