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Department of Pharmaceutics, Faculty of Pharmacy, Jamia Hamdard, New Delhi, 110062, India. Abstract: Cancer is a disease manifested as abnormal cells ...
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Nanostructured Lipid Carriers: A Novel Platform for Chemotherapeutics Md. Rizwanullah, Javed Ahmad and Saima Amin* Department of Pharmaceutics, Faculty of Pharmacy, Jamia Hamdard, New Delhi, 110062, India Abstract: Cancer is a disease manifested as abnormal cells division without control. If it is not detected and cured very timely, it can invade other healthy tissues resulting in metastasis. Chemotherapy is the first line treatment for cancer, but due to lack of specificity of most of the anticancer drugs, is associated with side effects that affect the quality of life. Nanostructured lipid carriers (NLC) are one of the promising nano-carriers for the development of effective targeted therapies for cancer chemotherapeutics. These bio-compatible and/or bio-degradable lipids based nanoparticles are composed of solid and liquid lipids as a core matrix dispersed in surfactant solution. NLC improve the aqueous solubility of most of the hydrophobic cancer therapeutics. Their surface modification can be used for overcoming drug resistance in cancer chemotherapy, to achieve site specific targeting for better efficacy and reduced dose related toxicity. The present review is an attempt to contemplate their pharmaceutical, biopharmaceutical aspects and application in cell targeting, gene delivery and in theranostics.

Keywords: Nanostructured lipid carriers, p-glycoprotein, receptors, targeting, tumor, multidrug resistance, theranostics. 1. INTRODUCTION Cancer is considered as one of the leading causes of death worldwide and is expected to raise the mortality further in coming time [1]. It can occur at any stage of life and in any age group but its early detection and treatment can improve the survival rate of the patient. Currently, cancer treatment involves a combination of surgery, radiotherapy and chemotherapy. Normally after surgical removal of tumor, radiation and chemotherapy are required for complete eradication of any reminisce of tumor cells or tissue that minimize or nullify the re-lapse of the disease [2]. Various chemotherapeutics have been identified such as alkylating agents (platinums, nitrogen mustard derivates, oxazophosphorines); cytotoxic antibiotics (anthracyclines, bleomycin, mitoxantrone); antimetabolites (pyrimidine analogs, antifolates); plant derivatives (vinca alkaloids, taxanes); topoisomerase inhibitors (topoisomerase-I inhibitors, topoisomerase-II inhibitors); and other antineoplastic drugs. These cytotoxic drugs act by inhibiting the cell division of tumor cells [3]. Unfortunately, these drugs have low specificity, narrow therapeutic window and high dose limiting toxicities. Mostly these are administered close to their maximum tolerated dose [4]. Such obstacles have led to limited application of these drugs. Therefore, there is constant surge to explore new ways to deliver the old and new chemotherapeutics for efficacious delivery. Nanotechnology based carriers have shown in past enormous potential for effective drug delivery in various diseases including cancer. It’s now established that nanoparticle based drug delivery in cancer has several advantages compared to the conventional chemotherapy with *Address correspondence to this author at the Department of Pharmaceutics, Faculty of Pharmacy, Jamia Hamdard, New Delhi 110062, India; Tel: 9111-26059688; Fax: 91-11-26059663; E-mail: [email protected] 1875-5704/16 $58.00+.00

regard to adverse effect, drug resistance and patient compliance. Nanoparticles including lipid nanoparticles are known to improve the pharmacokinetics, tumor specific drug accumulation and reduced bio-distribution that in turn result in reduced adverse effect of anti-cancer molecules [5]. As a chemotherapeutic delivery system, nanoparticles require a specific set of characteristics such as small particle size (< 200 nm), optimum zeta potential value, hydrophilic surface to facilitate escape from phagocytosis, higher loading controlled release for payload, biodegradability, maximum biocompatibility and minimal antigenicity [6]. Over the past decade, extensive work has been done in the area of lipid nanoparticles as carrier for anti-cancer drugs. Solid lipid nanoparticles (SLNs) and nanostructured lipid carriers (NLC) are common forms of lipid nanoparticles used in cancer chemotherapeutic delivery. These are highly promising due to their composition and potential for scale uptechnology [7]. SLNs have been used as effective carriers for drugs but their widespread use is limited due to difficulties in formulation, erratic gelation, phase transition of lipids, crystallization during storage, low encapsulation and eviction of payload [9]. It has been reported that NLC overcome these issues associated with SLNs due to the presence of liquid lipids along with solid lipids in an optimum ratio [10]. 2. NANOSTRUCTURED LIPID CARRIERS (NLC) The essential components in designing of NLC include solid lipids, liquid lipid, water and emulsifiers. NLC are prepared with lipids as a core excipient using mixture of solid and liquid lipids [11]. Solid lipids are the major fraction of the NLC matrix that keeps them in solid state at room temperature and selection is done on the basis of their physiochemical structure, miscibility, solubility, polymorphic nature and crystallinity [12]. © 2016 Bentham Science Publishers

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2.1. General Selection Criteria for Excipients

2.3. Surfactants

The excipients such as liquid lipid, solid lipid and surfactants/emulsifiers are selected considering their regulatory status (GRAS status as per USFDA), purity, chemical stability, solubility of drug in the lipid components, miscibility of solid and liquid lipids, concentration of solid and liquid lipids, concentration of surfactants, digestibility, fate of digested products (generally biodegradable lipids are preferred), processing temperature and cost of excipients. Generally, excipients with low level of peroxides or aldehydes are chosen as these contaminants may alter the chemical stability of the dissolved drug [13].

Hydrophilic, lipophilic and amphiphilic surfactants are used in NLC. Water-insoluble surfactants such as Span 20, Span 80, Myverol 18-04K penetrate and fluidize biological membranes. The water-soluble surfactants like Poloxamer 188 and Tween 80 solubilize the membrane components. These surfactants tend to show toxicity due to interaction with skin components [47]. Cationic surfactants such as linear alkyl-amines and alkyl-ammoniums are more toxic than anionic surfactants such as soaps and other carboxylates. The non-ionic surfactants (such as ethoxylated linear alcohols) are considered the safest of all the surfactants. Hydrophilic surfactants such as polysorbates or polyethoxylated vegetable oil derivatives are considered as non-irritant and safer. Irrespective of the site of application, non-ionic surfactants are widely used in the formulations because of their nontoxic nature within a certain limit [48]. It has been seen that Pluronic F68, polysorbates, polyethylene glycol (PEG), polyvinyl alcohol are commonly used stabilizer in the formation of NLC [49-52]. A mixture of surfactants in specific ratio is known to provide better stability by preventing the particle aggregation for particulate dispersed system like NLC [52]. In some of the recent studies, PEG has been used in NLC to improve its circulation half life that helps in accumulating higher concentration of drug to the tumor tissues [53, 54].

2.2. Lipids Lipids belong to a class of naturally occurring organic compounds which exhibit solubility in organic solvents such as chloroform, acetone and benzene and are practically insoluble in water. These can be fatty acids like stearic acid, linoleic acid or can be oils such as peanut oil, coconut oil, corn oil, olive oil and safflower oil. Solid lipids are the esterified derivates of glycerol and fatty acids and have specific characteristics in terms of melting point and polarity. These solid lipids are well tolerated GRAS substances. Some examples include beeswax, carnauba wax, Dynasan® 118 (glycerin ester of selected saturated, even numbered and unbranched fatty acids of plant origin), Precifac (palmityl palmitate), stearic acid, Apifil (PEG-8 beeswax), Cutina CP (cetyl palmitate) and Compritol® 888 ATO (glyceryl behenate). Liquid lipids (oils) are fatty acid esters or alcohols (2octyldodecanol). Due to excellent polar character, they are considered as good solvent for hydrophobic drugs as compared to hydrocarbons. Some examples include Cetiol V (decyl oleate), Miglyol 840 (propylene glycol dicaprylate), oleic acid, palm oil and olive oil. These lipids are amphiphilic (except castor oil and davana oil) due to presence of both lipophilic portion (hydroxyl group) and the hydrophilic portion (the esterified chain). The melting point or fusion temperature for a lipid increases and decreases with the increase of their molecular weight and unsaturation of the fatty acid chain respectively [13-15]. Hydrophile-Lipophile Balance (HLB), melting point and solubility of lipid in nonpolar organic solvents are the main parameters of selecting lipids for lipid based nanocarriers [13]. Literature has indicated the application of some other liquid lipids such as paraffin oil, isopropyl myristate, propylene glycol dicaprylocaprate (Labrafac®), 2-octyl dodecanol and squalene in the formulation of NLC [16]. In preparation of NLC intended for topical or transdermal application, fatty acids (such as oleic acid, decanoic acid, and linoleic acid) having penetration enhancing characteristics have been used with lipid phase [16]. Lipids of natural or synthetic origin affect the oral absorption of lipophilic drugs due to their high solvent capacity in the intestinal milieu [17]. They employ intestinal lymphatic drug transport which not only reduces drug first pass metabolism but even modifies the permeability of absorptive epithelia based drug transport and disposition [18]. Various liquid lipids and solid lipids used in formulating NLC are summarized in Table 1 and Table 2 respectively.

Various surfactants used in formulating NLC are summarized in Table 3. 2.4. Additives Other excipients such as preservatives, cryoprotectants and antioxidants are also added to enhance the stability of NLC. 2.4.1. Preservatives Since the NLC are formulated using relatively high water content, preservatives are incorporated [60-62]. Usually, ethanol, propylene glycol and pentylene glycol are used as preservatives in NLC. It has been observed that NLC preserved with 5-10% w/w propylene glycol did not show any significant change in particle size or in Zeta potential compared to the non-preserved formulation [63]. Similarly, the use of 5% pentylene glycol was also proved to provide stable NLC over a period of 120 days [63, 64]. 2.4.2. Antioxidants Oxidation of unsaturated fatty acid and sometime of the drug molecules is a major chemical instability in liquid formulation. Antioxidants are incorporated to shield the chemical degradation of liquid lipids used in NLC. Lipophilic antioxidants such as butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), β-carotene, α-tocopherol, and propyl gallate can be used for this purpose [65]. Teeranachaideekul et al. developed ascorbyl palmitate loaded NLC using BHA, BHT and DL-α-tocopherol (Vitamin E) as preservatives and evaluated the stability of developed NLC. The percentage of drug remaining intact at both 4 ◦C and room temperature (25 ◦C) was more than 85% during 90 days of storage [66].

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Table 1.

Rizwanullah et al.

Liquid lipids used in formulating NLC.

Liquid lipids

Chemical description

Chemical formula

HLB

Transcutol HP

Diethylene glycol monoethyl ether

C6H14O3

4.2

General chemical Structure

O

HO

O

O

Maisine™ 35-1

1-Monolinolein

C21H 38O4

4

Ref.

[19]

CH3

H3C

[20]

O

HO OH

O ®

Lauroglycol 90

Propylene glycol monolaurate (type II) EP/NF

C15H 30O3

5

H3C

CH3

O

[21]

HO

CH3 Capryol 90

Propylene glycol monocaprylate (type II) NF

C11H 22O3

6

CH3

O

HO

[22]

O O Capryol PGMC

Propylene glycol monocaprylate (type I) NF

C11H 24O4

5

HO

O

[23]

CH3

OH O

Capmul MCM

Medium chain monoand diglycerides

C11H 22O4

5-6

O

HO

CH3

[24]

CH3

[25]

OH

O

Capmul MCM C8

Glyceryl monocaprylate

C11H 22O4

5-6

O

HO OH O

H3C

Isopropyl myristate (IPM)

Isopropyl tetradecanoate

C17H 34O2

Isopropyl palmitate (IPP)

Isopropyl hexadecanoate

C19H 38O2

1.62

Oleic acid

cis-9-Octadecenoic acid

C18H 34O2

1

Caprylic/capric triglyceride

C11H 13Cl2NO3

2.82

CH3

O

H3C

O

H3C

CH3

O

H3C

[26]

[27]

O

Miglyol 812 N

CH3

HO 15.3

Squalene

Squalene

C30H 50

_

[30, 31]

_ CH3

CH3

CH3

CH3

H3C CH3

CH3

Glyceryl triacetate

C9H14O6

_

H3C

[32]

CH3

O

O

Captex® 500 P

[28, 29]

O

O O

O CH3

CH3

[33]

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(Table 1) Contd….

Liquid lipids

Chemical description

Chemical formula

HLB

General chemical Structure

Ref.

CH2CO2(CH2)7CH=CH(CH2)7CH3 Soyabean oil

_

_

7

[34]

CHCO2 (CH2 )7 CH=CHCH2 CH=CH(CH 2) 4CH3 CH2 CO2(CH 2 )7 CH=CHCH 2CH=CHCH 2CH=CHCH 2CH3

Olive oil

_

_

R

7

1

R

O

O O

2

O

O O

R

[35]

3

R1, R2and R3 are alkyl groups (approx 20%) or alkenyl groups (approx 80%) Labrafac CC

Caprylic/capric triglyceride

_

1

_

[36]

LabrafacTM Lipophile WL1349

Caprylic/capric triglyceride

_

1

_

[37]

Labrafil M 1944CS

Oleoyl macrogol-6 glycerides EP, Oleoyl polyoxyl-6 glycerides NF

_

4

_

Labrafil WL 2609 BS

Caprylic/Capric triglyceride

_

6

_

Table 2.

[38]

[39]

Solid lipids used in formulating NLC.

Solid lipids

Chemical description

Chemical formula

Melting point

HLB

General chemical structure

O Monostearin

Glyceryl monostearate

C21H 42O4

66-68 °C

3.8

Ref.

H3C [29, 40]

O

HO OH

O Geleol

Glyceryl stearate, Glyceryl monostearate 40-55 (Type I) EP

C21H 42O4

55-58 °C

3

H3C [41]

O

HO OH

HO

Glyceryl stearate, Imwitor 900 K

Glycerol monostearate (Type ll)

C21H 42O4

54-64 °C

3

OH O

H3C

[31]

O H3C CH3

Compritol 888 ATO

Glyceryl behenate NF

C69H 134O 6

70 °C

5

O O

O CH3

O

O

O

[25, 30]

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(Table 2) Contd….

Solid lipids

Chemical description

Chemical formula

Melting point

HLB

General chemical structure

Glyceryl palmitostearate, C37H 76O5

Precirol ATO 5

52-56 °C

H3C

O

CH3

O

O

2

Ref.

[32]

O

Glycerol distearate (type I) EP

OH

COOH

Stearic acid

n-Octadecanoic acid, Stearophanic acid

C18H 36O2

67-69 °C

15

[28] CH3 OH

O

Softisan154/ Hydrogenated Palm Oil

Triglyceride of C14C18 fatty acids

O

_

55 °C

10

O

[20, 35]

-

HO

H3C CH3

H3C Cetyl palmitate

Palmityl palmitate, Hexadecyl palmitate

C32H 64O2

54 °C

O

10

[26, 42]

H3C O H3C CH3

Glyceryl tripalmitate

Glycerol tripalmitate, Tripalmitin

C51H 98O6

64-66 °C

O

_

O

O O

O

CH3

O

O

Glyceryl dilaurate

1,3-Dilaurin, 1,3Dilauroylglycerol, Glycerol 1,3-dilaurate

C27H 52O5

58-59 °C

3.8

CH3

O

O

H3C

[43]

O

[24]

OH CH3

O

Glycerol trilaurate

Trilaurin, Glyceryl trilaurate, Glyceryl tridodecanoate

C39H 74O6

46-47 °C

O

O

_

[44] O

H3C

CH3

O O CH3

O

Glyceryl tridecanoate

Tricaprin, Glycerol tricaprate

C33H 62O6

46-47 °C

O

O

_ H3C

[45] CH3

O

O

O

Gelucire® 44/14

Lauroyl macrogol-32 glycerides EP

_

49-50 °C

11

_

[46]

Gelucire® 43/01

Hard fat EP/NF (Mixture of triglycerides, diglycerides and monoglycerides)

_

43 °C

1

_

[23]

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Table 3.

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Different surfactants used in formulating NLC. Surfactants

Chemical description

Chemical Formula

Nature

HLB

Ref.

Tween 80 (Polysorbate 80)

Polyoxyethylene (20) sorbitan monooleate

C64H 124O 26

Hydrophilic

15

[29, 35, 38, 43]

Poloxamer 188 (Pluronic F68, Lutrol F68)

Poly ethylene oxide (PEO)-poly propylene oxide (PPO) copolymers

C433 H868O204

Hydrophilic

29

[25, 32, 37]

Poloxamer 407 (Pluronic F127)

2-methyloxirane/ oxirane

C572 H1146O 259

Hydrophilic

18-23

[31]

Cremophor RH40

Polyoxyethylene glycerol trihydroxystearate

Unspecified

Hydrophilic

14

[55]

Cremophor EL

Macrogolglycerol ricinoleate/ Macrogol (25)-cetostearyl ether

Unspecified

Hydrophilic

13

[56]

Solutol® HS 15 (Kolliphor HS15)

Polyethylene glycol (15)-hydroxystearate

C20H 40O4

Hydrophilic

14-16

[40, 44, 45]

Sodium deoxycholate

Desoxycholic acid sodium salt

C24H 39NaO4

Hydrophilic

16-17

[37]

Sodium taurodeoxycholate

Taurodeoxycholic acid sodium salt

C26H 46NO 7SNa

Hydrophilic

16-17

[28]

Sodium taurocholate

Taurocholic acid sodium salt/ Monosodium N-choloyltaurinate

C26H 44NO 7SNa

Hydrophilic

16-17

[30]

Brij® 78

Polyethylene glycol octadecyl ether/ Polyoxyethylene stearyl ether

C58H 118O 21

Hydrophilic

15.31

[21]

Oleth-20 (Brij 98)

Polyoxyethylene(20) oleyl ether

C58H 116O 21

Hydrophilic

15.3

[57]

Plantacare® 810

Caprylyl/Capryl Glucoside

C22H 46O6

Hydrophilic

15-16

[58]

Span 40

Sorbitan monopalmitate

C22H 42O6

Lipophilic

6.7

[27]

Myverol 18-04 K

Hydrogenated Palm glyceride

C18H 12Br 8N2O 8

Lipophilic

3.8

[59]

Lecithin

L-alpha-phosphatidylcholine

C42H 82NO 8P

Amphiphilic

4-9

[34, 35]

Soybean lecithin

L-alpha-phosphatidylcholine

C42H 80NO 8P

Amphiphilic

4-9

[38]

2.4.3. Cryoprotectants Cryoprotectants are known to produce stable unimodal size distribution of particles on reconstitution or re-dispersion of lyophilized formulations [67, 68]. NLC as aqueous dispersion may lead to the issue of instability due to hydrolysis and oxidation of lipid phase in presence of water and oxygen therein, therefore require freeze-drying (lyophilization). Particularly, in lyophilization of nano-sized particles, cryoprotectants are used for the ease of re-dispersion. Significant work has been done so far in this particular area addressing the optimization of variables such as type and concentration of cryoprotectants and lyophilization temperature on the overall quality of NLC [69, 70]. PEG4000, Avicel, dextrose, sucrose, sorbitol and aerosil are commonly used cryoprotectants in R&D and are often used by researchers while carrying out lyophilization of NLC [67, 68, 71, 72]. The concentration of cryoprotectants should be within the limit of 1-5% for the additives because increase in concentration of cryoprotectants result in increase in particle size of NLC [73]. 3. OVERVIEW OF NANOSTRUCTURED LIPID CARRIERS Formulation of SLN has pharmaceutical challenge of poor drug loading because of perfect crystal lattice formed

by the solid lipids. Addition of liquid lipids deform the crystal lattice and prevent its growth that ultimately overcomes the issue of poor drug loading as encountered in SLNs. Fig. (1) illustrates the structure of SLN and NLC. NLC are the spherical structures where the oil droplet is trapped in a solid lipid matrix [74, 75]. Fig. (1), indicates that the lipid matrix of NLC have imperfections resulting in amorphous regions where the drug can be easily encapsulated. It is also observed that carriers prepared with single solid lipid do not allow incorporation of drug molecule, thus a blend of solid lipid forms less ordered matrix. Further, incorporation of liquid lipid into the solid lipid matrix results in modification of crystallization characteristics of lipid and ultimately the particle size distribution of particulate system [76]. NLC are of imperfect crystal, amorphous or multiple types as depicted in (Fig. 2). Based on the structural difference, distinct techniques have been attempted for an optimized nanostructure of NLC (Table 4). 4. METHOD OF PREPARATION OF NANOSTRUCTURED LIPID CARRIERS There are various techniques for formulation of NLC. The techniques include: high pressure homogenization [79-81], high shear homogenization/ultrasonication [82], microemulsion

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Fig. (1). Structure of solid lipid nanoparticle (SLN) and nanostructured lipid carrier (NLC).

Fig. (2). Types of NLC (a) imperfect crystal, (b) amorphous, and (c) multiple type. Table 4. Different types of NLC. Type of NLC

Name of NLC

Characteristic features

Technique

Figure

Ref.

I

Imperfect crystal

It contains imperfect matrix with numerous voids and vacancies to accommodate the drug in molecular state.

Mixing solid lipids with sufficient amount of spatially different lipids, e.g. glycerides composed of different fatty acids in order to achieve large distances between fatty acid chains.

2(a)

[77]

II

Amorphous

It minimizes the expulsion of drug during storage by preventing the recrystallization process.

Addition of liquid lipids e.g. isopropylmyristate or medium chain triglycerides (e.g; Miglyol) able to inhibit the crystalization in solid phase.

2(b)

[78]

III

Multiple

It avoids expulsion of drug by preventing crystallinity of lipid martix.

Very small oil nano- compartments produced inside the solid lipid matrix of NLC by mixing higher amount of liquid lipids with solid lipids.

2(c)

[15]

[83-85], solvent emulsification-evaporation technique [86, 87], solvent emulsification-diffusion technique [88, 89] solvent injection [90], water-in-oil-in-water double emulsion [91, 92], phase inversion [93], and technique based on membrane contractor [94].

5. FACTORS INFLUENCING FORMULATION OF NLC

Procedure of all the techniques with their advantages and disadvantages are summarized in Table 5.

5.1. Effect of Lipids

The major factors influencing formulation of NLC are as follows.

Lipids (solid and liquid lipids) enhance the solubility of hydrophobic drugs resulting in improvement of their oral

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Table 5.

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Techniques to prepare NLC.

Technique

Procedure

Advantages

Disadvantages

Ref.

High Pressure Homogenization (HPH)

Drug is mixed with lipids and the mixture is melted at temperature 5-10 °C above the melting point of solid lipid. It is then added to an aqueous surfactant solution at the same temperature. Then a hot pre-emulsion is prepared by using high shear device, which is then processed in a temperature controlled HPH. The nanoemulsion obtained recrystallizes on cooling forming NLC.

Good reproducibility, organic solvent-free method, Short production time.

High temperature process and high energy is required, complex equipment required, possible degradation of the drug caused by hot HPH

[79-81]

(i) Hot HPH (ii) Cold HPH

In Cold HPH, lipid and drug are melted together and rapidly ground under liquid nitrogen forming microparticles. A pre-emulsion is formed by homogenization of the particles in a cold aqueous surfactant solution which is then subjected to HPH.

Possibility of large scale production and easy to scale up, Thermolabile drug can be formulated by cold HPH.

High shear homogenization technique/ Ultrasonication

Lipid and drug are melted and combined with an aqueous surfactant at the same temperature and coarse emulsion is prepared using high shear mixture. Then coarse emulsion is converted to nanosized emulsion using ultrasonication. Finally, NLC are obtained by cooling down the hot nanoemulsion.

Feasible method, complex equipment is not required, high concentration of surfactants and co-surfactants are not required, method is free from organic solvents

Production of low dispersion quality products and possibility of metal contamination, high energy input is required.

[82]

Microemulsion

Drug and lipids are melted to the 5-10 °C above the melting point of solid lipid and added to an aqueous surfactant solution at the same temperature. A hot microemulsion is formed which is poured into cold water forming nanoemulsion, which then recrystallizes to form NLC.

Rapid, reproducible and cost-effective method, requires low energy input, industrial scale production is possible and easy to scale up, organic solventfree method.

Relatively high concentration of surfactant is required which is not desired. relatively high water content is required which is difficult to remove.

[83-85]

Solvent emulsificationevaporation

Drug and lipids are dissolved in water-immiscible organic solvent, and then emulsified in an aqueous phase containing surfactants under continuous stirring. The organic solvent evaporates during emulsification, resulting in development of NLC.

Suitable for thermolabile drugs, reduces mean particle size and results in narrow size distribution.

Very dilute NLC dispersions are produced.

[86, 87]

Solvent emulsificationdiffusion

Drug and lipids are dissolved in partially watermiscible organic solvent and organic solvents are saturated with water to generate initial thermodynamic equilibrium. The transient o/w emulsion is transferred into water with continuous stirring, which leads to solidification of lipid phase forming NLC due to diffusion of the organic solvent.

Water miscible solvents are used to dissolve lipids.

Ultrafiltration or lyophilisation of the final formulation is required, residue of organic solvents may remain in the final formulation.

[88, 89]

Solvent injection

Basic principle of this technique is similar to the solvent diffusion technique. Drug and lipids are dissolved in a water-miscible solvent or water miscible solvent mixture and quickly injected into an aqueous phase containing surfactants through an injection needle.

Easy to handle, rapid and reproducible process, technically sophisticated equipment is not required.

Use of organic solvents is the only major concern

[90]

Water-in-oil-in-water double emulsion

The drug is solubilized in the internal phase of double emulsion. An aqueous drug solution containing surfactant is emulsified in melted lipid by a high speed stirrer at an elevated temperature. The warm w/o nanoemulsion is then dispersed in the aqueous phase containing surfactant as the external phase of w/o/w emulsion at 2-3°C under mechanical stirring to obtain NLC. The NLC are then purified by ultrafiltration.

Allows incorporation of hydrophilic drugs, organic solvent is not required.

Relatively dilute NLC dispersion is produced, large particle size of final formulation.

[91, 92]

Organic solvent is required which might be present in the final formulation, ultrafiltration or evaporation is required.

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(Table 5) Contd….

Technique

Procedure

Advantages

Disadvantages

Ref.

Phase inversion

Drug and excipients are mixed together on magnetic stirrer, 3 heating and cooling cycles are carried out and then diluted with cold water causing phase inversion of the emulsion and breaking which results in the development of NLC.

Thermolabile drugs can be incorporated, organic solvent free and non-energy consuming method, easy to scale-up.

Cumbersome technique

[93]

Membrane contactor

Lipid phase is passed through a porous membrane at temperature 5-10 °C higher than melting point of solid lipid to the aqueous surfactant solution at same temperature. The lipid droplets are formed across the porous membrane dispersed in the aqueous phase. Further cooling of the entire system leads to development of NLC.

Simple low cost apparatus used, smaller particle size with narrow size distribution of the final formulation.

_

[94]

bioavailability. The selection of lipids is based on the solubility of drug in the lipid phase. Lipids having maximum drug solubility are chosen for lipid phase of NLC. In general, lipids constitute 5-10% of total composition of NLC [95]. Enhancing the total lipid content of the formulation leads to increase drug loading however it also results in increased particle size and reduced stability [95]. The viscosity of lipid solution is also an important consideration as it is reported that low viscous lipids can be dispersed more easily and thus improve the particle size distribution [15]. 5.2. Effect of Surfactants Surfactants are used to retain the stability of dispersed system such as emulsion and/or nanoparticulate dispersions by minimizing the aggression of dispersed particles [96]. Like other lipid based nanoparticles, the type and concentration of the surfactants strongly affects the particle size of NLC. Usually 1-5% surfactant is used for the preparation of NLC. However, higher concentration of surfactant relative to the lipid leads to smaller nanoparticles [95]. In general, smaller particle sizes are obtained when formulation design has higher surfactant/lipid ratio [95]. The decrease in surfactant concentration results in increase in particle size during storage [97]. Generally non-ionic surfactants (Tween 80, poloxamer 188) are used to prepare NLC. Non-ionic surfactants result in small particle size of NLC and provide steric stability to NLC formulations. Such an observation has been reported by Han et al. where ionic and non-ionic surfactants when used compositely resulted in a stable disperse system, with narrow particle size distribution and smallest mean particle size [98]. 5.3. Effect of Hydrophile-lipophile Balance (HLB) Values of Surfactants Generally, the HLB value of surfactants to stabilize the NLC system should be more than 10. It greatly affects the stability, particle size distribution, polydispersity index, and entrapment efficiency of the NLC system. HLB values of lipid phase used for the preparation of NLC plays a major role for the selection of surfactants. The HLB value of surfactants should be equal to or greater than the required HLB

value of lipid phase [21, 99]. As the concentration of hydrophilic surfactant increases, the overall HLB value of the NLC system increases and this reduces the surface free energy of the dispersed particles, which results in decrease in particle size distribution of NLC system. Reduction in particle size distribution, further increase the overall surface area of the colloidal system and ultimately improves the entrapment efficiency [21]. Kovacevic et al. investigated the effect of two polyhydroxy surfactants for the design of NLC and investigated their effect on particle size, physical stability and matrix structure of NLC [99]. They used cetyl palmitate (Cutina® CP, HLB=10) as solid lipid and Miglyol® 812 (HLB=5) as liquid lipid and two polyhydroxy surfactans like Plurol Stearique® WL 1009 (PS, HLB=9-10) and Plantacare® 810 (PL, HLB=15-16). Both the surfactants at 1% (w/w) of concentration produced particle size distribution of NLC system 50%) resulted in destabilization of NLC system as colloidal dispersion with both the type of surfactants. 5.4. Effect of Process Parameters 5.4.1. Effect of Temperature It is recommended that the temperature of the solid lipid must be 5-10 °C above its melting point then only it has solvent capacity for the drug. Usually high release is observed with increase in temperature [77]. In a study, it was found that the lower temperature of dispersion medium led to the lower diffusion rate of organic dispersion phase and consequently formed the relatively large particles with wide size distribution [100]. On the other hand, if the temperature is too high the lipids will degrade [96]. High temperature may also reduce the emulsifying capacity of surfactants as these have cloud point lower than 85 °C [100].

Nanostructured Lipid Carriers in Cancer Chemotherapeutics Delivery

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5.4.2. Effect of Stirring Time

6.3. Zeta Potential

Stirring at a constant speed is required to improve the drug emulsification as it affects the particle size of the composition. Usually, stirring for 3-5 minutes at higher rotation results in formation of a coarse emulsion [96].

The zeta potential (ZP) indicates the overall charge a particle attains in a particular medium. Stability of the NLC during storage can be predicted from the ZP value. The ZP indicates the degree of repulsion between close and similarly charged particles in the dispersion. High ZP indicates highly charged particles. Generally, high ZP (negative or positive) inhibits aggregation of the particles due to electric repulsion and stabilizes the NLC dispersion. Conversely, in case of low ZP, attraction exceeds repulsion and the dispersion coagulates or flocculates [82]. However, this assumption is not appropriate for all colloidal dispersions, particularly the dispersion which contains steric stabilizers. The ZP value of ‒30 mV is sufficient for good stabilization of NLC dispersion [114]. The ZP of the nanodispersions can be determined by PCS [103-105].

5.4.3. Effect of Formulation Techniques Formulation techniques greatly affect the particle size and polydispersity index (PDI) [96]. Until now, high pressure homogenization (HPH) has been found to be the most successful technique to reduce the particle size compared other methods discussed [101]. As advocated by Emami et al. solvent diffusion method is considered another effective procedure for the preparation of NLC [70]. 6. CHARACTERIZATION OF NANOSTRUCTURED LIPID CARRIERS Characterization of the NLC is very important due to complexity of the system and colloidal size of NLC. Moreover, appropriate characterization of the formulations is necessary to control the quality, stability, and release kinetics of NLC. Thus, accurate and sensitive characterization methods should be used. Following parameters can be evaluated that have direct impact on stability and release kinetics of NLC [82]. 6.1. Particle Size Particle size plays an important role in the uptake of NLC from GIT upon oral ingestion and their clearance by the reticuloendothelial system. Definite determination of the particle size is extremely important for their in vivo performance. Particle size less than 300 nm is suitable for the intestinal transport [102]. Photon correlation spectroscopy (PCS) [103105] and laser diffraction [106, 107] are the most commonly used techniques for the determination of particle size of NLC. The variation of the intensity of the scattered light, caused by movement of nanoparticles, is measured by these techniques. PCS is relatively accurate and sensitive method. However, this technique can measure the nanoparticles of size ranges from few nanometers to about 3 μm [108, 109]. This size range is adequate to characterize NLC. On the other hand, laser diffraction can measure bigger particle sizes (>3 μm) [108, 109]. It is based on the correlation of the diffraction angle with the particle radius. Smaller particles lead to more intense scattering at high angles than the larger particles. However, it is always recommended to use both PCS and laser diffraction methods simultaneously. This is because particles are non-spherical in many cases [110]. 6.2. Polydispersity Index (PDI) Since NLC are generally polydisperse in nature, measurement of polydispersity index (PDI) is essential to know the size distribution of the NLC [82]. The lower the PDI value, the more monodispered the nanoparticle dispersion is. Most of the researchers accept PDI value less than 0.3 as optimum value [111-112]. PDI can be measured by PCS [103, 113].

6.4. Shape and Morphology Microscopic techniques such as scanning electron microscopy (SEM), transmission electron microscopy (TEM), and atomic force microscopy (AFM) are generally used to determine the shape and morphology of NLC. These techniques can also be used to determine the particle size and size distribution [82]. SEM utilizes electron transmission from the sample surface, whereas TEM utilizes electron transmission through the sample. Although normal SEM is not very sensitive to the nanometer size range, field emission SEM (FESEM) can detect nanometer size range [115]. Sample preparation greatly influences the results of SEM analysis. Cryogenic FESEM can also be helpful where liquid dispersion is frozen by liquid nitrogen and micrographs are taken at the frozen condition. AFM provides a threedimensional surface profile unlike electron microscopy which provides only two-dimensional images of a sample. AFM directly gives structural, mechanical, functional, and topographical details about surfaces with nanometer to angstrom scale resolution [87]. 6.5. Crystallinity and Polymorphism Determination of the crystallinity of the components of NLC formulations is important as the lipid matrix and the drug may undergo a polymorphic transition leading to a possible undesirable drug expulsion during storage [116]. Crystallinity of lipid is also strongly interrelated with the incorporation of drug and release rates. The lipid molecules show three different polymorphic structures; the unstable α, the metastable β’, and the most stable β. Thermodynamic stability and lipid packing density increase, while drug incorporation rates decrease from a supercooled lipid mix due to polymorphic transitions from α through β′ to β form. This lipid crystallization and modification changes are retarded due to the small size of the particles and the presence of emulsifiers. Differential scanning calorimetry (DSC) [104, 105] and XRay diffractometry (XRD) [107] are most commonly used techniques to determine the polymorphic behavior and crystallinity of the components of the NLC. DSC gives information on the melting and crystallization behavior of all solid and liquid constituents of NLC, whereas XRD can recognize specific crystalline compounds based on their crystal structure [117]. DSC utilizes the fact that different lipid modifications

14 Current Drug Delivery, 2016, Vol. 13, No. 1

possess different melting points and melting enthalpies. In XRD, the monochromatic beam of X-ray is diffracted at angles determined by the spacing of the planes in the crystals and the type and arrangement of the atoms, which is recorded by a detector as a pattern. The intensity and position of the diffractions are unique to each type of crystalline material. XRD pattern can predict the manner of arrangement of lipid molecules, phase behavior, and characterize the structure of lipid and drug molecules [118, 119]. Infrared and Raman spectroscopy are also useful to investigate structural properties of lipids [114]. However, they have not been extensively used to characterize NLC. 7. DRUG RELEASE FROM NANOSTRUCTURED LIPID CARRIERS Since the NLC consist of solid lipid matrix, they provide controlled release for the drug [120]. The prolonged release can be modulated by controlling the amount of liquid lipid in the formulation [121]. In most of the cases, a biphasic drug release is observed with an initial burst release followed by release at a constant rate probably from the solid lipid core. The drug dissolved in liquid lipid present at the periphery shows initial burst release [122]. Due to high drug stacking in the unorganized lipid matrix, impulses such as temperature, agitation and heat can also trigger burst release [80]. Some of the examples of drugs showing different release kinetics are Dexamethasone (Weibull model kinetic) [44], Acyclovir (biphasic drug release) [21], Bicalutamide (Peppas-Korsmeyers model) [33], Tamoxifen (Zero order kinetics) [35] and Genistein (controlled release) [40]. 8. OBSTACLES IN DRUG DELIVERY TO TUMORS After systemic administration, cytotoxic drugs are distributed to different tissues via blood circulation and undergo elimination during the process. Drug delivery to tumor tissue is influenced by tumor physiology and physicochemical properties of drug and the carrier. 8.1. Tumor Physiology Affecting Drug Delivery Through NLC Malignant tumor is often characterized by uncontrolled cellular proliferation. Tumor blood vessels are highly irregular with incomplete endothelium (leaky endothelium) [123, 124]. Progressive tumor tissues have low oxygen due to uncontrolled cell division and lack of blood supply thus shows abnormal maturation and the poor vascularization [125]. Instead of normal structure of peripheral blood vessels, irregular development and branching of angiogenic vessels with disarranged coverage of pericytes are seen in tumour tissue [126]. Tumor endothelium also has modified intercellular junctions, fenestrations and transendothelial gaps, this leads to elevated permeability, increased proteolytic activities and hemorrhage [127, 128]. Intratumoral delivery is challenging due to anaerobic glycolysis making pH of extracellular fluid acidic due to release of components of lysosomes. This acidic environment of tumor leads to deformation of extracellular matrix (ECM). All such changes hamper the immunosurveillance functions of the cells. Further, fibroblast and macrophages present in the tumor microenvironment help in progression of tumor [129, 130].

Rizwanullah et al.

Little difference in arterial venous pressure in tumor physiology offers limited reabsorption of macromolecules. This along with leaky vasculature and lack of lymphatic vessels, contribute to movement of the macromolecules into tumor interstitium, thereby generating high interstitial fluid pressure (IFP). Due to high interstitial fluid pressure (IFP), blood vessels in intratumor region are collapsed [131-133]. Many studies have also reported that the penetrationresistance mainly occurs because the uptake by top cell layer inhibits diffusion of drug to the layers beneath [134]. Therefore, an ideal NLC has to overcome the obstacles in drug transport and the physiological constrains so to reach the tumor interstitium. 8.2. Induced Physiological Obstacles to Drug Delivery A high incidence of drug resistance is an important reason for unsuccessful chemotherapy. Multidrug resistant cells exhibit resistance to a variety of other drugs used in chemotherapy [135]. Microenvironment in cancer cells lead to inherent multidrug resistance (MDR) through over expressed growth factor receptors and enhanced P-glycoprotein (P-gp) expression [136-138]. However, the acquired multidrug resistance (MDR) is seen due to dose and schedule adjustments done in traditional chemotherapy [139-141]. Multidrug resistance (MDR) is often characterized by up regulation of Adenosine triphosphate binding cassette (ABC) transporters especially the p-glycoprotein (P-gp) efflux pumps located at the cell membrane [142]. P-gp effluxing is an energy dependent process. Consequently, tumor cells become cross-resistant and survive the cytotoxic offense although a cytotoxic drug has marked in vitro efficacy [143]. High expression of P-g inherently present in tumors originating from a variety of organs including the liver, the colon, the brain, the kidney and the pancreas. Enzymes over expressed at the tumor site such as cytochrome P450A, glutathione-s-transferases and aldehyde dehydrogenases- related phase II enzymes often inactivate the cytotoxic drugs leading to MDR [144]. Gene silencing is a recent approach to overcome MDR. Here, a double stranded small non coding RNA (formally called as small inhibitory RNA) which does not encode a protein, when introduced in disease-causing gene in various cell types results in gene silencing. The enzyme Dicer cleaves the double strand to small fragments and then one of the strands forms complex called as RNA induced silencing complex (RISC). The anti-sense strand then directs RISC on target mRNA [145-147]. Effective treatment strategy to combat MDR involves delivery of drug with siRNA, the latter inhibits the genes responsible for high expression of transporters responsible for drug effluxing. Till now, many polymer and lipid based siRNA based drug delivery systems have shown plausible outcomes in suppression of tumor [148]. 8.3. Unique Limitations of Cytotoxic Drugs Cytotoxic drugs often display unique problems such as lack of stability, poor specificity, highly toxic effects on healthy tissue, possibility of inducing MDR, variable pharmacokinetic

Nanostructured Lipid Carriers in Cancer Chemotherapeutics Delivery

and narrow therapeutic window. Metabolomic profiling is also required to select the drug targets [149]. Cells of hair, bone marrow and gastrointestinal tract (GIT) divide as rapidly as tumor cells and thus are exposed to cytotoxic drugs targeted to tumor. Such an exposure of normal cells is manifested by symptoms such as tiredness, nausea and vomiting, anemia and hair loss. Moreover, some agents exhibit severe selective toxicity. For example, cardiotoxicity and myelosuppression are the well-known doselimiting toxicities for anthracyclines and taxanes respectively [150, 151]. These toxicities prevent further increase in the dose or strength of the anticancer agent. Thus, there is an urgent need to develop suitable drug carriers to improve the therapeutic efficiency of cytotoxic drugs. In this regard, NLC is considered an effective carrier as these can partly resolve the problem of poor tissue specificity [152]. Like other drug delivery systems, NLC also offer stability, protection against degradation, controlled release and reproducible methodology. Like liposomes, they do not involve high cost of production. Toxicity and acidity associated with biodegradable polymers are also not observed with NLC [153]. The polymers used as drug carrier are not universal for all cytotoxic drugs [154]. But, NLC are observed to be the versatile carriers for cytotoxic drugs [8]. In addition, these NLC can effectively encapsulate lipophilic drugs such as paclitaxel, prednicarbate, cyclosporine and retinol [10]. However for hydrophilic drugs lipid drug conjugates or solid lipid nanoparticles are feasible as in case of doxorubicin [155]. Recently NLC of decitabine, a hydrophilic drug, has been prepared by Neupane et al. [19]. 9. APPROACHES TO ENHANCE ANTICANCER ACTIVITY OF CHEMOTHERAPEUTIC DRUGS THROUGH NLC So far a number of anticancer moieties have been successfully developed as NLC. Preclinical testing done on cell lines or using animal models have shown promising effects involving the improvement in the anticancer activity of cyto-

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toxic drugs with fewer side effects. Different targeting strategies of NLC are shown in (Fig. 3). 9.1. Tumor-specific Targeting Through NLC As mentioned earlier most cytotoxic drugs exhibit narrow therapeutic window since they do not have tumor selectivity properties. Many a times, the selected dose is close to maximum tolerated dose thus providing a challenge to an effective drug delivery [156]. Recently, NLC have been shown to exhibit great potential to target tumor cells. Tumor cell targeting is possible through passive or active drug targeting [156]. 8.1.1. Passive Tumor Targeting Through NLC Abnormalities in tumor vessels lead to enhanced vascular permeability since the administered nanocarriers extravasate and get concentrated in the interstitial space. This retention by passive phenomenon is termed as ‘Enhanced Permeability and Retention’ (EPR) effect [157, 158]. The enhanced permeability and retention (EPR) effect in solid tumors was introduced by Matsumura and Maeda in 1986 [159-161]. Their findings suggested that the neovasculature in most solid tumors (hypervasculature) usually have an abnormal architecture compared to normal tissues and organs, containing defective endothelial cells with large fenestrations, rough vascular alignment, absence of a smooth-muscle layer, wide lumen and damaged functional receptors for angiotensin II (AT-II) [159]. Also, the pore size of tumor vessels generally ranges from 100 to 780 nm. All these anatomical defectiveness, along with functional abnormalities, lead to extensive leakage of blood plasma components into the tumor tissue, such as macromolecules, lipid particles, nanoparticles [162]. Further, the dysfunctional lymphatic drainage clearance, and the slow venous return in tumor tissue indicate that macromolecules are retained in tumor sites, whereas extravasations into tumor interstitium continues [161]. Passive targeting can be accomplished by altering the shape, size and surface characteristics of the NLC. However,

Fig. (3). Targeting strategy of NLC. (1) The passively targeted NLC that exhibit a short t1/2 (2) The ligand conjugated NLC that exhibit site specific tumor targeting by receptor mediated endocytosis (3) The PEGylated NLC which elope RES.

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there remain significant barriers to transport that often result in insufficient drug concentrations at the tumor site and, consequently, little therapeutic efficacy [163]. Furthermore, passive targeting suffers from some of the same limitations of traditional chemotherapy such as an inability to actively distinguish healthy tissue from tumor tissue [164]. Wang et al. engineered nanostructured lipid carriers for co-encapsulating paclitaxel (PTX) and doxorubicin (DOX) for combinational lung cancer therapy [165]. The mean particle size of PTXDOX NLC achieved was 129.3 ± 4.2 nm. The formulation showed excellent cytotoxicity both in vitro on NCL-H460 cell line and in BALB/c nude mice bearing human non-small cell lung carcinoma xenograft tumor model. Berberine loaded nanostructured lipid carriers with particle size 189.3nm showed higher efficacy against H22 cell carcinoma bearing Kumming mice [166]. Intravenous administration of β-elemene-loaded nanostructured lipid carriers exhibited anti-tumor efficacy in Kunming mice bearing H22 cells due to small particle size of 138.9 nm [38]. The round shape and particle size of 214 nm showed higher targeting effect of curcumin NLC to the brain cancer cells and enhanced (90%) brain tumor inhibitory efficiency compared to free drug solution [167]. After intravenous administration, NLC are quickly bound with opsonins in blood and after that are cleared by the reticuloendothelial system (RES) within few minutes. Therefore, NLC are always concentrated in tissues with a rich RES, such as liver, spleen and lymph nodes. This passive targeting/EPR effect is favorable if the tumor is present in the RES. Moreover, the toxicity could be reduced because fewer drugs are distributed to other organs [149]. In this context, Tsai et al. developed baicalein loaded tocol NLC for enhanced stability and brain targeting [168]. After 360 minute of i.v injection of the tocol NLC, the resulting AUC in the cortex was 7.5 fold higher than control group. The brain stem also exhibited 4.7-fold improvement of compound accumulation. Tocol NLC also exhibited 2 to 3-fold enhancement in baicalein concentration in hippocampus, thalamus and striatum. 9.1.2. Active Tumor Targeting Through NLC The incorporation of active targeting ligands is designed to improve and enhance nanoparticle accumulation at the tumor site. The ligands commonly used include folate, hyaluronic acid, ferritin (Fr), monoclonal antibody (transzumab), aptamers and peptides [149]. Actively targeted drugs to the tumor sites provide several distinct advantages over non-targeted drugs. The main advantage includes high drug retention in the tumor tissue. Dose related side effects are also expected to be less [154]. Most actively targeted NLC can be designed to exhibit passive endocytosis or endocytosis involving specific interactions with the receptors [169]. A study carried out by Khajavinia et al. showed that transferrin conjugated stearylamine NLC of etoposide to target K562 acute myelogenous leukaemia cells exhibited 15-fold reduction in IC50 than the free etoposide [42]. In a similar manner, octadecylamine-retinoic acid conjugated NLC of 5Flurouracil was observed to show higher efficacy in colorectal carcinoma [170]. Drugs such as an EGFR receptor inhibitor tyrphostin AG-1478 also showed cytotoxicity for human hepatocellular carcinoma cells through NLC [171]. Though

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ligand linked and receptor mediated targeting through NLC can efficiently target tumors but it should be noted that the targeted nanostructured lipid carriers (NLC) can be removed by the RES within minutes before they are able to bind to tumor cells. 9.2. Fabrication of Long Circulating NLC Generally, the nanostructured lipid carriers are rapidly cleared by blood and RES [172], thus it is necessary to extend the circulating time of NLC, and this has been successful to some extent. The NLC with surface modified by particular hydrophilic polymers are not easily recognized by the RES [173]. PEGylation is a widely used surface modification technique to reduce immunogenicity and imparting long circulating property. High molecular weight PEG (PEG 20,000 to 50,000) offers enhanced recirculation of smaller NLC while low molecular weight PEG (PEG 3400 to 10,000) increases the hydrodynamic radius of large nanocarriers [174, 175]. Some hydrophilic materials, like polyethylene glycol (PEG), poloxamers or poloxamines and various amphipathic polymers, the lipophilic part of which can locked into the inner core of the NLC and the hydrophilic part of which can cover the surface, are widely used for this purpose [149]. PEGylated 10-hydroxycamptothecin NLC has produced long circulating effect in Kumming mice. There was 40 fold improvement in maximum concentration of drug in lungs than the free drug solution [54]. Pharmacokinetic analysis of Oridonin loaded polyethylene glycol coated NLC in SpragueDawley rats also exhibited improvement in the mean residence time (MRT) but with zero order kinetics [176]. Parenterally administered PEGylated Amoitone B loaded NLC have also shown longer mean residence time as well as improved bioavailability than the non PEGylated NLC and the free drug solution [177]. Similarly, Biochanin A (BCA) loaded PEGylated NLC (BCA-PEG-NLC) exhibited approximately 15.8 and 2.9 times higher Cmax values and AUC (area under curve) compared to free biochanin A solution, meanwhile, the mean residence time (MRT) was significantly longer [178]. Furthermore, BCA-PEG-NLC showed significantly higher cytotoxicity against MCF-7 cell line compared with BCA suspension. Ligand conjugated stealth NLC are also now studied for their better efficiency. They have been prepared with amphiphilic polymer, such as poly (PEG-cyanoacrylate-cocholesteryl cyanoacrylate) with ligand such as folate. They are known to produce long blood circulating effect and better targeting of anticancer drug. Drugs like docetaxel have been incorporated in the lipid carrier. Such a conjugated system prevents opsonization of NLC due to hydrophilic PEG chain imparting surface charge leading to steric stabilization [179]. 9.3. Approaches to Combat Multidrug Resistance (MDR) Through NLC Despite tremendous advancement in cancer treatment, risk of resistance to chemotherapy (multidrug resistanceMDR) is a challenge. The enhanced efflux rate of drug caused by overexpressed ABC transporters, normally P-gp and multidrug resistance-associated protein 1 (MRP1), reduce

Nanostructured Lipid Carriers in Cancer Chemotherapeutics Delivery

cellular uptake, increase RNA repair, drug detoxification by enzymes, resistance to Topoisomerase II are some of the reasons for MDR. Therefore, contemporary research into reversing MDR is primarily focused on blocking specific drug efflux. With the development of multifunctional NLC as an innovative and promising alternative over other carriers for chemotherapeutics, MDR can be avoided. Such NLC have confirmed desirable drug delivery characteristics such as solubilized hydrophobic agents, decrease drug clearance, less non-specific cellular uptake, delivery of multiple therapeutic payloads, targeted drug delivery, controllable drug release, and lesser pharmacokinetic interactions [161, 180]. Recently NLC have been developed to encapsulate or attach multifunctional agents like anticancer drugs, antibodies or ligands targeting MDR cancer cells, nucleic acid, and inhibitors of P-gp to inhibit different contributors to MDR. Paclitaxel - doxorubicin loaded NLC showed high cytotoxicities in adriamycin resistant MCF-7 cell line and paclitaxel resistant human ovarian cancer cell line. The reversal power of paclitaxel NLC for these two kinds of cells was 34.3 and 31.3-fold, respectively, while that of doxorubicin NLC was 6.4 and 2.2-fold, respectively [181]. Mitoxantrone Hydrochloride (MTO) encapsulated dextran conjugated NLC revealed high accumulation in breast cancer resistance protein (BCRP) overexpressed MCF-7 cell line than simple drug solution [55]. The uptake of drug was remarkable indicating the inhibition of breast cancer resistance protein (BCRP)mediated drug efflux. The in vivo radio γ-scintigraphy studies in Ehrlich’s Ascites Tumor (EAT) allograft model developed in Balb/c mice demonstrated that hyaluronic acid (CD44 ligand) coated HA-NLC encapsulated with Irinotecan (Ir) had selective accumulation in MDR tissues. The in vivo antitumor activity was also higher than control and free drug solution. Encapsulation of irinotecan in HA-NLC-Ir also remarkably reduced the thrombocytopenia and neutropenia associated with free irinotecan [25]. Co-loaded doxorubicin (DOX) and docosahexaenoic acid (DHA) NLC have also shown cytotoxicity on resistant MCF-7/Adr cell line at 16µm concentration of doxorubicin and 112 µm concentration of DHA, which is quite low [182]. Some of the potential anticancer drugs delivered through NLC by different route of administration are summarized in Table 6.

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10. NANOSTRUCTURED LIPID CARRIERS IN CANCER THERANOSTICS Theranostics is a novel term coined for medicines that are used for simultaneous diagnosis and treatment [201]. The primary goal of theranostics is to selectively target the disease confined to tissue or cell in order to increase diagnostic and therapeutic selectivity that makes the treatment shorter, safer, effective and inexpensive. Biocompatible or biodegradable nanomedicines are currently under development in cancer theranostics that would enable specific diagnosis and therapy [202]. The multifunctionality associated with nanomedicines includes imaging (single or dual modality), therapy (single or multiple drugs) and targeting (uni- or multi-ligand) (Fig. 4) [202]. Theranostic nanomedicines can be developed through various techniques. (i) therapeutic agents (e.g., anticancer drugs and photosensitizers) conjugated or loaded to imaging nanoparticles such as quantum dots, magnetic nanoparticles, and gold nanocages. (ii) tagging of imaging contrast agents, such as fluorescent dyes, optical or magnetic nanoparticles, and many other radioisotopes, to therapeutic nanoparticles. In addition, encapsulating both imaging and therapeutic agents together in biocompatible nanoplatforms such as lipid nanoparticles (solid lipid nanoparticles, nanostructured lipid carriers, liposomes), polymeric nanoparticles, ferritin nanocages, and porous silica nanoparticles [203]. In this context, Hsu et al. developed and evaluated camptothecin and quantum dot loaded nanostructured lipid carriers for integrating bioimaging and anticancer therapy [204]. In vivo real-time tumor monitoring by fluorescence imaging exhibited excellent fluorescence labeling of cancer cells. The developed theranostic NLC exhibited 6.4 fold higher camptothecin accumulations and enhanced cytotoxicity to B16-F0 melanomas cell line compared to free drug solution. Patel et al. formulated tumor homing PEGylated vascular endothelial growth factor (VEGF) peptide (CREKA peptide) conjugated theranostic NLC loaded with DIM-CpPhC6H5 (DIM-P) for treatment of lung cancer [205]. Developed CREKA peptide conjugated NLC exhibited 3 fold higher binding to clotted plasma proteins in tumor vasculature compared to unconjugated NLC. In vivo optical and ultrasound imaging studies showed ~40 folds greater movement of CREKA peptide conjugated NLC in tumor vasculature compared to peptide unconjugated NLC.

Fig. (4). Illustration defining the different characteristics of theranostic NLC such as imaging property, drug carrying and targeting capacity with long circulating behavior.

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Table 6.

Rizwanullah et al.

Application of NLC in treatment of cancer through different route of administration.

AdministraDrug loaded tion route

Tripterine (T)

Tripterine (T)

Excipients

Precirol ATO-5, Labrafil M 1944CS, Poloxamer 188

Precirol ATO-5, Labrafil M 1944CS, Poloxamer 188

Targeting/ Targeting Ligand

Passive

Tamoxifen (Tmx)

Non specific cancer

Animal/ Cell lines

Outcomes

Ref.

Male SpragueDawley rat/ Caco-2 cell line

T-NLC exhibited 4.7-fold enhancement in cell viability rate compared to tripterine solution. T-NLC also exhibited higher effective permeability across different sections of large intestine

[183]

Male SpragueDawley rats/Caro-2 cell line

Compared to T-NLC, CT-NLC exhibited 1.3 fold reduction of IC50 value. CT-NLC exhibited 4.8 and 1.5-fold improvement in AUC compared to the tripterine [184] suspension and T-NLC respectively. CT-NLC significantly suppressed proliferation of RM-1 and PC-3 cells in vitro in a dosedependent manner.

Passive

Prostate cancer

Passive

Tmx-NLC exhibited strong in Female Sprague vitro anticancer activity against Dawley rats/ MCF-7 MCF-7 cells compared to Tmx Breast cancer and ZR-75-1 cell suspension. Higher Cmax and lines longer T1/2 was also observed.

Glyceryl monostearate (GMS),

Oral

Type of Cancer

Labrafil WL 2609 BS, Poloxamer 188 Glyceryl monostearate (GMS), Passive Tamoxifen (Tmx) Labrafil WL 2609 BS, Poloxamer 188

[185]

Female BALB/c mice/ 4T1 cell lines

Tmx-NLC exhibited increased life span and less severe systemic [39] toxic effect in animals.

Lung cancer

Male albino rat/ A549 Cell line

DCB-NLC exhibited 4-fold increment in the permeation of drug. Greater affinity towards [19] tumor cells, along with cytotoxic activity for cancer cells was also seen.

Isosfamide

Glycerol monooleate, Oleic acid, PoloxPassive amer 188

Dalton’s ascitic lymphoma

Male Wistar albino rats

Drug loaded NLC showed improved bioavailability and significant reduction in the tumor volume and number of viable cells.

Docetaxel (DTX)

Glyceryl monostearate, Soya lecithin, Oleic acid, Poloxamer 188

Compared with Duopafei®, Female Kunming DTX-NLC exhibited 1.6, 2, 4 Metastatic mice/HepG2, and 4.9-fold reduction in IC50 breast cancer SKOV3, A549, B16 values against B16, HepG2, A549 and SKOV3 cells.

Precirol ATO 5, T ranscutol HP, Decitabine (DCB) Poloxamer 188, Tween 80

Docetaxel (DTX) Parenteral

Paclitaxel (PTX)

Glyceryl monostearate, Soya lecithin, Oleic acid, Poloxamer 188

Glyceryl monostearate, Soyabean oil, Soya lecithin

Passive

Passive

Passive and Active/ VEGFR-2 Antibody

Active/ CD44

Breast cancer

[186]

[187]

Compared with Duopafei®, tNLC exhibited 3.5, 12.3 and 3.4-fold reduction in IC50 values against HepG 2, A549 and B16 cancer Female Kunming cells respectively and 2.4, 6.1 Metastatic mice/HepG2, [188] and 2-fold reduction in IC50 breast cancer SKOV3, A549, B16 values against HepG 2, A549 and B16 cancer cells respectively than nNLC. tNLC exhibited 6.5fold reduction in tumor volume at the same therapeutic dose.

Female Kunming mice/ CT26, Colon cancer HCT116 and B16 cancer cells

HA-NLC exhibited strong antitumor effect than Taxol® and great reductions in IC50 values against HCT116, CT26 and B16 cancer cells. In addition, HANLC exhibited 2.1 and 1.6-fold improvement in AUC and MRT compared with Taxol®.

[189]

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(Table 6) Contd….

AdministraDrug loaded tion route

All-trans retinoic acid (ATRA)

Excipients

Cetyl palmitate, soybean oil, oleic acid, tween-80

Targeting/ Targeting Ligand

Type of Cancer

Animal/ Cell lines

Outcomes

Non specific cancer

HL-60 and HepG2 cell

ATRA-NLC exhibited approximately 2.06-2.78-fold higher [190] cytotoxicity on HL-60 cell and 45-137-fold on HepG2 compared with ATRA solution.

Passive

Liver cancer

ISL-NLC exhibited higher tumor inhibition rate on S180 and H22 Female Kunming cell lines than suspension. NLC [191] mice/ S180 and H22 exhibited 2.5-fold higher ISL cell lines concentrations in H22 bearing mice.

Passive

LymphoblasJurkat cell line tic leukemia

Passive

Glyceryl Isoliquiritigenin (ISL)

monostearate, Miglyol 812, Poloxamer 188

Hydrogenated palm Zerumbone (ZER) oil, Olive oil, lipoid S100, Tween 80

Glyceryl monostearate, Soybean oil, Soya leciCisplatin (CDDP) thin, Tween 80 5-Fluorouracil (5-FU),

Active/ Gastric Hyaluronic acid cancer (HA)

Ref.

ZER-NLC exhibited higher antiproliferative effect than drug [192] solution. ZER-NLC showed inhibition at G2/M phase through cyclin B1 protein inactivation.

Hyaluronic acid coated 5-fluorouracil-stearic acid prodrug and cisplatin loaded NLC BALB/c nude mice, (HA-FU/C-NLC) exhibited a Human gastric synergistic effect in combination [193] cancer cell line therapy and showed the highest BGC823 antitumor activity than all of the free drugs or uncoated NLC in vitro and in vivo. HA-decorated BCL- and DOXloaded NLC (HA-BCL/DOXNLC) exhibited maximum cytotoxicity and synergistic effect of two drugs in tumor cells in vitro. Developed NLC exhib[194] ited 12 folds reduction in IC50 value in vitro. The in vivo antitumor efficacy study exhibited highest anti-tumor activity than without HA decorated NLC in the murine breast cancer model.

Baicalein (BCL), Doxorubicin (DOX)

Stearic acid, soybean Kunming mice, Active/ phosphatidylcholine Hyaluronic acid Breast cancer MCF-7/ADR cells (SPC), Precirol ATO line (HA) 5, Cremophor ELP

Paclitaxel (PTX)

Glyceryl monostearate, Oleic acid, Tween 20

2-DG-PTX-NLC actively and Active/ StearylAthymic nude mice, efficiently accumulated at the 2-amino-2[195] Breast cancer Human breast tumor site of the tumor. Developed deoxyglucose cell line MCF-7 NLC exhibited excellent antitu(2-DG) mor efficacy in vitro and in vivo.

Compritol® 888 ATO, Miglyol 812, sodium taurocholate

Passive

Cxb-NLC exhibited strong cytotoxicity against adenocarcinomic human alveolar basal epithelial cells compared with [196] Cxb-sol. Nebulization of Cxb further increases the drug deposition in lung tissue of male Balb/c mice. It also exhibited slower systemic clearance of Cxb.

Compritol® 888 ATO, Miglyol 812, sodium taurocholate

Passive

Lung cancer

Nu/Nu mice/ A549 cells

Aerosolized Cxb-NLC + Doc i.v. exhibited higher reduction in the [30] tumor volume.

Active targeting/ LHRH peptide

Lung cancer

Nu/Nu mice/ A549 cells

NLC exhibited higher antitumor effect than free or ntravenously administered drug.

Celecoxib (Cxb)

Male Balb/c mice/ Lung cancer A549 cells

Inhalational Celecoxib (Cxb), Docetaxel (Doc)

Precirol ATO 5, Doxorubicin Squalene, Soybean (DOX), Paclitaxel phosphatidylcholine (PTX), siRNA (SPC), Tween-80

[197]

20 Current Drug Delivery, 2016, Vol. 13, No. 1

Rizwanullah et al.

(Table 6) Contd….

AdministraDrug loaded tion route

Excipients

Targeting/ Targeting Ligand

Type of Cancer

Animal/ Cell lines

Outcomes

Ref.

Paclitaxel (PTX)

Glyceryl monostearate, Oleic Passive acid, Tween 80, Tween 40, Tween 20

Lung cancer

Male Wistar rats, Caco-2 cell cell line

PTX-NLC prepared with Tween 20 as surfactant exhibited highest cellular uptake in Caco-2 cells. [198] In-vivo studies exhibited better localization of drug within the lungs.

Topical

Tripterine

Compritol 888 ATO, Precirol ATO 5, Medium-chain triglycerides (MCTs), Passive Isopropyl myristate (IPM), Poloxamer 188

Skin cancer (Melanoma)

Male C57BL/6 mice/ B16BL6 cells

Cationic NLC exhibited higher tumor inhibition rate compared with neutral or negatively charged NLC.

[199]

Intranasal

Precirol OTO 5, Capmul MCM, Curcumin (CRM) Tween 80, Soya lecithin

Brain cancer

Astrocytomaglioblastoma

CRM-NLC showed 4.3 folds higher bioavailability compared to free CRM and excellent in vitro cytotoxicity.

[200]

Passive

The results corroborated the in-vitro cytotoxicity (H460 and HUVEC cell lines) and in-vivo cytotoxicity. Theranostic preparation containing cancer targeting moiety and MMP2 cleavable peptide conjugated with manganese oxide nanoparticles formulated as NLC showed preferential accumulation in primary and metastatic tumors and increasing the MRI signal in mice with melanoma, lung and ovarian cancers. Vemurafenib a BRAF (gene) inhibitor loaded in NLC exhibited excellent anticancer efficacy in vitro in human lung (A549), ovarian (A2780), melanoma (COLO 829) cancer cells and Chinese hamster ovary cells (CHOK1) and in vivo using different models of cancer [206]. 11. GENE DELIVERY FOR CANCER THERAPY BASED ON NANOSTRUCTURED LIPID CARRIERS The advances in bioengineering in recent years have led to the discovery of many therapeutic genes. Increasing attention has been paid to the research and development of these genes for clinical therapy. Gene therapy techniques involve the development of well-organized vehicles that can deliver foreign genes such as siRNA, DNA to target cancerous cells. Recently, the potential of NLC used as a vehicle for gene delivery has also attracted great interest [207, 208]. Han et al. developed transferrin-modified doxorubicin (DOX) and enhanced green fluorescence protein plasmid (pEGFP) (DNA) co-encapsulated NLC (T-NLC) and solid lipid nanoparticles (T-SLN) for the treatment of lung cancer [208]. The in vitro cell viability study in human alveolar adenocarcinoma cell line (A549 cells) showed over 80% of cell viability compared with the control by T-NLC. The in vivo transfection efficiency study of naked pEGFP, SLN, NLC, T-SLN, and T-NLC in tumor-bearing C57BL/6 mice showed highest transfection by T-NLC. Shao et al. develop transferrin (Tf)-decorated multifunctional NLC for codelivery of paclitaxel (PTX) and DNA [209]. In vitro cytotoxicity study in human non-small cell lung carcinoma cell line (NCl-H460 cells) showed Tf-decorated PTX and DNA

cell line (U373MG)

co-encapsulated NLC (Tf-PTX-DNA-NLC) exhibited more than 4 fold reduction in the IC50 value compared to PTX solution in reducing viability of lung cancer cells, accounting for the highest antitumor activity. Tf-PTX-DNA-NLC also exhibited excellent cytotoxicity in vivo in NCl-H460 cellbearing male BALB/c mice. Furthermore, Tf-PTX-DNANLC exhibited high gene transfection efficiency in vitro and in vivo. Similarly, Chen et al. formulated multifunctional NLC for co-delivery of DNA and temozolomide (TMZ) [210]. TMZ- and DNA-loaded NLC (TMZ/DNA-NLC) exhibited more than 4 folds reduction in the IC50 value than TMZ solution in in vitro cytotoxicity study carried out in U87MG cells, suggesting highest antitumor activity for malignant glioma cells. In vivo cytotoxicity in BALB/c nude mice bearing glioma xenografts showed that TMZ/DNANLC exhibited 3.3 fold higher tumor inhibitions compared to TMZ solution. Furthermore, TMZ/DNA-NLC also exhibited higher in vivo gene transfection efficiency compared to DNA-NLC and TMZ-NLC. In addition to their high transfection efficiency, NLC have additional advantages as a promising gene delivery system, including low cytotoxicity and high gene loading efficiency [209, 211]. CONCLUSION A complete understanding of physiology and changes involved in the microenvironment of cancer cells have provided better strategies such as nanostructured lipid carriers to target the tumor tissue. These are formulated with minimum process variables therefore, provide opportunity for an easy scale up. NLC offer unique advantages including the ability to bypass drug efflux as in MDR- tumor (due to surfactants and emulsifiers used), long circulating effect and possible surface modification for target specific delivery of cancer chemotherapeutics. They also have served as potential carriers of gene for cancer therapy. Recently their role in theranostics has offered great interest in drug delivery.

Nanostructured Lipid Carriers in Cancer Chemotherapeutics Delivery

Current Drug Delivery, 2016, Vol. 13, No. 1

CONFLICT OF INTEREST The author(s) confirm that this article content has no conflict of interest.

[20]

ACKNOWLEDGEMENTS The principle author acknowledges the financial assistance provided by All India Council for Technical Education (AICTE), New Delhi. PATIENT CONSENT

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Accepted: August 12, 2015

DISCLAIMER: The above article has been published in Epub (ahead of print) on the basis of the materials provided by the author. The Editorial Department reserves the right to make minor modifications for further improvement of the manuscript.

PMID: 26279117