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Polymeric Micelles

  • Iliyas Khan
  • Avinash Gothwal
  • Gaurav Mishra
  • Umesh GuptaEmail author
Living reference work entry
Part of the Polymers and Polymeric Composites: A Reference Series book series (POPOC)

Abstract

Polymeric micelles (PM) are means of novel drug carriers for poorly soluble hydrophobic drugs. Outer shell of polymeric micelles is hydrophilic in nature which further led these carriers to stay longer in blood and can accumulate in tumor-specific region due to their smaller size through enhanced permeation and retention (EPR) effect. The polymeric micelles can also be modified through different ligand to achieve active targeting of drugs. Polymeric micelles can be synthesized and prepared through different self-assembly methods. These can be used to improve solubility, residence time of drug in blood, and inhibition of efflux pump, to enhance pharmacokinetic parameters, and to achieve sustained release of drugs at target site without any side effects in an efficient manner. These types of novel drug delivery systems are aimed to enhance the efficacy and reduce the side effects of anticancer drugs in an efficient way. The present chapter highlights the structure, methods of preparation, the micellar architecture, and the role of these carriers in the anticancer drugs.

Keywords

Polymeric micelles Solubility Hydrophobic Hydrophilic Anticancer drug delivery 

Abbreviations

(mPEG-b-p(HPMAm-lactate)

(Poly(ethyleneglycol)-b-poly[N-(2-hydroxypropyl) methacrylamide-lactate]

(PEG-b-PPhe)

poly(ethylene glycol)-block-poly(phenylalanine)

(Vitamin E TPGS2k)

D-α-Tocopheryl polyethylene glycol succinate 2000

ABC

Accelerated blood clearance

ATP

Adenosine triphosphate

BCS

Biopharmaceutics classification system

CMC

Critical micelle concentration

DMF

Dimethylformamide

DOX

Doxorubicin

DSC

Differential scanning calorimetric

EPR

Enhanced permeability and retention

GIT

Gastro-intestinal tract

mPEG-PDLLA

monomethoxy poly(ethylene glycol)-block-poly (D,L-lactide)

MPS

Mononuclear phagocyte system

MRI

Magnetic resonance imaging

NMR

Nuclear magnetic resonance

PCL

Poly ϵ-caprolactone

PEO

poly(ethylene oxide)

pHPMAmDL-b-PEG

poly(N-(2-hydroxypropyl) methacrylamide lactate) poly(ethylene glycol)

PLA

Polylactic acid

PLL-PEG

Poly-l-lysine-poly(ethylene glycol)

PM

Polymeric micelles

ppm

Parts per million

SEM

Scanning electron microscopy

TEM

Transmission electron microscopy

THF

Tetrahydrofuran

From ancient time there was a big problem of protecting the drug from degradation and excretion and to avoid adverse effects of lethal drugs. The traditional way of drug delivery is continuously changing and getting advanced day by day. The introduction of nanocarrier has changed the entire scenario of drug delivery research. Current chemotherapy has a lack of selectivity toward neoplastic cells. Resistant types of tumor required high dose of chemotherapy instead of normal dose, resultant in toxicity to normal cell and enhance the toxicity of treatment. Hence to keep in mind to reduce the toxicity and targeted delivery of chemotherapeutic drugs, novel nanocarriers are used [1]. The use of different nanocarriers such as nanoparticles, liposomes, dendrimers, carbon nanotubes[s], etc. has resulted in enhanced effectivity and reduced side effects. Each of nanocarrier has its own pros and cons. They slowly release drugs at targeted site and slowly degrade in in vivo, stimuli reactive such as temperature or pH sensitive and long circulation time in the body [2, 3]. Hence, nanocarriers were discovered and have used frequently deliver drugs through different routes for the reason of protecting the drug against degradation and/or excretion to prevent adverse effects of toxic drugs and targeted drug delivery. In these, polymeric micelles have been widely used nanocarrier for anticancer drug delivery. Micelles are colloidal dispersion size range between 5 to 100 nm mainly. Nanometric size leads to a very cosmic chance to develop the formulation into the injectable dosage form. Cancer has a leaky vasculature characteristic, and the nanosized formulations are penetrated easily to the tumor site due to enhanced permeability and retention (EPR) phenomenon [4]. They are made up of amphiphilic colloids. At certain concentration and temperature, these colloids are formed through amphiphilic or surface active agent [5]. These amphiphilic molecules exist separately at low temperature in aqueous medium, but at higher concentration, aggregation takes place. These aggregates are called micelles. The concentration at which the formation of micelles starts is called critical micelles concentration (CMC) [6] and the temperature lower where amphiphilic molecules represent as unimers and beyond exist as aggregates, called critical micellization temperature (CMT) [7]. If, CMC value is lower; resulting into stable micelles formation [8]. Conventional surfactant micelles have less thermodynamic stability in physiological solution. So due to this disadvantage, new micelles have been discovered for drug delivery which is made up from block copolymeric chain of hydrophilic and amphiphilic monomer unit. They have less CMC value which makes polymeric micelles (PM) more stable as compared to conventional micelles [9]. PM were first proposed by Ringsdorf et al. in 1984. PM displayed a class of micelles which is made up from block copolymer entailing hydrophobic and hydrophilic monomer unit (Fig. 1). Amphiphilic block and AB-type graft copolymers with increasing the chain length of hydrophilic block beyond the range of hydrophobic part, resulting in spherical micelles in aqueous environments [10]. The release pattern of drug from polymeric micelles from its hydrophobic core is in a sustained manner, and it depends on the length of the hydrophobic blocks and monomer species. Scientists developed many types of the polymeric micelles with new monomer units, and they have vast groups concerning moieties and targeting ligands, but only a few were reported successfully for the delivery of drugs. Due to longer circulation time within, blood system indicates to improve congregation at tissue sites because of EPR effect (Fig. 2). The above specific characteristic makes available one of the solidest influences in the use of polymeric micelles for delivering of anticancer drugs, maximum of which have very low solubility in aqueous medium [11]. The ground rule of polymeric micellar drug delivery system is revised with an attention on the application of delivery of oral drugs and anticancer therapy, the most widely inspected applications for polymeric drug delivery. Flexibility in monomer classes, surface modification, and block polymer length ratio offer polymeric micelles having multifunctionality. But simultaneously polymeric micelles have mainly two weaknesses: one is the low payload of drugs and second is less stability in aqueous medium. This part pledges with the drug loading property of polymeric micelles [12]. The present chapter is all about the applicability and properties of the polymeric micelles used in the drug delivery with special emphasis on anticancer drugs. The previous reported study revealed that the polymeric micelles can target very effectively the solid tumors which is a convincing approach for the passive targeting [13, 14]. The cellular uptake of the drug is enhanced due to the polymeric carrier to the cancerous cells and believed that increases in endocytotic transportation and also sidestepping multidrug resistance [15].
Fig. 1

Association of polymeric micelles by self-assembling process

Fig. 2

Enhanced permeability and retention (EPR) effects by polymeric micelles

1 Architecture of Polymeric Micelles

Amphiphilic polymers are self-assembled in aqueous environments, to form the core-shell structure, either fluid or solid core. If the solid core is formed, then it’s called nanospheres; and when the fluid core is formed, then it is called PM. The core of PM is a dense region consisting of the hydrophobic part. The core encapsulates the low water-soluble drugs due to hydrophobic interactions. The outer surface of PM made up from hydrophilic part of an amphiphilic polymer (Fig. 1) [16]. Polymeric micelles have specific roles in drug delivery which is described below.

1.1 Core (Internal Case)

Hydrophobic core is the main component which determines the PM capacity to solubilize the less water soluble drugs. Capability of the hydrophobic core to encapsulate the drugs or compounds mainly depends on compatibility between the drug molecules and hydrophobic internal core [17]. Compatibility between less water soluble drugs and hydrophobic internal core of PM can be assessed by comparing polarity. To quantify this interaction, Flory-Huggins parameters used to estimate the congeniality using polarity.
$$ {\upchi}_{\mathrm{s}\mathrm{p}}={\left({\updelta}_{\mathrm{s}}-{\updelta}_{\mathrm{p}}\right)}^2\ {\upnu}_{\mathrm{s}}/\upkappa \mathrm{T} $$
(1)

Here,

χsp = Solubility parameters for drugs and hydrophobic core

ν = Molar volume of drugs

κ = Boltzmann constant

T = Temperature in Kelvin

Hypothetically, if χsp is decreased or minimized, it leads to better compatibility and more effective encapsulation of less soluble drug [18].

Core-forming components cover a broad array of structural assortment and polarity for solubilizing the less soluble drugs. Hydrophobic interactions are responsible for the stability between drugs and the hydrophobic core, due to its thermo-dynamically stable formed complex [19].

1.2 Outer Shell (Corona)

The outer shell (corona) of PM is made up from hydrophilic part of the amphiphilic polymer. Corona should possess the effective stealth property for the PM. It should contain sufficient hydrophilicity, surface charge, block copolymer chain length, and reactive group for attachment of targeting moieties [20, 21, 22, 23, 24]. Corona is responsible for the protection of drug from aqueous environment and also enables it for the stability and stealthy recognition in vivo through the reticuloendothelial system (RES) and also enhanced its vascular permeability [25, 26]. Owing to these properties, PMs possess effective pharmacokinetics property, biocompatibility, and better biodistribution of drug incorporated into it. Therefore in vivo behavior of the drug may be controlled independently through the outer shell of the inner core [27]. Various types of hydrophilic block of polymer are used in PM, which generally possesses molecular weight between 1 to 15 kDa. Generally, solubilization can increase PM size due to enlargement of hydrophobic core, and other factors which can affect drug loading are core and corona size. If the hydrophobic blocks are larger than the core size, increase the encapsulation efficiency. If the hydrophilic block chain length increases, then the CMC value also increases [2]. Corona also acts for the interaction with a biological active component like protein within circulating blood [28].

2 Merits and Demerits

One of the major pros of PM is good edifice stability in comparison to the micelles containing lower molecular mass, so it is the promising carrier for in vivo delivery. The second major advantage of the PM is increasing water solubility, and it integrates a large amount of hydrophobic drugs [29]. Initially it was a very inordinate problem with polymer-drug conjugate system, and due to this, loss of solubility was observed due to the incorporation of hydrophobic drugs. Many of the researchers reported this problem with the synthesis [30, 31, 32, 33]. Further, this problem was shorted out with the incorporation of hydrophobic drug in large amount within the inner core of the micelles [34, 35]. Concurrently the PMs can endure the solubility of the drugs by hindering intermicellar aggregation of the hydrophobic core through the use of hydrophilic part on the outer surface of the shell, and it acts as a boundary for the intermicellar aggregation. Lower toxicity is another characteristic which leads to the polymeric micelles. It is generally seen that lower polymeric surfactants are behaving as a less toxic material. So it is more used as a carrier system for drug delivery. It is also advantageous because it can be filtered through renal and the molecular mass of the constituting micelles that is lesser than the critical molar mass of the renal filtration. It is seen that PMs have two phases: the first one is inner core and the second phase is an outer shell. This geometrical behavior of the PMs is utilized for many purposes in the drug delivery process. The inner core of the micelles is responsible for drug loading and the pharmacological activity, whereas the outer surface is playing the role of interaction with the bio-components like cell and proteins. This one leads to the determination of pharmacokinetics profile of biodistribution of the drug. So, in vivo release of the drug is maintained by outer shells of polymeric micelles [34]. This unique feature is favored nowadays at a very rousing rate because of the biphasic nature of the PMs which are dependent on the types of the chain forming the polymeric micelles through block copolymer.

Within this series there is one more advantage attached with the PMs, i.e., its particle size, which is very small, and diameter, which mainly lies between 5 and 100 nm with very narrow distribution. Due to this smaller size range, it is very easy to attain stability and longer extent of movement in the blood stream. Owing to its smaller size, it is not easily captured by reticuloendothelial cells, and it is also rapidly excreted through the kidney [31]. One of the major drawbacks is stated here, that it cannot be easily recognized in scientific papers that relatively high levels of the chemistry of polymer are desirable in the polymeric micelles studies. Another drawback is the method of incorporation; if it is not satisfactory, then it can create a problem. Yokoyama et al. reported that physical combination efficiencies were reliant on approaches of incorporation [35]. Through trial and error, researchers needed to search an appropriate incorporation method for every drug separately. Many of the incorporation methods are appreciable at laboratory scale, but it fails at industrial scale due to the physical factors such as solvent exchange rate and diffusion process so that it is needed to develop a substantial development of technology of incorporation of drug molecule into the polymeric micelles [36]. Similarly, it is valuable citing that the regulator of micelles dissociation and drug release rate is crucial for drug aiming and it rheostat of these problems are occasionally technically problematic to improve for the targeting. One line statement for the pros of polymeric micelles is smaller diameter with the lean distribution, high stability in structure, good water solubility, and low toxicity.

3 Methods of Preparation

There are various methods that encompass the preparation of polymeric micelles such as o/w emulsion, dialysis, solid dispersion, and microphase separation method. All the above different process covers in two steps: synthesis of amphiphilic block co-polymer and then transformation of it toward critical micelle concentration (CMC) [37]. It is observed that at CMC, both the interface and the bulk turn out to be saturated form with the monomers. Under CMC, the quantity of the amphiphilic polymer at the air/water interface upsurges with increasing concentration; for both surfactant and high-molecular-weight block copolymer, removal of ordered water molecules into the bulk aqueous phase carries association of micelles, that is, in stable form [38]. Polymeric micelles consist of highly regulated block copolymers with distinct core-shell structure. Functional groups, such as amines and carboxylic acids in the core-forming segments, are useful for introducing drugs into the micelle core [39]. Another groundbreaking, single-step process of formation of PMs comprises the solution mixture of drug and polymer in a water-tert-butanol system by the help of lyophilization. Reconstruction of this freeze-dried cake of drug-polymer mixture with injectable vehicle catalyzes the impulsive formation of PMs [40]. Other different methods are direct dissolution, [41] complexation [42], chemical conjugation [43], and several solvent evaporation methods. After polymer synthesis, polymers are permissible to self-assemble in biphasic systems followed by exhaustive modification. PMs having cross-linking in the core are produced after quickly heating aqueous media of block copolymer to above their CMC, followed by illumination in the presence of a photoinitiator [44]; this cross-linking is responsible for stabilization of morphology of micelles [20].

3.1 Solid Dispersion Method

In solid dispersion method, polymer and drug are dissolved into a suitable organic solvent system. The organic solvent was evaporated under reduced pressure to form a polymeric matrix. Further, water was added into preheated polymeric matrix, to form drug-loaded polymeric micelles [45, 46]. Lei and co-workers prepared curcumin-loaded polymeric micelles using single- or one-step solid dispersion method. In this method they dissolved curcumin and MPEG-PCL copolymer in dehydrated alcohol. Further, the solution was dried using rotary evaporator, and afterward it was dissolved into NS to self-assembled micelles [47].

3.2 Dialysis Method

As the name suggested, in this technique dialysis bag is used. Briefly, addition of fewer amounts of water to the solution of polymer and drug in a water-miscible organic solvent such as dimethylformamide (DMF) with continuous stirring which is then dialyzed against excess amount water [48]. In this process, water replaces the organic solvent gradually so that process of self-association is fast and entrapment of drug is also desirable rate in assembled structural format (Fig. 3). The micelles remain in dialysis bag with the help of semipermeable membrane, and only unloaded drug is removed from micelles during the dialysis [49]. The method described here is well suited to the laboratory scale rather than feasible to the large scale industry. One of the major drawbacks is noted in this method, i.e., the removal of the complete unbounded drug from the formulation [50]. Sung and co-workers prepared micelles of poly(ethylene oxide)–poly(β-benzyl L-aspartate) (PEO-PBLA) copolymer, and they used different organic solvents such as DMF, acetonitrile, THF, DMSO, ethyl alcohol, N,N-dimethylacetamide (DMAc), etc. which are dialyzed against water using dialysis tube. They found that the highest yield of micelles was obtained with DMAc which was 87% [51].
Fig. 3

Schematic graphical preparation of polymeric micelles through dialysis method

3.3 Oil-in-Water Emulsion Solvent Evaporation Method

In this method, the formation of emulsion was reported with continuous aqueous phase and internal organic phase. Formation of emulsion is done by dissolution of the polymer and drug simultaneously in water-immiscible organic solvent such as tetrahydrofuran, acetone, chloroform, or mixture of ethanol and chloroform [52, 53]. Further, solution is slowly added to distilled water by instant shaking and stirring, and many times polyvinyl alcohol (PVA) is added into water, and resulted into formation of emulsion rearranged to form expected polymer (Fig. 4). This emulsion is then preserved in the air with stirring so as to remove all the organic solvent [54]. This method is beyond the limit for the addition of the polymer which can be added either in an aqueous or organic phase and exemplified by the reported literature [55, 56, 57] that solubilization of doxorubicin (DOX) and indomethacin in poly(ethylene oxide)-b-poly(β-benzyl-L-aspartate) (PEO-b-PBLA) forms a micelle through the o/w emulsion method.
Fig. 4

Schematic graphical preparation of polymeric micelles through o/w emulsion solvent evaporation method

3.4 Microphase Separation Method

Polymeric micelles are molded impulsively and drugs are entrapped in the inner part of the micelles. In this method, polymer and drug were added into organic solvents such as tetrahydrofuran (THF). The drug and polymer solution were added into aqueous solution dropwise under continuous stirring. Further, the organic solvents were removed under reduced pressure, and a blue color micelles solution is formed [58].

3.5 Freeze-Drying Method

The freeze-drying method (Fig. 5) used an organic solvent like t-butanol which can be freeze-dried for purpose of dissolution of drug and polymer. After that this solution is added with water and then freeze dried. Further it was reconstituted in aqueous isotonic media [59]. This method is pharmaceutically feasible and can be utilized in large-scale production within industry. Freeze-drying was used for the encapsulation of PTX with its derivatives in poly(N-vinylpyrrolidone)-b-PDLLA (PVP-b-PDLLA) [59]. Another side, one thing should always keep in mind is that the freeze-drying method may not be used with the PEO-containing block copolymer due to insolubility of PEO in t-butanol [60].
Fig. 5

Schematic graphical preparation of polymeric micelles through freeze-dried cake method

4 Characterization

The main purpose of characterization of the PMs is because it is being used for the delivery of drug, and for this it should be stable for a sufficient amount of time in blood stream so that it should reach the target site.

4.1 Nuclear Magnetic Resonance

Nuclear magnetic resonance (NMR) is used frequently to disclose the structure and composition of polymers synthesized to produce PMs. It expresses number-average molecular weight of the polymer in which first calculated the molar composition of the polymer from the integral proton intensity at different parts per million (ppm), then the data observed is calculated by molar ratio of the recovered polymer from NMR [61], and then the average molecular weight was calculated from that data based on the assumption that the weight of initial polymer is taken.

4.2 Morphological Characterization

For determination of surface morphology of prepared micelles, atomic force microscopy (AFM) is used to characterize the particle size. A probe tip with atomic-scale sharpness restored on the sample a data generated on the basis of force operated between surface and tip of the probe. For the observation of three-dimensional microscopy of the colloidal particle, confocal microscopy can be performed with very high precisions rate with time rate at large limit by avoidance of the scattered light outside the plane of interest [48]. Scanning electron microscopy (SEM) and transmission electron microscopy (TEM) provide the way to observe the surface of micelles which gives the structural information through electron diffraction when needed [62].

4.3 CH50 Test (Complement Activation)

By the help of this test, the amount of human serum protein (complement protein) adsorbed on the PMs is calculated. The activation of the complement by opsonization though which the immune system eliminate the foreign particles. Butsele et al. measured complement activation by measuring the lytic capacity of a normal human serum toward antibody-sensitized sheep erythrocytes afterward introduction to the micelles. The test is done by the incubation of the aliquots of the human serum through increasing concentration of the micelles [63]. The total amount of serum needed to hemolyze 50% of the sheep erythrocytes to expose in micelles was calculated, and the released amount of the hemoglobin was applied for the dye in colorimetric titration. Small amount of the adsorbed protein on micelle gives large amount of the lysis of erythrocyte.

4.4 Determination of CMC of Polymeric Micelles Through Dye Solubilization Method

In this method, fluorescent probes are used which are nonpolar in nature such as 1,6-diphenyl-1,3,5-hexatrineor pyrene [64, 65]. Pyrene is a polyaromatic particle, especially partitions to the hydrophobic core of the micelles, with a synchronous alteration in property of fluorescent such as vibrational change in the spectrum, and in excitation spectrum, there should be red shift. The CMC is defined as the point where cross-linking of the extrapolation in the absorbance for a large range of the concentration of polymer occurs [66, 67]. There are many more methods employed to determine the CMC value, and earlier the widely used technique was the light scattering for the observation of aggregation number and the molecular weight. In this the inception of micellization may be only detected when the CMC lie only within the range of the scattering sensitivity, but it is very rare for block copolymer in water [68]. There are several copolymers on which the hydrophobic chain length decides occurrence of the micellization and the hydrophilic chain length is less considered [69].

4.5 Differential Scanning Calorimetric (DSC) Method

Nature and crystal space within the PM are measured by the glass, melting point temperature, and enthalpy in DSC. Owing to this various states of polymeric core and the interaction between the polymer and drug are observed through DSC [61].

4.6 Electrophoretic Technique

This method is utilized to measure the nature of surface coverage with respect to PMs. It gives information about the biodistribution and in vivo clearance. This technique utilized the separation on the basis of size and charge. The charged molecule passes across the gel when they are situated in the electric field, and the gel filters the molecule according to the charge and size of the molecule. For this technique isoelectric focusing and two-dimensional polyacrylamide gel electrophoresis are used as an analytical tool [70].

4.7 Flow Cytometry Method

This method mainly involves for the counting of the microscopic particle in which a beam of light is focused on the liquid or fluid. The detector is attached where the stream of single wavelength of light is passed for detection [71]. In the case of PM which is ligand coupled, observed for the capability of binding of micelles to the receptor [48].

4.8 Measurement of Optical Transmittance and Lower Critical Solution Temperature (LCST)

The LCST is a temperature below which the mixture is miscible in all ratio, the optical transmittance measurement method it generally used to determine polymer’s LCST. The determination of the LCST lies on the degree of polymerization of polymer, branching, and polydispersity when it is polymer mixture. To know the effect of the temperature in case of thermosensitive polymer, optical transmittance is measured by varying temperature of aqueous polymer at specific wavelength under ultraviolet light [48]. It is useful for the determination of the thermoresponsive micelles size. Diameter of these polymers was rapidly increased with the temperature above the LCST [72].

5 Drug Targeting Strategies

Major hurdles in treating cancer are delivery of anti-neoplastic agents to the cancerous cells and cytotoxicity of the anti-neoplastic agents to the normal cells and moreover, increasing resistance in the cancer needs to the increased dose which increases toxicity and put the patient with more incompliance [48]. Surgery is the choice of treatment, but it can’t be good for all patients because of factors such as tumor size, site, and metastasis, and the second choice is systemic chemotherapy, but the dark side of it is systemic toxicity. Hence, polymeric micelles are the best option for the targeted delivery and to reduce the toxicity as well; additionally, polymeric micelles enhance bioavailability because of stealth nature and targeted delivery through enhanced permeability and retention (EPR); and hydrophobic drugs can be administered intravenously (I.V.). There are two possible well-defined mechanisms for targeted delivery: active targeting and passive targeting. In this section we will discuss about polymeric micelle-based targeting of bioactive agents.

5.1 Passive Targeting

In starting it was thought that there was only one targeting strategy for anticancer drugs, that is, receptor-mediated targeting to therapeutic sites; thus, several reports were documented of engineered polymeric micelle in which various ligands have been attached to polymeric micelles [10, 73]. Plethora of literature available is related to enhanced bioavailability by passive targeting in polymer-conjugated and drug-encapsulated nanocarriers [74]. The best possible mechanism for passive targeting of polymeric micelles in solid tumors is enhanced permeability and retention (EPR) (Fig. 2), which was first acknowledged by Maeda et al. 2001 [75, 76], as the histopathological and pharmacological studies reveal that solid tumor possesses characteristics such as highly unorganized, incomplete, hyper-vasculature, secretion of vascular permeability factors stimulating extravasation, and immature lymphatic capillaries [77]. Studies have shown that EPR leads to passive accumulation of macromolecules and nanoparticulate in solid tumor, resulting decreased side effects and enhanced therapeutics. Most of the human solid tumors have the effective pore size of 200–600 nm in diameter which allows for passive targeting to tumors [78]. Secretion of various factors such as nitric oxide, prostaglandins, bradykinin, basic fibroblast growth factor in tumor tissues, and overexpression of genes such as vascular permeability factor or vascular endothelial growth factor these factors cause enhanced permeability of tumor microvasculature.

5.2 Active Targeting

The principle of active targeting is receptor-mediated endocytosis using ligand as receptor agonist. As the micelles are made up of polymers and can be decorated with ligands, ligands play the critical role in the targeting which leads to increase the selectivity for tumor cells and reduces systemic toxicity and adversative effects compared to untargeted chemotherapy [79]. When the ligands bind to their specific receptors on the cell membrane, the micelles are taken on by endocytosis [80]. Active targeting felicitates higher intracellular drug concentrations in the tumor. Ligands for active targeting can be any agent which has a higher binding affinity toward the receptors on the cell membrane, like monoclonal antibodies (mAbs) or their Fab fragments, oligosaccharides, or peptides [79]. Kabanov et al. were one of the first to report micelle-based active targeting by using murine polyclonal antibodies against α2-glycoprotein to deliver the haloperidol to the brain [22]. Similarly, Vega et al. reported mAb-based targeting of micelles in antineoplastic therapy [81]. Solid tumors were also targeted with the mAb C225 which has binding affinity with epidermal growth factor receptor (EGFR) [82]. Other than monoclonal antibodies, folate is also a vital ligand for active targeting of cancer cells as folate is an essential vitamin for the biosynthesis of nucleotide bases and consumed cancerous cell so it can be used as a ligand [79, 83, 84]. The folate receptor is overexpressed in most of the cancers, including the ovary, brain, kidney, breast, myeloid cells, and lung, so it can be used in all the aforementioned malignancies as targeting ligand. Similarly angiogenesis regulators can be used as a targeting ligand based on ligand-receptor interactions [85]. When tumor cells cluster and reach a size of around 2–3 mm, diffusion of oxygen and nutrients to the tumor is repressed. This induces tumor angiogenesis, which allows tumors to grow beyond their diffusion limit [86]. Nasongkla et al. explored active targeting using αvβ3 integrin with the micelle-conjugated cyclic pentapeptide c(Arg-Gly-Asp-d-Phe-Lys) (cRGDfK) [87].

At present, polymeric micelles are being investigated in targeted anticancer therapy in in vitro and in vivo due to promising characteristics and targeting efficiency. Polymeric micelles have higher cellular uptake and cytotoxicity, and tumor regression was demonstrated, making active targeting a significant added value to passively targeted polymeric micelles for anticancer therapy.

6 Anticancer Drug Delivery

Plethora of literature available regarding PMs based drug delivery for the effective and efficient treatment of cancer because of the promising nanocarrier for the delivery of hydrophobic anticancer drugs (Fig. 6 and Table 1).
Fig. 6

Various types of anticancer drugs encapsulated in polymeric micelles

Table 1

Drug incorporated into polymeric micelles

Block copolymer

Drug

References

mPEG-PDLLA

Paclitaxel

[88]

PEG-b-PPhe

Paclitaxel

[89]

MPEG-PLA

Docetaxel

[90]

Dextran-PLGA

Docetaxel

[91]

PLLA-mPEG

Doxorubicin

[92]

PLGA-mPEG-folate

Doxorubicin

[93]

PEG-PLG

Cisplatin

[94]

6.1 Paclitaxel

Paclitaxel is obtained from bark of pacific yew tree Taxus brevifolia. It acts on tubulin and inhibits cellular division resulting in cell death [95]. It is hydrophobic in nature and needs to be delivered through nanocarrier such as PMs. Several strategies were reported regarding PMs for paclitaxel drug delivery. In this contrast, many authors prepared PMs using different block copolymer. Block copolymers are self-assembled into micellar form in aqueous media. Polymeric micelles are mostly used to solubilize the hydrophobic drugs. So due to this, increasing water solubility, better efficacy, and safety profile parameter were enhanced using polymeric micelles. Drug delivered through polymeric micelles was less toxic compared to naïve paclitaxel. Kim et al. (2001) reported paclitaxel drug delivery through PMs. The author prepared PMs using amphiphilic diblock copolymer (mPEG-PDLLA) monomethoxy poly(ethylene glycol)-block-poly (D,L-lactide) and evaluated safety profile and pharmacokinetic and tissue distribution of polymeric micelles compared to naïve paclitaxel. In vitro cell line studies were done using human ovarian cancer cell line OVCAR-3 and MCF-7 human breast cancer cell line. The obtained results concluded that the IC50 values of polymeric micelles in both of the cell lines was 0.002 μg/mL compared to naïve taxol which was 0.002 and 0.004 μg/mL for ovarian and breast cancer cell lines. The toxicity was reduced and improved anticancer efficacy [88]. Similarly, solubility enhancement was reported by Cho et al. (2004). They reported that after using a hydrotropic agent, sodium salicylate, the solubility of paclitaxel was enhanced 100-fold in aqueous media without disrupting block copolymer of (PEG-b-PPhe) poly(ethylene glycol)-block-poly(phenylalanine). This is due to sodium salicylate, and it was a predictable tool for maintaining better sink condition for less soluble drugs such as paclitaxel [89]. Further, more exhaustive study was carried out by Soga et al. (2005), in which they explained the block copolymer pHPMAmDL-b-PEG {poly(N-(2-hydroxypropyl) methacrylamide lactate) and poly(ethylene glycol)}. This block copolymer has thermo-sensitivity, which was one of the important advantages for selection. Using this block copolymer, the drug loading was up to 2 mg/mL in PMs [96]. For targeting delivery, Seow et al. (2007) reported cholesterol-grafted poly(N-isopropylacrylamide-co-N,N-dimethylacrylamide-co-undecenoic acid). In this, folate was attached into hydrophilic moiety of polymer for targeting into folate receptor on cancer cell lines. The overall conjugated micelles showed better solubility, enhanced targeting, and significant cytotoxicity [97]. After that a dual-targeting approach was established by Liu et al. (2011), in which they explained two targeted molecules such as folate and hyaluronic acid for polymeric micellar formation of paclitaxel. This dual-targeting moiety has an ability for high payload, sustained-release property, and effective and prominent cellular uptake [98]. Another research was carried out using triblock copolymer by Zhang et al. (2012). They investigated poly(ɛ-caprolactone)-poly(ethylene glycol)-poly(ɛ-caprolactone) copolymer for preparation of polymeric micelles. The results suggested that the overall improvement in pharmacokinetic property and in vivo efficacy of PMs compared to naïve drug [99].

6.2 Docetaxel

Docetaxel is an anticancer drug obtained from Taxus baccata. It acts on beta tubulin, stabilizing the microtubule formation and resulting in cell death [95]. The main drawback of this drug is its hydrophobic in nature and so some new carriers are needed for docetaxel delivery to the cancer cells. In this regard, Mu et al. (2010) reported effects of mixed MPEG-PLA and pluronic micelles for improved bioavailability and multidrug resistance of docetaxel. Mixed micelles shown improved and admirable solubility profile over naïve drug. Pluronic polymer displayed an effective and promising role in high payload, improved pharmacokinetic profile, and overcomes multidrug resistance in vivo [90]. Another research group, Mi et al. (2011), prepared targeted formulation for docetaxel using folic acid-conjugated D-α-tocopheryl polyethylene glycol succinate 2000 (vitamin E TPGS2k) micelles. TPGS2k formed micelles were used for delivery of hydrophobic drug which showed the more stability. Significantly synergistic effects were obtained using copolymeric micelles formulations. Folic acid was used as a targeted ligand for targeted drug delivery for better enhancement of cellular uptake [100]. Chen et al. (2012) reported Pluronic P105 and F127 copolymers using thin film hydration method. They evaluated that the prepared micellar formulation showed significantly improved pharmacokinetic as well as solubilization property compared to naïve docetaxel. The in vivo tumor efficacy was also impressive for effective tumor suppression than docetaxel alone [101]. Further new strategy was reported by Raza et al. (2016) using dextran-PLGA copolymer. They too reported that the micelles formation of copolymer showed effective pharmacokinetic profile and biological half-life. Bioavailability was approximately 16 times enhanced than naïve drug [91].

6.3 Doxorubicin

Doxorubicin (DOX) is an anthracycline antibiotic isolated from fungus Streptomyces peucetius. It is a chemotherapeutic agent used against non-Hodgkin lymphomas, breast cancer, etc. It inhibits the synthesis of nucleic acid, resulting in cell death. Many researchers delivered doxorubicin through nanocarriers such as micelles, nanoparticles, liposomes, etc. [102]. Yoo et al. (2000) prepared PLGA-PEG copolymer-based micelles for DOX. They evaluated that the cytotoxicity of formed micelles was enhanced than free DOX due to endocytosis mechanism. Co-polymeric micelles sowed more intense fluorescent in the nucleus than DOX alone [103]. Similarly again the same research group, Yoo et al. (2002), prepared PLLA-mPEG copolymer-based micelles using self-assembled method. Encapsulated doxorubicin was released from micelles slowly up to 25 days as a sustained-release manner which exhibits its sustained-release behavior. Cytotoxicity was performed in lymphoblast cell line HSB-2. The observed cytotoxicity of micelles was 5 times more than naïve DOX. It was concluded that the micelles formation showed better and effective IC50 value compared to DOX alone [92]. Further Yoo et al. (2004) also described the targeted strategy using ligand at the terminal of copolymer. They used folate as a ligand for targeting delivery. In this PLGA-mPEG-folate was used as long-chain molecules for attaching the DOX at the one terminal of PLGA. They used these molecules for self-assembled in to PMs. Folate act as targeted molecules in this formulation. Flow cytometry, confocal images, and cytotoxicity results showed that the folate ligand attached micelles have more cellular uptake and are more cytotoxic than without ligand attached micelles. Biodistribution and in vivo study also suggested that the folate ligand attached micelles had more availability in tumor region and had significantly decreased tumor volume than naïve DOX [93]. Other group of researchers, Talelli et al. (2005), reported core cross-linked PMs with sustained release of DOX. They used (poly(ethylene glycol)-b-poly[N-(2-hydroxypropyl) methacrylamide-lactate] (mPEG-b-p(HPMAm-Lactate) diblock polymer for micelles. They explained that the di-block co-polymeric micelles were more accumulated in tumor-specific region and prolonged circulation in blood stream due to EPR effect. Cytotoxicity and in vivo results were more comprehensive in co-polymeric micelles compared to DOX alone [104].

6.4 Cisplatin

Cisplatin is a metallic compound and a well-known anticancer drug used in many sarcomas such as bone, soft tissues, blood vessels, etc. It is also used in solid tumor. The main side effects of cisplatin are nephrotoxicity [105]. To overcome this side effect and increasing efficacy, a new novel carrier is needed for delivery of cisplatin. In this point of view, Nishiyama et al. (2001) investigated cisplatin-loaded polymer metal complex micelles delivered to the lung cancer. They observed that the cisplatin-loaded micelles had more circulation in plasma and tumor accumulation in specific area due to micelles. They also evaluated that nephrotoxicity was reduced due to specific organ tumor accumulation of cisplatin-loaded micelles [106]. Further, other research group, such as Oberoi et al. (2012), explained cisplatin-loaded poly(ethylene glycol)-b-poly(methacrylic acid) cross-linked micelles for ovarian cancer. They also observed that the copolymeric micelle-loaded cisplatin showed more prolonged blood circulation and tumor accumulation. The main side effects of cisplatin were renal damage, and the results indicated that the overall exposure of cisplatin to kidneys was minimized with the use of polymeric micelles [107]. Subsequently in the same year, Wang et al. (2012) reported PEG-PLG-conjugated dithiodipropionic-Pt (IV) micelles for ovarian cancer cell line. They found that the consequential micelles show high payload capacity of cisplatin and improved in vitro cytotoxicity against ovarian cancer cells compared to naïve cisplatin [94].

7 Scientific Opinions

7.1 Yokoyama’s Report

Yokoyama et al. (2004), enumerated that the enumerated that various PMs were used as anticancer drug targeting systems since the late 1980s, and most of this research team’s report involved the elementary study stage mainly on three important explanations. The main point of attraction of this report was enhanced antitumor effect, biodistribution and pharmacokinetic profile, and also the physiochemical characteristic of the carrier system. It also explains the limits, the biological behavior, and the toxicity of the carrier which are explained below.

In the first report, the research team successfully prepared PM formulations with anticancer drug, i.e., DOX, and it was chemically conjugated to aspartic acid residues of the poly(ethylene glycol)-b-poly(aspartic acid) block copolymer through amide bond formation. Prepared micellar structure have amphiphilic characteristics Doxorubicin was further assimilated into the inner core by means of physical entrapment having π-π interaction with established chemical conjugation with the DOX molecule [35]. Thus PMs encompassing both the physically entrapped and chemically conjugated and DOX in the inner core remained with the PEG. Outer shell did not demonstrate any in vitro or in vivo actions. Cytotoxic activities were found with physically entrapped DOX. The inactivity of the conjugated DOX resulted from the fact that the DOX is directly conjugated without any spacer forming amide bond with the aspartic acid residue of the block co-polymer which is a very stable bond for the further cleavage. Further by more exploration, it shows the more providence of pharmacological active free DOX. Therefore for the purpose of the anticancer activity assay, the block co-polymer acts as the carrier molecule not as active ingredient [35].

In this study, they showed tumor-selective delivery and enhanced in vivo antitumor activity. Physically entrapped DOX in the polymeric micelles was showing nine times more activity than the naïve DOX, whereas the accumulation of the micellar DOX (physically entrapped) in normal organs and tissues was lesser than or the same as the accumulation of free DOX. This study stated that the increment in the pharmacokinetic behavior of the micelles with DOX. The point of notice is that after 1 h of intravenous administration, it was found that the amount of DOX-entrapped micelle was much more than the free DOX. The results showed the effectivity and importance of the EPR effect in drug targeting strategies [35].

The third and main study reported by this group was biological activity of polymeric micelle as a carrier regarding the accelerated blood clearance (ABC) phenomenon. ABC is a process where clearance rate of the carrier system is substantially increases with the rapid injection. It is very well studied with the liposome coated with PEG, having long circulating phenomenon at the first injection. PEG-coated liposome when injected in appropriate first dose and second dose of the same liposome at appropriate interval (5–7 days). This activity resulted in the immunological activity caused by the first dose and the clearance is considerable. They reported that ABC induction developed at mainly two organs such as the liver and spleen. Both organs are most relative organ to the MPS. So rheostat uptake at the MPS might be an important aspect of ABC induction [35]. It is also reported that the phenomenon of the ABC is blocked when the cytotoxic drug was carried by the PEG-coated liposomes trials on experimental animal model or the clinical trials on human. So cytotoxicity plays a greater role in the ABC phenomenon, and the use of less cytotoxic drug is a new direction of therapy suggested by this report.

7.2 Kabanov’s Report

Kabanov et al. (1997) reported their study with the unique polymer. In this system at specific site, at the place of carrier, the block co-polymer worked as a biologically active agent. A polymer chain was used, such as poly(ethylene oxide)-b-poly(propylene oxide)-b-poly(ethylene oxide); it is also known as ABA type of polymer. They reported that pluronic polymers explicitly inhibited the production of adenosine triphosphate (ATP) in mitochondria p-glycoprotein [108, 109], which showed a significant role in multidrug resistant cancer cells and the efflux action of anticancer drug in an ATP-dependent manner. Thus, the drug efflux action was inhibited by pluronic polymer over the inhibition of ATP production by the help of such block co-polymer successful avoidance of the multidrug resistance both in vitro and in vivo [108]. It was an unexpected result in cancer therapy by block co-polymer as pluronic polymers deficient with the charge containing the functional group, and it was assumed that strong interaction with the protein. They also reported that the appropriate chain lengths with good hydrophilic/hydrophobic balance with the pluronic polymers. Further many more researchers did not showed the inhibition of the P-glycoprotein with synthetic polymer. It was limited with the polymer, but the matter of concern was biological activity, mainly anticancer activity. Because the inhibition of mitochondrion and P-glycoprotein by the carrier system was a major concern of toxicity, Kabanov et al. reported that the enhanced in vivo anticancer activity with animal model and the confirmation of this enhanced activity were noticed with the in vitro cytotoxicity study (with presence and absence of polymers). There was an advisable step to the researcher to examine and explore more P-glycoprotein in much more detail, if researchers observe that the anticancer drug in combination with the polymer showing more effectivity [108].

8 Applications

8.1 Pharmaceutical Application

Polymeric micelles are mainly planned to show fundamental parameters in drug depiction; the first one is solubilization of hydrophobic drugs, and the second one is the controlled or sustained release of a drug.

8.1.1 Solubilization of Hydrophobic Drug

It is expected that 90 percent of the chemical entity of the drug is hydrophobic in nature, and they mainly belong to the Biopharmaceutics Classification System (BCS) II and IV [110, 111]. The major problem with these classes of drugs is the very low bioavailability due to the low solubility profile, although it has potential pharmacodynamics profile. So they are not effective due to low bioavailability. Conventional way of increasing solubility by solubilizing agent shows the toxicity behavior as well [60]. In this regard, PMs showed very effective behavior toward the dissolution rate and the increasing of solubility profile. They provide the hydrophobic environment to the drug so that the drug can incorporate into micelles according to its favorable environment, ionic interaction, and chemical conjugation. Due to its solubility, it may increase from 10 to 8400 fold, that is, a very beneficial application of polymeric micelles [112].

8.1.2 Sustained Release of Drug

Polymeric micelles are found to be more stable profile with lower CMC when it is compared to low molecular weight surfactant micelles. They show good retention of drug for longer circulating time period within the systemic circulation, and their dissociation is also slow. Due to this characteristic feature, PMs can reach at tumor target site with higher accumulation in large amount [113]. For the sustained release of drug, there should be specificity into the micelles, i.e., it should be stable to dilution due to low CMC value, good viscosity, and chain mobility behavior that is lower at core [114]. The novel drug delivery system enhances the bioavailability shielding of the loaded drug from the cruel atmosphere of the gastrointestinal tract (GIT) [115], so that they provide the safe conveyance of drug and pH-sensitive micelles to specific target site of delivery. They have adhesive properties with mucous so the residence time in gut is increase. One of the important applications of the PMs is increasing absorbance in GIT due to the smaller size and high membrane permeability [116].

8.1.3 Delivery of Genes

Recently, the progress in therapy is enhanced by the biological mechanism driving life process at molecular state, and it provokes the innovation in the novel nucleic acid-based therapies such as DNA and siRNA as modern medicines. But the clinical handling and application are hindered due to its long molecular weight, anionic nature, and lower stability on physiological conditions. There is one more hurdle associated with it, lower cellular uptake. If DNA or RNA is directly put into the blood stream, then it will be eliminated very quickly due to obstacle attack of the DNase and RNase. These problems may be eradicated by the incorporation of the DNA and RNA into the nanocarrier. For the intracellular delivery to the nucleus in gene therapy, accumulation at the specific site of tissue is needed, and it is achieved by the use of the vectors like retroviruses and adenoviruses which are very common carriers in the section of gene therapy in clinical trials [117, 118].

On the other section, it is seen that the non-viral vectors having the active polymer constituent are more effective, and they are very good and reliable alternative on the aspect of safety, are cheaper, and also may be prepared in larger amount [119, 120, 121, 122, 123, 124, 125]. Due to the advantages, polymeric micelles are prominent for the delivery of the nucleic acid by forming the polyion complex with the anionic nature of the DNA and RNA. Block copolymer having cationic charge so the complex is found to be more stable and the plasmid DNA (pDNA) associated with a PEG-polycation such as PEG-poly(lysine) (PEG-PLys) giving polyion complex micelle (PIC micelle or polyplex micelle) having very good size range of 100 nm. Therefore the zeta potential of the complex was natural. Further the complex having pDNA exhibits the better introduction of gene into the cultured cells. The more advanced achievement was that pDNA was degraded rapidly by the nucleases, but due to incorporation into the polymeric micelles, it was found effective up to 3 h; it is much more than the necked insertion of pDNA into the blood circulation [124].

8.2 Biomedical Application

Biomedical application of PMs is in photodynamic therapy for treatment of different disease mainly for macular degradation and tumors. It is also having active involvement in administration of photosensitizer [126]. They are observed as a means of transportation for photosensitizer to avoid side effect like hypersensitivity and work for the efficacy and selectivity of the photodynamic therapy. One of the study reported by the Guo et al. that, photosensitizer loaded PMs integrating cyanine dye for the accurate anatomical tumor localization through near-infrared fluorescent imaging and side by side cancer therapy through consecutive synergistic photo thermal therapy. In this series PMs are also used for various types of medical imaging techniques such as magnetic resonance imaging (MRI), ultrasonography, and X-ray computed tomography and for visual optimization on delivery of drug incorporated in micelles. In the above imaging technique, micelles have role as a contrast agent [127]. In recent years it is confirmed through many studies that micelles accomplished a good biodistribution with longer retention of carbocyanine dye within the tumor, and due to this retention, the increase in the near-infrared fluorescence is observed by long duration of imaging in both hypovascular tumor and hypervascular tumor [128]. Polymeric micelles are nowadays used in both of the purposes such as high-contrast cancer imaging and superior photothermal therapy. It also triggered photothermal damage to cancer cell by organelle destabilization and this causes tumor necrosis to photo-irradiation [129]. In X-ray computed tomography technique for high resolution, iodine is absorbed by X-ray as a contrast agent. Torchilin et al. reported that PLL-PEG polymeric micelles containing iodine have average diameter 80 nm and having iodine 34% w/w used for the computed tomography. In another extent in this series, the above compound was administered through tail vein in rat and enhancement in blood pool spleen and heart for 3 h, and this technique was used for computation of the biodistribution of DNA micellar nanoparticle and pharmacokinetic activity [130].

9 Conclusion and Future Prospects

Polymeric micelles are the novel and cogent carriers for anticancer drug delivery. This new and versatile approach allows encapsulation of hydrophobic drugs, sustained drug release, targeted tumor site action, enhancing pharmacokinetic properties, reducing side effects, and effective tumor accumulation. Polymeric micelles have demonstrated effective and versatile delivery carrier for anticancer drugs. This approaches for drug delivery is very prominent and successful. The new block copolymers and new core-forming blocks give the newer occasion to integrate new molecules with suitable compatibility and solubilization property. They can help to provide a new versatile carrier for least soluble drugs to more toxic drugs in a universal formulation which will be in lower risk factor such as toxicities and instability problem.

Notes

Acknowledgment

The authors are grateful and would like to acknowledge the University Grants Commission (UGC) New Delhi, India, and Science and Engineering Research Board (SERB), Department of Science and Technology (DST), New Delhi, India, for providing research funding to the corresponding author.

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Copyright information

© Springer Nature Switzerland AG 2018

Authors and Affiliations

  • Iliyas Khan
    • 1
  • Avinash Gothwal
    • 1
  • Gaurav Mishra
    • 1
  • Umesh Gupta
    • 1
    Email author
  1. 1.Department of Pharmacy, School of Chemical Sciences and PharmacyCentral University of RajasthanBandarsindri, AjmerIndia

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