Keywords

9.1 Introduction

Herbal medicine is used since ancient times for the treatment of various diseases. Plant-derived phytoconstituents show multiple pharmacological actions and chances of fewer side effects. Developed countries increase the demand for various natural phytoconstituent due to their safety and efficacy. The extract and isolated phytoconstituent play a key role in therapeutic action including anticancer, antibacterial, antidiabetic, antifungal, and antimalarial treatment (Karar and Kuhnert 2017). In the nineteenth century the importance of herbal medicine decreased due to newer synthetic drugs and their quick action helps to get immediate relief. The derived phytoconstituent with synthetic drug shows synergistic action with a decrease in toxicity and resistance (Pal and Shukla 2003) that required carrier formulation for targeted delivery with minimal interaction between therapeutic active ingredients. Phytoconstituent require a significant delivery system to deliver drug in sustain release manner with less adverse effects. The nanocarriers enhance patient compliance and reduce toxicity by increasing therapeutic value. Some phytoconstituents have poor water solubility that leads to decreased bioavailability, therapeutic potential, and stability. To overcome that problem, the development of nanocarriers like nanocapsules, nanospheres liposomes, phytosomes, nanoemulsion, polymeric micelles, colloidal nanogels, solid lipid nanoparticles (SLN) help to enhance solubility, pharmacological effect, and stability. Thus, nanocarriers support the development of novel carriers to overcome problem-related delivery of phytoconstituent (Handa et al. 2022).

In nanocarriers, polymeric micelles are mostly used to improve the water solubility of phytoconstituent with weak solubility by using various copolymers. Mostly amphiphilic block copolymers contain both hydrophilic and hydrophobic block that help to achieve a small size (less than 100 nm). Various parameters affect the size of polymeric micelles including length and molecular weight of copolymers, the ratio of drug and copolymer, surface charge, temperature, and synthesis approach. The small size of polymeric micelles easily crosses the systemic barrier without clogging blood vessels. Polymeric micelles can enhance blood circulation time, increase permeability and absorption, targeting capability with high drug accumulation It supports the delivery of different monoclonal antibodies, proteins, as well as peptides and prevents them from enzymatic breakdown or the outside environment. Polymeric micelles are an effective drug delivery strategy for improving stability and helping to establish a good pharmacokinetic profile of phytoconstituent (Kaur et al. 2021a).

9.2 Micelles

Micelles are colloidal systems formed by the self-assembly of amphiphilic nanocarriers containing hydrophilic heads and hydrophobic tails in aqueous solvents. The hydrophilic shell dissolves in the aqueous phase which helps to deliver a drug that is poorly soluble in water present inside the hydrophobic core. The size of micelles is less than 50 nm (Aguilar 2013). Majorly non-ionic type of surfactant is used for delivery of drug through oral or parental route with less adverse effects than ionic surfactant. Non-ionic surfactant produces clear as well as stable micellar solution and has better targeting ability. The aggregates of surfactant rise different shapes of micelles and they are classified as spherical shape micelles, rod-shaped micelles, hexagonal phases, and lamellar phases (refer Fig. 9.1). Only the lamellar phase has the property to form reverse and normal orientation. The surfactant concentration changes the shape of micelles. In oil-in-water, they show the normal lamellar micelles, while the water-in-oil phase shows reverse lamellar micelles. Solvents like hexane, cyclohexane, and benzene show reverse orientation of micelles formation. The dilution of surfactant solution may alter the shape of micelles like spherical micelles change into lamellar phase, these create dose dumping related problems in the body. In polymeric micelles, the polymer creates specific cross-linking that helps to stabilize the micelles. They form polymeric aggregates with micelles using a polymerization reaction. Reverse micelles show aggregation in non-polar media. These phenomena are used for the reparation of therapeutic aerosols and metered dose inhalers (MDI) (Lawrence 1994).

Fig. 9.1
An illustration of 7 different shapes of micelles including surfactant molecule, spherical micelles, rod-shaped micelles, lamellar phase, hexagonal micelles, reverse micelles and reverse hexagonal micelles.

The different shapes of micelles formed above the critical micellar concentration (CMC)

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Most of the internal body preparation contains a non-ionic surfactant that polyoxymethylated non-ionic surfactant has greater importance in ophthalmic preparation. J. Jiao describes the role of non-ionic surfactants in the delivery of water-insoluble compounds through the micellization process. The water-insoluble drug is partitioned into the micelles forming surfactant molecules. The micelle’s core polarity plays important role in the shape as well as the size of a micelle but they do not alter the surfactant arrangement. Generally, the core polarity is inversely proportional to micelle solubilization. Polyethoxylated non-ionic surfactants like Cremophor EL has smaller micelle core polarity of about 1.05 and a bigger one is Triton X-100 that has 1.40 (Jiao 2008).

9.3 Polymeric Micelles

Polymeric micelles are a novel approach in nano delivery and contain core shells that have self-association formed by amphiphilic block copolymer inside water and the capacity to retain hydrophobic phytoconstituent within the core of micelles. In 1984, Bader et al. proposed different polymeric systems for the transport of a biologically active substance. They mentioned hydrophilic or hydrophobic cores are formed by micellar structure (Bader et al. 1984). Polymeric micelles have a size of about 10–100 nm. Depending on copolymer molecular weight, the chain length of the hydrophilic and hydrophobic copolymer affects the size. Polymeric micelles have a powerful tool for the delivery of less water-soluble drugs and also help in solubilization improvement. Other properties shown by polymeric micelles are attaining sustained release profile, protect the drugs from the activity of various enzymes, and help to accumulate the drug to the targeted location. Additional qualities include high biocompatibility, low toxicity, micellar association, core-shell, and high stability. Due to poor solubility problems, various phytoconstituent did not achieve the marketing potential and show toxicity problems by drug or excipient or both in the formulation. S. Croy et al. estimated that in 1999 total market sale of poorly water-soluble drugs was about $37 billion, even the formulation-related problems affect the market potential (Aliabadi and Lavasanifar 2006). There are various techniques to enhance the solubility of poorly or less water-soluble drugs using crystal modification, salt formation, and cocrystal formation are used, but using altering the pH technique decrease the chances of forming stable moiety. The counterions present in salt form also affect the dissolution rate of very poor water-soluble drugs. Reduction in particle size is another approach to enhance solubility. Also micronization of active ingredient done through using instruments like a jet mill or ball mill, nanocrystal formation by wet milling or high-pressure homogenization these methods mostly used. The major drawback of is affect the stability of heat liable phytoconstituent and API (Kawabata et al. 2011). Chemical entities obtained from a natural source or semisynthetic derivative show toxic action above a certain limit. Certain vehicles and cosolvents are used for the solubilization of water-insoluble drugs. In unionized drugs, cosolvents like ethanol, polyethylene glycol, propylene glycol, and dimethylacetamide show a toxicity profile by the increasing amount in the formulation. H. Gelderblom et al. studied the drawbacks as well as the advantage of Cremophor EL as a vehicle. Cremophor EL improves the solubility of water-insoluble as well as very less water-soluble drugs including various anticancer agents. Cremophor EL is a heterogeneous non-ionic surfactant that acts as a formulation carrier and solubility enhancer. An anticancer drug like the Paclitaxel derivative of Taxol has hardly water soluble and has a solubility of less than 0.03 mg/mL. It is slightly soluble in octanol, butanol, and propylene glycol and freely soluble in methanol, acetone, ethanol, chloroform, ether, and Cremophor EL. United States Pharmacopeia (USP) choose the 1:1 ratio mixture of Cremophor EL and dehydrated ethanol used to dissolve 30 mg paclitaxel in a 5 mL mixture. The research study found that Cremophor EL with paclitaxel shows severe anaphylactoid hypersensitivity reactions. Other symptoms of Cremophor EL like red rashes on body, skin flushing, dyspnoea, hypotension, and chest pain. One major side effect of Cremophor EL is neurotoxicity, peripheral neuropathy with axonal degeneration and demyelination. Therefore, a novel version of paclitaxel that is free of Cremophor EL is currently being developed. In that Cremophor EL is replaced by cosolvents like ethanol, Tween 80 and polymeric micelles help to increase bioavailability and decrease side effects (Gelderblom et al. 2001).

9.4 Polymers Used in the Preparation of Polymeric Micelles

Different polymers are mainly used in the preparation of polymeric micelles. The graft copolymers like chitosan on vinyl monomers and stearic acid, di-block copolymers like polyethylene glycol (PEG), and polystyrene and triblock polymer including polyethylene oxide and polypropylene oxide (refer Fig. 9.2). These polymers protect the drug from degradation and provide in vivo stability, enhanced efficiency, and biocompatibility. The block copolymer role in polymeric micelles is to enhance the solubility of hydrophobic molecules in a hydrophobic core stabilized by a hydrophilic aura. Block copolymers also play an important role in targeted delivery in both active and passive ways. They help to enhance circulation time and decrease the lysosomal activity in the presence of a hydrophilic shell. Polymeric micelle’s nano range size makes it easier for them to pass through numerous barriers. Block copolymers are classified according to intermolecular interaction in the core segment. They are classified as polyion complex micelles, amphiphilic micelles, and micelles stemming from metal complexation. In that polyion complex micelles formed by electrostatic interaction, while amphiphilic micelles resulting from hydrophobic interactions (Nishiyama et al. 2001). In block copolymer the shapes of polymeric micelles are spherical, and the chain length in the core region increases showing the direct effect on the shape of polymeric micelles. As the long core polymeric micelles become rod and lamellae shape. In polyion complex micelles are formed by segregation and neutralization of oppositely charged ions. The property of electrostatic interaction is due to the interaction between polycation and polyanion. Di-block copolymers mostly contain PEG’s primary role in the hydrophilic segment. The polymerization reaction starts by using initiators like alpha-methoxy, hydroxyl group, and omega amino group. Here ethylene oxide is the functional initiator to achieve anionic polymerization and methoxy group as growing block polymer at the end terminal. If two or more than two di-block copolymers are coupled to produce multiblock copolymers. The coupling reaction produces a side product that should be avoided. The multifunctional core formed by coupling helps to initiate polymerization in the shell. This mechanism applied for the synthesis of poloxamers is a triblock copolymer that incudes polyethylene oxide (PEO), polypropylene oxide (PPO), and polyethylene oxide (PEO) (Gaucher et al. 2005; Singh et al. 2022).

Fig. 9.2
2 diagrammatic representations. A graft copolymer is on the left, and a block copolymer with a surface labeled at the bottom is on the right.

Diagrammatic representation of graft and block copolymers attached on a surface

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Graft copolymers are large-sized macromolecules in which one or more blocks are attached to the main chain. Mostly monomolecular micelles formed from graft polymer contain multiple branches of macromolecules with covalent linkage. The bonds formed by side connecting the block to the main chain behave as a side chain showing constitutional or configurational features. The structure of graft polymer is comb-shaped. The preparation of graft copolymer is simple than block copolymer. The graft polymers prepared by long chain of one monomer is attached to the main chain backbone polymer through the process of polymerisation. The large-sized monomers of macromolecules best way to synthesize the graft copolymer. The graft polymerization helps to modify the physicochemical properties of cellulose. In cellulose, the surface creates certain grafts of synthetic polymers. It helps to impart specific properties on cellulose surfaces without altering intrinsic properties. The various grafting approaches are used for polymerization of cellulose, in that “grafting from” approach is mostly used. In the “grafting from” technique, the development of the polymer chain takes place at the cellulose’s beginning point. The advantage of this method is the high graft density of polymer observed on cellulose derivative (Roy et al. 2009) (refer Table 9.1).

Table 9.1 Type and structures of amphiphilic copolymer
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9.5 Mechanism of Micelle Formation

Two forces play important role in micelle formation: one is the attractive force used for the association of molecules and the other is repulsive for controlling the growth of micelles. Mostly amphiphilic copolymers play a selective role in hydrophilic as well as hydrophobic copolymers. In polymeric micelles, the formation process is the same as for micelles formed by surfactants. The micellization process starts with a low concentration of polymer, they form a single chain of the polymer. The critical micelle concentration (CMC) is concentration in which below that polymer exist at single molecule and above CMC they self assemble into micelles. The micelles are formed in a way that hydrophobic regions avoid the aqueous phase and tail-like structures are shown by hydrophilic regions in which the polymer is diluted (refer Fig. 9.3). Loose aggregates in micelles are formed due to the increased size of micelles at high concentrations (Jones and Leroux 1999). In comparison to phospholipids and surfactants, amphiphilic block copolymers often display greater stability and durability. It encapsulates the drug and enhances its stability and bioavailability. Critical micelle temperature (CMT) of the copolymer also archives micellar formation same way as CMC. The detailed mechanism of polymeric micelles from the growth of micelles to the encapsulation of drug or phytoconstituent by copolymer is recently unknown (Li et al. 2019).

Fig. 9.3
A schematic representation. In amphiphilic copolymer, if critical micelle concentration is greater, it produces drug-loaded polymeric micelles with the addition of hydrophobic drugs. The reverse process happens if the critical micelle concentration is lesser.

Schematic representation shows formation of drug loaded polymeric micelles

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9.6 Phytoconstituents

Ayurveda is one of the ancient and traditional medicine systems that originated over thousands of years. Ayurveda comes from a combination of two Sanskrit words Ayur means life and Veda means science. It describes the science of life. Ayurveda is also known as the “Mother of All Healing.” It describes knowledge about herbal medicine and its use for curing various diseases. Ayurveda listed more than 700 plants containing various phytoconstituents used for treating various diseases. At present time advanced techniques are available that help to separate phytochemicals from different herbs. A very small amount of potent active phytochemicals are obtained from the bulky raw materials of herbals (Parasuraman et al. 2014).

The phytoconstituents are non-nutritive and contain chemical compounds obtained in the plant for their protective action. These are secondary metabolites of plants with active therapeutic properties. Phytochemistry directs the qualitative as well as quantitative activities of phytoconstituents and also checks the biological activities. The active drug constituent in plants plays important role in pharmacological activity. Inert nondrug constituent is preferred as an excipient such as bulking agent (Alamgir 2018). The phytoconstituents contain phenolics, alkaloids, cryogenics, saponins, glycosides, terpenes, tannins, anthraquinones, steroids, and various essential oils. In plants, they play a role in protection against various infection, pathogens, and microbes These phytoconstituent has potent inhibitor activity against enzyme that leads to desired pharmacological actions. The collecting of phytoconstituent from the herbal plant in high percentage yield requires special collection skills. Ayurveda describes the specific period from a selection of land to collection time, they affect yield percentage and potency of phytoconstituent. Chemo-profiling is an advanced way for standardization of several groups and classes in phytoconstituent obtained and fingerprinting used for evaluation purposes. Additionally, a variety of chromatographic methods, including gas chromatography (GC), high-performance liquid chromatography (HPLC), thin layer chromatography (TLC), and high-performance thin layer chromatography (HPTLC), are used to separate phytoconstituent from herbal for both lab and industrial scales (Akinyemi et al. 2018).

Different phytoconstituents from herbal plants are employed in nutraceuticals and the treatment of many ailments. Akinyemi et al. mentioned the global market for herbal medicine is about US $80 billion annually and grows daily. In some West African countries like Nigeria, Ghana, Mali, and Zambia about 60% of children show primary symptoms of malaria like fever treated at home using herbal medicines. WHO has declared that 11% of synthetic drugs obtained from plant origin mostly for treating diseases like cancer, bacterial, and viral about 60% of drugs in a clinical trial are from natural origin. A daily increment is observed in the usage of life-saving medications made from herbal plants and their phytoconstituents (Akinyemi et al. 2018).

9.7 Role of Nanocarriers for Delivery of Phytoconstituent

Herbal phytoconstituents are a safer alternative for achieving therapeutic delivery systems. The modification in plant-derived medicines is required to enhance stability and solubility. These approaches give rise to nanocarriers for the delivery of various phytoconstituents and behave as novel drug delivery systems (NDDS). The major limitation of phytoformulation is shown toxicity due to the low therapeutic index of phytoconstituents determined by performing toxicity analysis. Different nanocarriers help to enhance the therapeutic index and decrease cytotoxicity. Other factors as entrapment efficacy and drug loading are considered important parameters in nanodelivery systems. Therapeutic phytoconstituents are delivered via a variety of nanocarriers including liposomes, polymeric micelles, dendrimers, phytosomes, nanocrystals, dendrimers, nanoemulsion, cerasomes, and nanocrystals. Various nanoparticles like silica-based nanoparticles, solid lipid nanoparticles, and magnetic nanoparticles have an adjuvant role in the delivery of phytoconstituent (Ng et al. 2020).

V. D. Leo et al. prepared liposomes containing curcumin for targeted drug delivery to the colon. In that liposomes are coated with Eudragit S100 and act as a pH-responsive polymer and a characterization study is performed. Curcumin is a polyphenol derivative naturally obtained from roots and rhizomes of Curcuma longa and belongs to family Zingiberaceae. For centuries, there are potential advantages of curcumin like antibacterial, antiviral, antioxidant, anticancer, and anti-inflammatory. Curcumin has low solubility, poor bioavailability, high metabolism, and clearance as a phytoconstituent. These limitations are overcome by the preparation of curcumin liposomes. The small unilamellar vesicles of curcumin (size up to 100 nm) were prepared by solvent-free micelle-to-vesicle transition method (MVT) and then coated with Eudragit S100 polymer. The small unilamellar vesicles of curcumin (sized up to 100 nm) are prepared by the solvent-free micelle-to-vesicle transition method (MVT) and then coated with Eudragit S100 polymer. These liposomes help to enhance release rate, high encapsulation efficacy, better stability, and enhanced bioavailability (De Leo et al. 2018). Y.-M. Tsai et al. describe the kinetic study of curcumin and its ability to cross BBB using Curcumin-loaded PLGA nanoparticles for cancer treatment. The nanoparticles are prepared by emulsification solvent evaporation technique and further characterized by performing pharmacokinetic studies on different organs containing the brain, spleen, lung, liver, and kidney performed. A significant change in parameters half-life, average residence time, and area under the concentration curve (AUC) in PLGA nanoparticles of curcumin is higher than normal curcumin. This nanoformulation increases the accumulation of drugs at the target organ (Tsai et al. 2011).

Phytosomes are nanodelivery systems made up of phyto-phospholipid complex structurally similar to liposomes. The lipid complex contains a phospholipid head group and two long fatty chains work to encapsulate the polar part of the chain from the lipophilic surface. Phyto-phospholipid complex structurally works to enhance permeability and bioavailability. Most of the constituents derived from plants are polyphenols and biologically active with a high affinity toward the water. But some of them have poor permeability and even do not cross biological membranes like hesperidin as same in poorly water-soluble phytoconstituent like curcumin and rutin. The phytosomes most promising approach is to enhance the solubility of lipophilic polyphenol phytoconstituent and enhance the permeability of hydrophilic ones. Instead of that phytosomes protect the active constituent from degradation and other chemical factors like oxidation, hydrolysis, and photolysis (Lu et al. 2019).

Volatile oils are the secondary metabolite of plants derived from various oil glands and secretory cells. They have a regulatory role and complex mechanism to treat disease. About 60 families contain volatile oils including Zingiberaceae, Alliaceae, Umbelliferae, Lauraceae, Dipterocarpaceae, Compositae, etc. (Zhang et al. 2021). R.K. Harwansh et al. reported the formulation for delivery of active phytoconstituent in the form of nanoemulsion. Nanoemulsion droplets range in size from 20 to 200 nm. It may vary depending on the method of preparation and homogenization method used. The smaller is the size of globules in emulsion, leads to enhance surface area and it help to improve the solubility profile of drug. To create a clear and transparent formulation, a precise ratio of oil, water, and a combination of surfactant and co-surfactant is needed (Harwansh et al. 2019). The preparation of Quercetin containing nanoemulsion-based gel and its characterization is reported by J.P. Gokhale et al. for the management of rheumatoid arthritis (RA) using quercetin as a disease-modifying anti-rheumatic drug (DMARDs). Quercetin shows anti-inflammatory activity by inhabiting nitric oxide, IL-6. With high plasma protein binding, low permeability, and solubility their availability is low in the body. For enhancement in permeability for topical application prefer to choose a suitable excipient and optimized batch. Various types of oils are selected to examine the solubility of quercetin and it is found that the solubility of quercetin in arachis oil is 11.14 mg/ml, while in oleic acid is found to be 9.10 mg/ml. Both Tween 20 (surfactant) and PEG-400 (co-surfactant) added concentration were kept at 6% concentration. The accurate ratio of quercetin, oil, surfactant and co-surfactant is mixed in screw capped bottle and further vortex at optimum speed to form Smix. The formed Smix is added dropwise in magnetically stirred aqueous phase to obtain clear and transparent nanoemulsion (Gokhale et al. 2019).

9.8 Application of Polymeric Micelles for Delivery of Phytoconstituent

Polymeric micelles promise strategy for the delivery of various phytoconstituent with a problem related to stability and solubility. The block copolymer and graft copolymers play a key role in the stability aspect of polymeric micelles.

9.8.1 Anticancer Agent

Cancer is a leading disease that causes abnormal growth of organs or tissue. The major root cause of cancer is metastasizing, the spreading of cancer from one organ to another. According to World Health Organization (WHO) survey in 2018 the second leading cause of death is cancer. Approximately 9.6 million deaths occur annually and the death rate is about 1:6. There are various types of cancer like lung cancer, skin cancer, breast cancer, colorectal cancer, and blood cancer especially leukemia and non-Hodgkin lymphoma. In women mostly breast cancer, cervical and thyroid cancer are commonly occurring cancer (WHO n.d.). The multiple mutation in gene that contribute to cancer cancer development, such as germline mutation in women leads breast cancer. Various herbal plants preparation and their phytoconstituents are used for the treatment of anticancer agents (refer Table 9.2).

Table 9.2 Phytoconstituent shows anticancer effect delivered through polymeric micelles
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In Ayurveda, Vedic literature of India, it is mentioned that plant-derived products are nontoxic to human health and produces less tolerance. Different phytoconstituent have different mechanisms to treat cancer some of them kill rapidly dividing cells, decrease oxidative stress, stop gene mutation as well as the alteration in the gene, inhibit cell proliferation, and induce apoptosis. Polyphenols like resveratrol and gallocatechin, flavonoids like alpinumisoflavone, and methoxy licoflavanone show an apoptosis effect. The phytoconstituents including curcumin, rutin, allicin, epigallocatechin gallate, β-carotene, thymol, quercetin, rosmarinic acid, and coumarin treat cancer by antioxidant mechanism (Singh et al. 2016).

C. Gong et al. developed curcumin polymeric micelles for antiangiogenesis and anticancer purposes. Curcumin polymeric micelles are prepared by solid dispersion method using monomethyl poly(ethylene glycol)-poly(ε-caprolactone) (MPEG-PCL) as a copolymer. MPEG-PCL is a di-block copolymer with an atactic structure formed by ring-opening polymerization between poly(ethylene glycol) methyl ether (MPEG) and ε-caprolactone and different ratios of the copolymer used for the preparation of polymeric micelles. Using the MTT test, curcumin micelles and free curcumin were studied for cytotoxicity and apoptosis. The percentage cell viability of curcumin micelles is less than free curcumin and the apoptosis rate of curcumin micelles is higher than free curcumin showing that polymeric micelles of curcumin improved cytotoxic activity. In vitro antiangiogenic activity was studied by the MTT method. Here inhibitory activity of Cur micelles inside endothelial cells is greater than free curcumin. The conclusion found that curcumin micelles have a more suppressive effect on tumor growth and also enhance retention time and plasma, survival rate, and antiangiogenesis effect (Gong et al. 2013). L. Liu et al. also develop curcumin-loaded polymeric micelles using MPEG-PCL as a biodegradable copolymer for inhabiting breast tumor. Surgery is another option for breast tumor but the chances of recurrence and metastasis are high. To avoid recurrence and metastasis chemotherapy is a better option. Chemotherapy shows side effects like myelosuppression and immunosuppression. The nanodelivery of curcumin-loaded polymeric micelles promises delivery with high drug accumulation at the target site. The neutral surface charge of curcumin micelles provides stability to the formulation. Poly(ethylene glycol) forms the core and poly(ε-caprolactone) forms the shell. These copolymers cause less aggregation and have a limited affinity toward micelles. A cytotoxicity study was performed on 4T1 cells placed on 96-well plates and then incubated for 24 h. Curcumin polymeric micelles have high cell uptake, with high cytotoxicity observed during the experiment. Apoptosis was performed by TUNEL staining assay on 4T1 cells using immunofluorescence. It is observed that curcumin polymeric micelles have a more apoptosis induction effect than free curcumin (Liu et al. 2013).

Berberine is a quaternary derivative of isoquinoline alkaloid obtained from Berberis vulgar (European barberry) and belongs to the Berberidaceae family. Various advanced techniques are used for the extraction of berberine showing potential anticancer properties. Berberine has poor water solubility with low bioavailability, tissue uptake, and distribution (Khan et al. 2022). Shen et al. reported the preparation of berberine-containing polymeric phospholipid micelles as a promising strategy to enhance the delivery of berberine to target cancer. The solubility of berberine is enhanced by mixing phospho-ethanolamine-N-[methoxy(poly-ethyleneglycol)-2000] (PEG-PE) with d-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) in ratio 3:1, helps to solubilize berberine in the hydrophobic core of micelles. PEG–PE conjugates formed by polyethylene glycol (PEG) and diacyl-lipids help to achieve a size range between 10 and 100 nm. TPGS is a pegylated derivative of vitamin E that provide increased solubility and absorption rate of berberine. TPGS also inhabits Pgp efflux pumps and helps decrease multidrug-resistant to various chemotherapeutic drugs including paclitaxel, vinblastine, doxorubicin, and gemcitabine. These increase up to 5 times improvement in oral bioavailability of berberine. Uptake study results show berberine lipopolymeric micelles have 18 times high in vitro cellular uptake than free berberine and a cytotoxicity study on cancer cell spheroid models like PC3 shows that free berberine kills only 20% of cancer cells, while berberine lipopolymeric micelles kill>60% of PC3 cells in 48 h (Shen et al. 2016).

An effective anticancer activity is shown by Paclitaxel (Taxol®) obtained from the bark of the Taxus Brevifolia (Pacific yew tree) belonging to family Taxaceae. The paclitaxel has tetracyclic diterpenoid that is sparingly soluble (0.3 mg/L at 37 °C) in water. To enhance the solubility of paclitaxel use Cremophor EL and dehydrated ethanol. They are commercially available in the market under the brand name Taxol®. The use of Cremophor EL shows hypersensitivity reactions and side effects in patients. Also, the organic medium used for the preparation of formulation leached a carcinogenic compound from the infusion bag used in the hospital. W.Y. Seow et al. reported for targeted delivery of paclitaxel with the help of multifunctional polymeric micelles contain poly (N-isopropylacrylamide-co-N,N-dimethylacrylamide-co-undecenoic acid). These help encapsulation of paclitaxel in core conjugation of cholesterol to carboxylic group of polymer and attachment of folate to amine group within the hydrophilic chain segment as a targeting moiety as well as nonimmunogenic property. This formulation is temperature and pH sensitive, mostly in cancer cells that produce an acidic environment that helps the rapid release of a drug. Dropping the lower critical solution temperature (LCST) of micelles below 37 °C destruction of the core and drug release occurs. In the release study at pH 7.4 only 8% of total drug release occurs, while at pH 5.0 about 21% of its total drug content occurs in the first 4 h and 44% by the first 24 h. The paclitaxel encapsulated polymeric micelles coated with folate start precipitation and deformation at a temperature below 37 °C and maximum release occurs. In a condition like LCST of micelles above 37 °C at pH 7.4 drug is encapsulated in polymer and does not show any release property. The cell viability of paclitaxel PM conjugated with folate increases with an increase in free folate concentration, these suggest that free folate shows competitive binding to paclitaxel PM conjugated with folate. For increasing in vitro therapeutic efficiency of paclitaxel PM conjugated with folate avoid a folate-contain diet (Seow et al. 2007). For enhancing the chemotherapeutic efficacy and producing synergistic action the combination of two drugs is used in nanoformulation. Paclitaxel and cisplatin are used by X Wan et al. to treat ovarian and breast cancer. In that cisplatin are delivered together in poly(2-oxazoline) polymeric micelles. Paclitaxel work as anti-microtubule agent, they bind to the microtubules and prevent them from disassembly. Also At high concentration of paclitaxel arrest cell growth at G2/M phase. Cisplatin is the most powerful member of the platinum family. They form an adduct with DNA and inhibit protein synthesis. They show dose-limiting toxicity and rapid development of MDR. Both cisplatin and paclitaxel have low solubility in water. The poly(2-oxazoline) copolymer containing micelles enhances the solubility of the drug up to 100,000 times with 4–100 times high drug loading of paclitaxel micelle and slow down release rate (Wan et al. 2019). B. Cote et al. describe the use of resveratrol and quercetin polymeric micelles to decrease cardiotoxicity induced by doxorubicin. Natural phytoconstituent resveratrol (polyphenols) and quercetin (flavonoid) were obtained from grapes. They prevent the heart from myocardial damage and show cardioprotective effects. The mechanism behind cardioprotective effects is free radical scavenging and antioxidant effect. Resveratrol behaves as a chemotherapeutics and chemosensitizer. The anticancer drug quercetin exhibits cell cycle arrest at G0/G1 phase with significant antioxidant action through reactive oxygen species (ROS) generation. Both resveratrol and quercetin have a low level of oral bioavailability and aqueous solubility. Most of the antibiotics belong to the anthracycline class effective for cancer treatment. That doxorubicin (DOX) hydrochloride (Adriamycin for Injection, USP) is used to treat various cancer like breast, ovarian, Wilms’ tumor, and neuroblastoma. The side effect of DOX formulation shows cardiotoxic side effects at a dose greater than 15 mg/kg, with an unknown mechanism. Mostly adriamycin plays an important role in the generation of free radicles and lipid peroxidation, these are the main reason behind the generation of cardiotoxicity. Triblock copolymer is formed by one polypropylene oxide (PPO) chain and two polyethylene oxides (PEO) known as Pluronics®. The resveratrol and quercetin (1:1) were solubilized using Pluronics® by solvent casting method formation. Polymeric micelles co-administered with DOX by enhancing anticancer effect as well as cardioprotective action (Cote et al. 2015).

9.8.2 Antibacterial Agent

Antibacterial agents are compounds that either kill bacteria or halt their development. The main drawback of antibacterial drugs is they show resistance produced due to consumption of excessive antibiotics beyond the limit. They produce aggressive strains that do not respond to rational treatment. According to a WHO report, antibiotic resistance results in 700,000 deaths worldwide every year. The antibiotic resistance crisis attribute huge loss of about $55–70 billion per annum in the USA and €1.5 billion annually in the UK. Other reasons like low water solubility and oral bioavailability, stability problems, toxicity, low patient compliance create a major challenge in antibiotic therapy. The polymeric micelles play a key role as a nanocarrier to overcome bacterial resistance. Curcumin-loaded polymeric micelles have a size range between 90 and 95 nm and contain silver-coated amphiphilic di-block copolymers made up of poly (ε-caprolactone) and poly (aspartic acid). Biofilm-associated bacteria contain Pseudomonas aeruginosa and Staphylococcus aureus show synergistic activity against both gram-positive and gram-negative bacteria. The curcumin-loaded polymeric micelles show high biocompatibility with RBC and decrease the rate of drug release in the absence of lipase enzyme. When incubated with P. lipase, the release rate increases; approximately 95% of the release occurs within 48 h (Eleraky et al. 2020). The biodegradable antimicrobial polycarbonates are important in polymeric micelles for the delivery of the antibacterial agent. The triblock polymer of poly(ethylene oxide) as PEO, poly(ε-caprolactone) as PCL, poly[(2-tert-butylaminoethyl) methacrylate] as PTA self-assembled by ring-opening polymerization reaction give rise to (PEO-b-PCL-b-PTA). In that PEO block gives rise to biocompatibility and stability. PTA block shows antibacterial activity by bacterial lysis with divalent cation exchange mechanism. PCL block works as a biodegradable hydrophobic core in an aqueous solution (Ding et al. 2019).

F. Huang et al. designed the polymeric micelles containing silver nanoparticles with encapsulation of curcumin to produce synergistic antibacterial action. The rapid development of MDR is a global issue. In such a way antibacterial produces resistance within a very short period. Silver is the best antibacterial agent with less resistance and low toxicity. They enter bacterial cytoplasm and denature the protein by interfering with DNA synthesis. Silver is used for combination treatment with other antibiotics including penicillin, kanamycin, and vancomycin helps significantly decrease the MDR. The polymeric micelles contain block copolymer to prevent aggregation of silver nanoparticles and enhance their stability. Curcumin is used for its antibacterial, antifungal, antioxidant, anticancer, and other multiple activities. Curcumin produces a synergistic effect with antibiotics. Curcumin shows poor bioavailability and less water solubility, these can be overcome by preparing polymeric micelles. The composition of curcumin and silver nanoparticles in polymeric micelles prepared by using di-block copolymer formed by poly(ε-caprolactone) as PCL and poly(aspartic acid) as Asp comes together to form (PCL-b-Asp) di-block copolymer biodegradable in nature. In polymeric micelles silver nanoparticles decorated on the shell and curcumin encapsulate in a hydrophobic core. The PCL-b-Asp di-block copolymer shows electrostatic interaction by absorbing Ag + ions on poly(aspartic acid). Antibacterial activity is determined by performing an antibacterial test on P. aeruginosa (Gram-negative bacteria) and S. aureus (Gram-positive bacteria), by developing a colony on an agar plate and then transferring it into culture media incubate overnight at 37 °C. The result obtained is evaluated by measuring optical density. The test result shows that silver-curcumin contains polymeric micelles that have strong antibacterial activity on both P. aeruginosa and S. aureus than only silver-decorated polymeric micelles. The release of curcumin micelles increased in the presence of lipase about 95% release over 48 h. Hemolysis study of silver-curcumin contains polymeric micelles good biocompatibility with RBCs (Huang et al. 2017).

R. Bakr et al. developed a polymeric micelles formulation containing mentha showing anti-Helicobacter activity. Mentha species contain various phytoconstituents and various therapeutic applications. Different species of mentha like M. suaveolens, M. sylvestris, M. piperita, M. longifolia, and M. viridis belong to family Lamiaceae (Labiatae). They contain various types of volatile oil, flavonoids, tannins, and phenolic oil with various therapeutic effects including antiviral, antibacterial, antioxidant, and antiobesity effects. To study functional genomics, it is necessary to understand metabolite levels using plant metabolomics. Various mentha species are used for treating peptic ulcers caused by Helicobacter pylori bacteria. These are flagella-shaped, gram-negative bacteria also cause gastric cancer. Most antibiotics develop MDR against rational therapy. Antibiotics used to treat ulcers cause resistance; this issue is solved by using natural phytochemicals. The preparation of the nano formulation is needed due to the limited solubility and bioavailability of mentha. The polymeric micelles were prepared by using Pluronic® F127 as a polymer. The Pluronic® F127 has a biodegradable and biocompatible character with enhanced drug encapsulation and increases the therapeutic potential of mentha species. That disc diffusion method helps to determine the activity of different Mentha species against the H. pylori strain. Metabolomics analysis was performed using a mass spectrometer. The minimum inhibitory concentration (MIC) and minimum bactericidal concentrations (MBC) assist in selecting mentha species with anti-Helicobacter properties. The result obtained from cytotoxic activities shows M. viridis expose excellent anti-Helicobacter activity with a maximum zone of inhibition (14 ± 1.5 mm). After that M. piperita shows good anti-Helicobacter activity delivered with polymeric micelles (Bakr et al. 2021).

G. D. Kumar et al. used pelargonic acid (PA) obtained from tomatoes as an antimicrobial agent. It commonly acts as an antifungal agent approved by Generally Recognized as Safe (GRAS) status, other use like in food additives and sanitizer purposes. Quillaja contains high amount of saponin obtained from the bark of Quillaja saponaria used as micelle formulation for antimicrobial activity. A variety of fatty acids including oleic acid, capric acid, and palmitoleic acid derived from plants show good antibacterial activity. The low solubility of fatty acid in oil increased by adding a surfactant to overcome the solubility problem. PA micelles were prepared using surfactants including Tween 80, Triton X100, and Sodium Dodecyl Sulfate (SDS) (Dev Kumar et al. 2020).

9.8.3 Antidiabetic Treatment

Diabetes mellitus (DM) is the third leading disease after a heart attack and cancer. DM is caused due to insufficient insulin secretion or insulin resistance or both leading to an increased concentration of glucose in the blood (hyperglycemia). The survey found that about 69.1 million cases of diabetes in India and 415 million cases of diabetes in the world increase every day. It will forecast that there would be 140 million cases of diabetes in 2040. DM is classified into two types in that Type 1 diabetes (insulin-dependent) causes a lack of insulin production due to the destruction of β islets cells present in the pancreas. Type 2 diabetes (non-insulin-dependent) is due to ineffective use of insulin and the reason behind is a sedentary lifestyle and carbohydrate metabolism problems. In India, about 8.7% diabetic population is between the age 20–70. There are additional methods to maintain the sugar level in the body, including a balanced diet, exercise, yoga, and weight management, and these help minimize the use of oral hypoglycemic tablets and insulin injections. Herbal medicines are the drug of choice for a diabetic patient showing excellent therapeutic action. About 300 phytoconstituents extracted from 100 herbs establish antidiabetic action with different mechanistic pathways. The main aim is to develop pharmacologically active phytoconstituent for diabetes patients with novel delivery in a cost-effective manner (Bharti et al. 2018). Y. Fu et al. report the use of PEGylated micelles in antidiabetic treatments to enhance targeting delivery and cellular uptake. The amphiphilic block copolymer is self-assembled with enhanced solubility of poorly water-soluble phytoconstituent. Cationic polymeric micelles efficiently deliver insulin-producing electrostatic interaction between insulin and cations on the PEI-PEG layer with excellent glucose regulation. Glucose-responsive polymeric micelles are novel therapy to deliver the antidiabetic drug that decreases the level of insulin under 100 mg/dL with rapid release of insulin from polymeric nanovesicles (Fu et al. 2021). M.U. Akbar et al. described the use of curcumin polymeric micelles for antidiabetic and wound healing effects using chitosan, alginate, maltodextrin, and pluronic. In the daily use of plastic containers for food and beverage, synthetic plastic bags contain bisphenol A (BPA) to enhance the durability of that material. Various environmental conditions and changes in pH cause the release of BPA. According to a literature survey if daily intake of BSA is greater than 0.05 mg/kg body weight it causes harmful effect on insulin secretion and pancreatic glands. Curcumin-loaded mixed polymeric micelles are used to reduce the toxicity of BPA and show antidiabetic and wound healing activity. Mixed polymeric micelles containing curcumin prepared by thin-film hydration method give thin layer of curcumin-pluronic copolymer matrix. Add different polymer in appropriate amount to obtain formulation. Curcumin-loaded polymeric micelles show decrease in glucose level with increase in red blood cells and excellent wound healing response due to antioxidant, antibacterial, and anti-inflammatory properties of curcumin (Akbar et al. 2018a). The use of poloxamers or pluronic are amphiphilic, non-ionic surfactants that show the phenomenon of reverse thermal gelation, in that conversion from liquid to gel with a temperature change. Pluronics is FDA approved excipient mentioned in the US and British Pharmacopoeias. Two grades of pluronic, PF127 and P123 made a triblock structure. Micelles containing pluronic solutions show gelation properties determined by altering temperature with the movement of the magnetic bar. The rpm speed of the magnetic bar is inversely proportional to the gelation process. The antidiabetic activity of curcumin polymeric micelles is due to inhabiting α-amylase activity (Akbar et al. 2018b).

P. Mukhopadhyay et al. describe the use of quercetin as a hypoglycemic agent. The multiple medicines prescribed to older patients may produce complication in anti-diabetic treatment and high chances to display adverse drug reaction. Most secondary metabolites and bioactive drugs isolated from plants are used for antidiabetic purposes. These help to reduce hyperglycemic episodes and improve the life of the diabetic patient. Quercetin is a flavonoid, easily found in green vegetables and fruit. They have been used for multiple biological activities antidiabetic, anti-ulcer effects, and anticancer activity. The problem related to low bioavailability and permeability, short half-life, and first-pass metabolism is overcome by using polymeric nanocarriers like nanoparticles, polymeric micelles, and hydrogels. Quercetin maintains the glucose level by enhancing glucose uptake. It stimulates the glucose transporter 4 (GLUT 4) receptors as well as insulin receptors present on adipose tissue and skeletal muscles of the body. Another mechanism is a decrease in hyperglycemic effects due to enhanced glucokinase activity in the liver leads to high storage of glucose. Various study shows that quercetin helps to regenerate beta cells of islets of Langerhans by stimulating the ductal stem cells. In the small intestine glucose transporter 2 (GLUT 2) receptors present for enhancing glucose absorption. Quercetin decrease GLUT 2 expression, that leads to decrease the glucose absorption in gastrointestinal tract. The function of polymeric micelles for the delivery of quercetin is to protect from endolysosomal damage and enhanced oral drug delivery. Various polymers encapsulate quercetin and easily transport it to the colon by avoiding enzymatic degradation (Mukhopadhyay and Prajapati 2015).

9.8.4 Antifungal Treatment

The various phytochemicals and standaedized plant extract work against opportunistic fungal pathogens. These phytoconstituents have a potential activity to treat fungal activity caused due to Candida, Aspergillus, and Cryptococcus spp. These mostly affect skin and other body parts like skin, scalp, vagina, mouth, armpits, feet, and fingers. The warm and wet parts of the body include the part between two fingers, between the thighs, and wet armpits due to sweat. Fungal infections may be categorized according to the site of infection, route of acquisition and type of virulence, most common fungal diseases include dermatophytosis, Ringworm (Tinea corporis), Candidiasis or yeast infection, Jock itch (Tinea cruris), Tinea pedis, Tinea faciei, Tinea barbae belongs Trichophyton species. In the current approach for the treatment of both systemic and topical fungal diseases, various antifungal formulations are available in the market including azole drugs, polyene, allylamines, echinocandins, and morpholine. Most of them show side effects like erythema, burning sensation, redness of the skin, stinging, and some allergic reactions. Toxicity and development of resistance and uneven distribution of plasma profile is a limitation of an antifungal agent which is overcome by nanocarriers. Polymeric delivery systems mostly use biodegradable polymers for targeted activity. The chitosan-containing nanoparticles help to reduce toxicity profile of the antifungal drug and excellent antifungal activity against Fusarium solani, A. niger, and C. albicans (Priya et al. 2017).

N. Kaur et al. described the use of various plant extracts as an antifungal. The antimycotic drug is also known as antifungal drug. The natural plants include Bucida buceras, Vangueria infausta, and Olinia ventosa. Various essential oil including clove, peppermint, cinnamon, citronella, camphor behaves as antifungal agent. The synthesis process affects the activity of herbal antifungal formulation due to high temperature. The epimerization process disrupt the structural integrity of phytoconstituent, that create significant problem in herbal extract. The stability of phytoconstituent is enhanced using a polymeric delivery system. Polymer shows crosslinking phenomenon, these help phytoconstituent for an effective and controlled delivery system. The copolymer binds with crosslinkers and gives better stability (Kaur et al. 2021b). T. Suwan et al. described the use of the herbal plant Psidium guajava aqueous extract (PE) delivered through polymeric micelles with silver nanoparticles shows synergistic antifungal activity. The plant extract obtained from leaves of Psidium guajava belongs to family Myrtaceous. The common Psidium guajava is commonly known as guava, mainly found in Asia, European countries, South America, and Africa. The main chemical constituent present in P. guajava is gallic acid, kaempferol, catechin, naringenin, rutin, and epicatechin. The extract shows excellent biological therapeutic effects including antimicrobial activity, hepatoprotective, anti-hyperlipidemic effect, anti-inflammatory activity as well as antidiabetic effect. P. guajava acts as a reducing agent and helps to synthesize silver nanoparticles. These synthesis processes increase the size of silver nanoparticles due to aggregation. Polymeric micelles help to obtain small-sized silver nanoparticles. In literature Poloxamer 407 (F127) triblock copolymer used to stabilize silver nanoparticles with Psidium guajava extract work as a reducing agent. A Kirby-Bauer method used to inspect antifungal activity of silver polymeric micelles formulation against C. albicans. (Suwan et al. 2019).

9.8.5 Antimalarial Treatment

Malaria is an acute febrile parasitic disease caused by a single-celled parasite belonging to the genus Plasmodium and transmitted through female Anopheles mosquitoes. Majorly four Plasmodium species spread malaria including Plasmodium malariae, Plasmodium falciparum, Plasmodium vivax, and Plasmodium ovale. In that P. falciparum is the most dangerous species found in Africa, America, and Asia. According to a WHO global survey report, there will be 241 million cases of malaria and 627,000 deaths due to malaria in 2020. The data obtained from the WHO global survey reported that in 2020 there would be an additional 69,000 deaths and 14 million cases as compared to 2019 (World Malaria Report 2021). Various phytoconstituents show positive results against Plasmodium parasites. Since ancient times, medicinal plants have been used as effective antimalarial drugs. The first antimalarial drug is quinine extracted from the bark of Cinchona calisaya belongs to the family Rubiaceae, having potent antimalerial action. In 1632 first infusion of quinine has been given for the treatment of human malaria and first case of resistance is observed in 1910. In 1972 Chinese scientists discovered new phytochemical called artemisinin isolated from Artemisia annua (sweet wormwood) belonging to the family Asteraceae. Artemisinin act as a novel natural product and it is used with a combination of another malaria medicines to enhance half-life and efficacy. Artemisinin-based combination therapy (ACT) is a promising statergy that is currently employed to overcome drug resistance (Erhirhie et al. 2021).

B. Zhai et al. described the use of Bixa orellana as antimalarial. The plant extracts including ishwarane, 5-tocotrienol, sitosterol, and stigmasterol show antimalarial activity. In that stigmasterol is potent antimalarial compound and shows modest activity against3D7 and K1 malerial strains (Zhai et al. 2014). D. Bhadra et al. use copolymeric dendritic micelles for delivery of artemether. Copolymeric micelles contain PEG conjugation at outer shell for avoiding reticuloendothelial system (RES) barrier and core formed using block copolymers including poly(ortho ethers) (POE), PLGA (polylactide co-glycolide), poly(butylene terephthalate) (PBT), poly-l-lysine (dendrimers), and PCL as (poly-caprolactone). The negative side of artemisinin is poor bioavailability and shorter half-life up to 5 h. Here the use of amphiphilic peptide-based AB-dendritic copolymeric core is used for enhancing the solubilization of artemether and increases half-life. The challenge like resistance produced by P. falciparum strains and chloroquine-sensitivity is overcome by using a derivative obtained from artemisinin (Bhadra et al. 2005).

9.9 Future Prospective

Globally the demand of natural product is increased per day, but poor solubility and bioavailability limit their application. Phytochemical-based nanoformulation is promising approach to overcome solubility and bioavailability parameter. The formulation strategy is based on the treatment of various chronic diseases with targeted delivery. The poor solubility of phytoconstituents creates a challenge regarding the delivery of drugs to the targeted site. The role of nanocarriers is to enhance solubility, bioavailability and stability in phytoconstituent. The multifunctional property of a single phytoconstituent including antioxidant, antibacterial, antiviral, and much more helps to cure multiple diseases at the same time by a single formulation. The nanocarriers containing phytoconstituent will change the approach toward the modern delivery of phytoconstituent (Handa et al. 2020, 2022).

In the future, the availability of modern extraction techniques increases the number of phytoconstituent with potent therapeutic action. The challenge is the development of a nanodelivery system. As compared to other nano-drug delivery systems, polymeric micelles are an effective delivery system with good stability. Polymeric micelles are excellent drug carriers for the delivery of poorly water-soluble phytoconstituent. The hydrophobic core of amphiphilic block copolymer micelles loaded with poorly water soluble phytoconstituents that enhance solubility, bioavailability and therapeutic efficacy of drug. Polymeric micelles possess good stability in blood. The micelles loaded with poorly water soluble anticancer drugs The targeting ability of polymeric micelles increased by attaching various antibodies, carrier ligands and protein on the surface. Also, stimuli-sensitive including pH and temperature sensitive polymeric micelles enhance targeting ability with less damage to other cells. In future major challenge for polymeric micelles is to enhance the drug efficacy (Kulthe et al. 2012; Varma et al. 2020).

9.10 Conclusion

The herbal plants and their phytoconstituent play promising therapeutic role for treating various diseases. The extraction of phytoconstituent from herbs gives flavonoid, alkaloid, glycoside, tannins, polyphenol, carbohydrates, and proteins. These phytoconstituents had medicinal properties with good therapeutic action. Various phytoconstituent is avoided in formulation due to solubility, absorption, degradation, short half-life with high clearance rate, and toxicity issue. These problems are overcome by developing a nanocarrier delivery system. Various nanocarriers dendrimers, organic nanoparticles, nanoemulsions, emulsomes, liposomes, phytosomes, and nanocrystals increase solubility and bioavailability of phytoconstituent, for delivery of poorly water-soluble phytoconstituent polymeric micelles helps in enhanced delivery. The graft and block copolymers play an important role for enhance solubility. The stability of polymeric micelles is more than liposomes. The delivery of phytoconstituent like curcumin, berberine, and paclitaxel through polymeric micelles shows significant anticancer activity. They also decrease MDR and increase intracellular uptake in cancer treatment. Phytoconstituent showing antibacterial, antifungal, antidiabetic, and antimalarial activity is improved by polymeric micelles. The combination of two drugs like Quercetin and Doxorubicin containing polymeric micelles shows synergistic effects with minimal adverse effect of doxorubicin. The polymeric micelles are first choice formulation for poorly water-soluble drugs and to enhance targeting ability.