Design and synthesis of new s-triazine polymers and their application as nanoparticulate drug delivery systems

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Design and Synthesis of New s-Triazine Polymers and its

Application as Nanoparticulate Drug Delivery Systems

Received 00th January 20xx,

Accepted 00th January 20xx

a,

a

Sherine N. Khattab, * Samar E. Abdel Naim, Mousa El-Sayed, Aly A. El Bardan, Ahmed O.

b,c

d

a,e *

Elzoghby, Adnan A. Bekhit and Ayman El-Faham

DOI: 10.1039/x0xx00000x

Herein, we report the synthesis of a library of new s-triazine polyamides containing glycine and thioglycolic acid. The

reaction of s-triazine dicarboxylic acid derivatives with ethylenediamine, benzidine, piperazine or p-phenylenediamine,

afforded the target designed s-triazine polyamides. Thermal properties of the polymers were evaluated by different

techniques. Thermodynamic parameters of decomposition processes were evaluated. The feasibility of the synthesized

polymers as drug nano-delivery systems was investigated. The nanoparticles were loaded with celecoxib (CXB), an anti-

inflammatory drug with a highly promising anti-cancer effect, resulting in high entrapment efficiency levels (62.3–99.8%)

with a good drug loading in the range of 1.58–4.19%. After 48 h, 46.90, 64.20, 57.81, 53.95, and 49.43% of CXB was

released from polymeric NPs 26, 43, 44, 45 and 46, respectively, demonstrating a sustained drug release profile. Notably,

free CXB, and CXB-loaded polymeric NPs CXB-43, CXB-45, and CXB-46 demonstrated considerable reduction in cell viability

in a dose-dependent manner.

www.rsc.org/

formulation is preferred.

Introduction

The most important advantages of biodegradable polymers as drug

carriers include: localized delivery of the drug to the target site of

The design of suitable polymeric materials is an increasingly

important research area due to demands for applications as

biomedical, pharmaceutical, artificial surgical implants and scaffolds

action, sustained drug release, and stabilization of the unstable

1

drugs.

1

–4

Aliphatic polyesters are the most explored family of biodegradable

polymers. Although numerous variations of aliphatic polyesters

based on L-lactic acid, glycolic acid, e-caprolactone, and their

for tissue engineering.

Many efforts have been recently

dedicated to design, investigate and synthesize biocompatible,

biodegradable polymers for medicinal applications in either the

1

2,13

2

,5– copolymers have been used as biodegradable biomaterials,

they

fabrication of biodegradable devices or as drug delivery systems .

8

14,15

still lack certain optimum properties.

For example, polymer

degradation rate depends on many factors, such as molecular

structure and composition of the polymer, molecular weight of the

polymer, polymer crystallinity, percent of the cross-linking present

Natural polymers suffer from some disadvantages such as microbial

contamination, batch to batch variation dependent on

9

environmental and seasonal factors, uncontrolled rate of hydration

1

6

in the polymeric chain, and additives, etc. The hydrolytic

degradation of poly(α-hydroxyacids) is mostly influenced by four

major factors: (1) the hydrolysis rate constant of the ester bond; (2)

the diffusion coefficient of water in the polymer matrix; (3) the

diffusion coefficient of the chain fragments within the polymeric

which result in variation in the percentage of chemical constituents,

due to differences in the collection of natural materials at different

times as well as differences in region, species, and climate

1

0

conditions, and reduced viscosity on storage. The use of synthetic

polymer overcomes above disadvantages and hence their use in

1

5, 17

matrix and (4) the solubility of the degradation product.

In

addition, it has been reported that the acidic degradation by-

products of these polyesters are toxic to some cells, limiting their

a

Department of Chemistry, Faculty of Science, Alexandria University, P.O. Box 426,

Ibrahimia, Alexandria 21321, Egypt. E-mail: sh.n.khattab@gmail.com

1

8,19

use as functional tissue engineering scaffolds.

In attempt to

b

Department of Industrial Pharmacy, Faculty of Pharmacy, Alexandria University,

Alexandria 21521, Egypt.

address these limitations, poly (α-amino acids) and polyamides

c

5,20,21

Cancer Nanotechnology Research Laboratory (CNRL), Faculty of Pharmacy,

Alexandria University, Alexandria 21521, Egypt.

containing α-amino acids have been considered.

Among the

d

synthetic polyamides, only those containing the naturally occurring

α-amino acids, being structurally close to the natural polypeptides,

have potentially degradable linkages which make them suitable as

Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Alexandria

University, Alexandria 21521, Egypt.

e

Department of Chemistry, College of Science, King Saud University, P.O. Box 2455,

Riyadh11451, Saudi Arabia. E-mail: aymanel_faham@hotmail.com

6

,7,22–24

†

Footnotes relaꢀng to the title and/or authors should appear here.

biomaterials.

In the aim to create polymers containing

Electronic Supplementary Information (ESI) available: [details of any

supplementary information available should be included here]. See

DOI: 10.1039/x0xx00000x

naturally occurring α-amino acids various approaches have been

carried out successfully in the synthesis of new type of monomers.

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Besides the large number of vinylic monomers containing α-amino The synthesis of triazine polymers have been considerably

3

4,41

acids as pendants, monomers suitable for polycondensation, investigated by different research groups.

The properties of the

polyaddition or ring-opening polymerization also were obtained s-triazine polymers are influenced by the nature of substituents on

from these metabolites. Diamine type monomers derived from the s-triazine nucleus and also by the nature of diamine

2

5,26

27–29

glycine (Gly),

(D,L)- and (L)-alanine (Ala),

(D,L)- and (L)- components of polymer chain. These aromatic polyamides are

3

0

phenylalanine (Phe), and various aliphatic diols or from tyrosine- promising materials of high thermal stability and processibility.

26

41

leucine-dipeptide (Tyr–Leu) and different diamines, were utilized Sojitra et al. synthesized a new set of high-performance

in the obtainment of polyester amides (PEAs) or polyamides. polyamides based on s-triazine ring as flexibilizing linkages into the

Preliminary biodegradation studies demonstrated that these backbone of wholly aromatic polyamides which results in soluble

3

1

polymers degrade both hydrolytically and enzymatically.

polyamides with higher thermal stability along with good

processibility.

Furthermore, polyamides (PAs) derived from 10 and C

C

14

dicarboxylic acids and diamines derived from 1,6-hexanediamine or We have previously described the synthesis and thermal properties

,12-dodecanediamine and L-phenylalanine, L-valyl-L-phenylalanine of new type of polyamides-containing amino acids based on new

or L-phenylalanyl-L-valine residues have been reported as symmetric meta-oriented protected diamines derived from

1

3

2,33

biocompatible polymers.

Moreover, the presence of the amide coupling of amino acids with m-phenylenediamine or 2,6-

4

2

group provides a focal point for hydrogen bonding, which results in diaminopyridine. A family of polyamides based on benzene

the formation of crystalline structures that are characterized by dicarboxylic acid, pyridine dicarboxylic acid, and α-amino acid linked

4

3

toughness, resistance to oils and solvents, superior physical to benzidine and 4,4'-oxydianiline was also recently studied.

strength, a degree of sensitivity to moisture and high melting Here we describe another family of polyamides based on triazine

points. Because of these versatile properties and applications, many moiety containing glycine and thioglycolic acid with diamines, such

research activities have been undertaken to synthesize new as

ethylenediamine,

phenylenediamine, to study the effect of triazine moiety

have been investigated incorporated with glycine and thioglycolic acid on the nature and

benzidine,

piperazine

and

p-

3

4

polyamides and to modify them for desired properties.

3

5,36

Since early 2000’s, polyamide polymers

in cancer nanomedicines. Polymeric nanocarriers provide the thermal stability of the polymers. The incorporation of morpholine,

possibility to encapsulate water insoluble drug, protect unstable piperidine and aniline to the triazine moiety was also studied in

bioactives, and modify their pharmacokinetics and systemic attempt to increase the hydrophobicity of the target polyamides.

circulation behavior. These properties are interesting in the field of

oncology by encapsulating anti-cancer drugs within nanoparticles to

Results and Discussion

reduce their toxicity and improve their physicochemical

3

7,38

properties.

Biodegradable polymers including polyamides and

Chemistry

polyesters are commonly utilized for development of nanoparticles

as delivery systems for anti-cancer drugs. The enhanced

permeability and retention (EPR) effect has been considered the

gold standard in anti-cancer drug delivery. It describes the process

by which polymeric nanocarriers can be delivered to the tumor

interstitium where leaky tumor vessels allow macromolecular

extravasation into the tumor tissue through the capillaries

Preparation of s-triazine polyamides containing glycine and

thioglycolic acid.

Preparation of s-triazine dicarboxylic acid derivatives 9-14

:

The s-triazine dicarboxylic acid derivatives 9-14 were prepared by

two methods. In method A, the two chloride atoms of cyanuric

chloride were replaced by two glycine or two thioglycolic acid

molecules, while the third chloride was replaced with piperidine,

3

9

fenestrations. These endothelial fenestrations can reach sizes

morpholine,

or

aniline

group

respectively.

2,2'-(6-

ranging from 200 to 2000 nm, depending on the tumor type, its

3

8,39

morpholino/piperidino/phenylamino-1,3,5-triazine-2,4-

surrounding environment and its region.

However,

diyl)bis(azanediyl/sulfanediyl)diacetic acid derivatives 9-14 were

prepared through the following sequential reaction: cyanuric

chloride 1 was reacted first with two equivalent glycine or two

thioglycolic acid in the presence of sodium carbonate (acid

scavenger) to afford the corresponding products, 2-chloro-4,6-

nanoparticles may undergo rapid clearance from the circulation

following their opsonization and uptake by the reticuloendothelial

(RES) system. Since opsonization process occurs mainly via

hydrophobic interactions between the carrier surface and opsonins,

modification of nanoparticle surface with hydrophilic polymers (e.g.

PEG or poloxamer) can be utilized for development of long-

disubstituted-1,3,5-triazine derivatives

4 and 5, respectively.

40

Compounds 4 or 5 were allowed to react with piperidine,

morpholine or aniline at 70-80°C in the presence of sodium

carbonate in dioxane as solvent as shown in Scheme 1. Compounds

circulating nanocarriers. Thus, the aim of this study was

extrapolated to the design of therapeutic nanoparticles based on

the synthesized polymers for treatment of cancer. Therefore, our

trial is to prepare small sized drug-loaded polymeric nanoparticles

with hydrophilic poloxamer coat allowing their prolonged

circulation and enabling extravasation through tumor fenestrations

and subsequent accumulation in tumor tissue by the EPR effect.

9

-14 were also prepared by the replacement of one chloride atom

of cyanuric chloride with piperidine, morpholine, or aniline group at

°C, followed by subsequent replacement of the two chloride atoms

with two equivalent glycine or two thioglycolic acid molecules at

0

2

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70-80°C in the presence of sodium carbonate in dioxane as solvent, Physical Properties of the Prepared Polyamides Containing

(Scheme 1, method B). Amino Acids

Preparation of s-triazine polyamides 25-48. The s-triazine Solubility: The prepared s-triazine polyamides 25-48 showed

dicarboxylic acid chloride derivatives 15-20 used in this similar solubility behavior in different organic solvents.

investigation were prepared by the reaction of their Moderate to complete dissolution was observed in a variety of

corresponding dicarboxylic acids, with thionyl chloride and aprotic solvents such as NMP, DMSO, DMAc, boiling alcoholic

dichloromethane as solvent. Direct polycondensation reaction solvents such as methanol, ethanol while insoluble in

3 4 2 2 2 2

of an equimolar mixture of the acid chloride derivatives 15-20 halogenated solvents such as CHCl , CCl , CH Cl , ClCH CH Cl or

with the diamines (ethylenediamine 21

,

benzidine 22

,

in ethers such as Et

2

O, THF, 1,4-dioxane or 1,2-

piperazine 23 or p-phenylenediamine 24), in presence of dimethoxyethane (DME).

triethyl amine (TEA) as base, in DMF solution at 0–5°C

furnished the corresponding s-triazine polyamides 25-48

,

respectively in high yields, Scheme 2. The polymer structures

were confirmed by elemental analysis, IR spectroscopy.

Cl

Method A

N

+

2 HX

COOH

Na CO / RT

2

3

Cl

N

Cl

X

N

X

acetone / H O

HOOC

COOH

2

3

, X = NH

, X = S

2

1

4

5

, X = NH

, X = S

Method B

1

2

R R NH (6-8)

Na CO / CH Cl

2

3

2

0^o

C

1

2

o

R R NH (6-8) Na CO / 70-80 C

2

3

dioxane / H O

2

R¹

R²

N

R¹

N

R²

N

2 HX

COOH

o

N

X

+

Na CO / 70-80 C

2 3

Cl

dioxane /H O

2

X

2

, X = NH

3

, X = S

HOOC

COOH

1

2

1

2

1

5, R , R = C H O

9, X = NH, R , R = C H O

4 8

4

8

1

2

1

2

6, R , R = C H

10, X = S, R , R = C H O

4 8

5

2

10

1

2

7, R = H, R = Ph

11, X = NH, R , R = C H

5 10

1

2

1

2, X = S, R , R = C H

5 10

1

2

3, X = NH, R = H, R = Ph

1

2

4, X = S, R = H, R = Ph

Scheme 1: Synthesis of triazine dicarboxylic acid monomers 9-14

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Scheme 2: Synthesis of polyamides 25-48

FT IR Spectroscopy: The FT IR spectra of the polymers exhibited (DTG) is a method of expressing the results of TG by giving the first

−

1

characteristic absorbance at the range of υ 3445-3348 cm and derivative curve as a function of temperature or time to precisely

−

1

698-1601 cm , corresponding to the N-H and C=O stretching of locate the temperature transitions. Differential thermal analysis

−1

the amide group, respectively. Bands around υ 2800-2900 cm

(DTA) detects the change in the heat content (enthalpy) with

changing temperature. DSC measures the temperatures and heat

flows associated with transitions in materials as a function of time

and temperature in a controlled atmosphere. A controlled thermal

program is operative. The thermal properties of these new

materials were carried out in the temperature range from 20 °C to

were assigned to the alkyl H-C stretching.

Thermal Properties: The thermal properties of the prepared

polymers were evaluated by thermogravimetric analysis (TGA),

derivatives thermogravimetry (DTG), differential thermal analysis

(

DTA), and differential scanning calorimetry (DSC) techniques.

7

1

00 °C in air atmosphere. Samples were heated at a heating rate of

0°C/min.

Thermogravimetry (TG) is a technique in which the weight of a

sample is measured as a function of temperature whilst it is subject

to a controlled heating program. Derivatives thermogravimetry

4

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Figure 1 shows as a prototype, the TGA/DTG curves of the glycine- The value of the decomposed substance fraction, α , at the

m

containing polymers 25, 27, 29 and thioglycolic acid-containing moment of maximum development of reaction (with T = T ) was

4

6

polymers 26, 28, 30, derived from the ethylene diamine21, determined from the relation.

respectively. Structure-thermal property correlation based on

1/1-n

1-α ) = n

m

(

changing the diacid residue and the amine substituent at the

triazine moiety, revealed that the prepared polymers have

comparable thermal stabilities.

The values of collision factor, Z, can be obtained by making the use

4

7

of the relation.

*

2

Z= (Ea /RT ) βexp (Ea /RT _m)

m

Glycine-containing polymers 25, 27, 29 exhibited subsequent major

degradation processes and their major amide linkage degradation

processes appeared at 568°C (82.2 % wt loss), 555°C (89.7 % wt

loss) and 557°C (87.4 % wt loss) leaving 17.8 %, 10.3 % and 12.6 %,

respectively, as remaining mass residues (Table S1, SI). Thioglycolic

acid-containing polymers 26, 28, 30 exhibited also subsequent

major degradation and their major amide linkage degradation

processes appeared at 568°C (84.4 % wt loss), 560°C (94.5 % wt

loss) and 544°C (74.4 % wt loss) leaving 15.6 %, 5.5 % and 25.6 %,

respectively, as remaining mass residues (Table S1, SI).

-1

m

where R is the molar gas constant, β is the heating rate (KS ), T is

the peak temperature.

4

8

The entropies of activation ΔS are calculated from the equation:

Z = (kT /h) exp ΔS⁄/R

where k is Boltzmann constant and h is Planck’s constant.

The change in enthalpy (ΔH*), taking place at any peak

temperature, T , can be given by the following equation:

ΔS*) = ΔH*/T

m

(

m

On the other hand, glycine-containing polymers 31, 33 and 35, Based on least square calculations, the ln Δt versus 1000/T plots for

derived from the diamine, benzidine 22, exhibited their major all polymers, for each DTA curve, gave straight lines from which the

amide linkage degradation processes at 542°C (99.7 % wt loss),

08°C (96.6 % wt loss) and 516°C (90.2 % wt loss) leaving 0.3 %, 3.4 Piloyan et al. The slopes were of the Arrhenius type and equals to

and 9.8 %, respectively, as remaining mass residues (Table S1, SI). Δ Ea* /R.

activation energies were calculated according to the method of

4

9

5

%

Thioglycolic acid-containing polymers 32, 34, 36, derived from the

diamine, benzidine 22, exhibited also subsequent major

degradation and their major amide linkage degradation processes

appeared at 563°C (92.8 % wt loss), 582°C (99.0 % wt loss) and

According to the kinetic data obtained from DTA curves all polymers

have negative entropy (ΔS*), which are nearly of the same

-1

magnitude (-0.231 to -0.249) KJ mol , which indicates ordered

systems and more ordered activated states that may be possible

through the chemosorption of other light decomposition products.

Indicating that the transition states are more ordered than the

498°C (89.5 % wt loss) leaving 7.2 %, 1.0 % and 10.5 %, respectively,

as remaining mass residues (Table S1, SI).

Glycine-containing polymers 37, 39, 41 and 43, 45, 47 and reactants, thus in a less random molecular conﬁguration than the

5

0

thioglycolic acid-containing polymers 38, 40, 42 and 44, 46, 48 Reactants. The kinetic data obtained from the nonisothermal

derived from the diamine, piperazine 23 and p-phenylenediamine decomposition of the prepared polymers are given in Table S2;

24 respectively, gave similar thermal properties to the previous Supporting Information.

discussed polymer series. These results revealed the thermal

stability of the newly synthesized polyamides.

The thermodynamic parameters of decomposition processes of

polymers, namely, activation energy ΔEa, enthalpy (ΔH), entropy

(

ΔS) were evaluated by employing the Horowitz–Metzger

4

equation, (Table S2, SI). The order of chemical reactions (n) was

45

calculated via the peak symmetry method by Kissinger. The

asymmetry of the peak, S, was calculated as follows:

2

S = 0 : 63n

1

/2

n = 1.26 (a/b)

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Figure 1: TGA/DTG curves of glycine-containing polymers 25, 27, 29 and thioglycolic acid-containing polymers 26, 28, 30.

All the polymers possess high activation energy values assigning Biology

their high stability. It is observed that many polyamides have nearly

Drug-loaded polymeric nanoparticles. In this study, drug-loaded

a

the same E values for the all decomposition steps, indicating a

nanoparticles were successfully fabricated from the synthesized

similar degradation mechanism in these compounds. For instance,

51

polymers via nanoprecipitation/solvent displacement technique.

polymers (26, 29, 42) and (28, 35, 38, 47) and (27, 33, 34, 39, 44, 46,

This technique involves spontaneous precipitation of the

hydrophobic polymer into nanoparticles with the adsorption of

a

48) have the same E at the last decomposition step, (Table S2, SI).

Thermal transitions of polyamides 25-48 observed from DSC curves, pluronic (poloxamer) molecules onto their surface when an organic

indicate that most polymers exhibited a melting and glass transition solution of polymer and drug was introduced into aqueous solution

5

2

peak indicating that most of the polymers are amorphous. The glass containing the poloxamer stabilizer. In pharmaceutical industry,

®

transition temperature (T ) of the newly synthesized polymers pluronics have been used as emulsifiers, solubilizers, surfactant

g

m

ranged from 280°C to 452°C. The melting temperature, T , of all stabilizers, and wetting agents.

polymers ranged from 505°C to 643°C, indicating the high stability

of the polymers.

®

Pluronics (poloxamers) are nonionic amphiphilic triblock polymers

composed of PEO–PPO–PEO alternating units with the general

2 4 a 3 6 b 2 4 a

In general, it is to be expected that derivatives of glycine could be formula HO(C H O) (C H O) (C H O) H. PEO/PPO block copolymers

highly crystalline with extensive hydrogen bonding in contrast to can be adsorbed onto surface of hydrophobic nanoparticular

the amorphous character of polymers that could be synthesized systems via their hydrophobic PPO central block whereas the

from α-amino acids with bulky side groups.

hydrophilic PEO chains protrudes to the external aqueous medium

5

3,54

providing steric stabilization to the nanoparticles.

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38

By the centrifugation-washing step, the excess molecules of time. Therefore, we can predict our NPs, by virtue of their size and

unadsorbed pluronic® could be eliminated from the bulk. All hydrophilic poloxamer corona, to have prolonged circulating

nanoparticle samples were easily redispersible in water and showed behavior in systemic circulation thus enabling accumulation in

enhanced wettability by virtue of the surface presence of PEO tumor tissue by the EPR effect. Zeta potential measurements of the

residues of pluronic providing hydrophilicity to the nanoparticle CXB-loaded polymeric NPs are presented in Table 1. The NPs were

surface.

negatively charged with a zeta potential of -24.2 to -37.9 mV (Figure

Celecoxib (CXB) is an anti-inflammatory NSAID that specifically 2b) indicating a good colloidal stability against aggregation.

inhibits COX-2 and has drawn much attention for its anti-cancer

TEM micrographs of the CXB-loaded polymeric NPs CXB-46 showed

properties. The COX-2 inhibitor reduces mammary tumor incidence

small monodispersed spherical NPs with a core-shell structure

induced by (7, 12-dimethylbenz[a]anthracene) DMBA in rats. It is

(

Figure 3). This may be explained by the hydrophilic shell of pluronic

also effective in blocking the growth of breast cancer xenografts in

nude mice. CXB could evoke cell cycle arrest, anti-angiogenesis, and

apoptotic cell death in cancers. It has also been used for treatment

of lung cancer, colorectal cancer, colon cancer, ultraviolet (UV)

layer adsorbed onto the surface of the hydrophobic polymer

nanoparticle core. The aggregation of NPs was prevented

effectively via the stabilizing effect of pluronic which provide a

surface layer surrounding the NPs and stabilizes it through steric

5

5,56

light-induced skin cancer and breast cancer.

52

repulsion. The diameter of NPs was smaller than that obtained

The method of nanoparticle preparation is highly desirable for

hydrophobic compounds, such as celecoxib (CXB) resulting in high

entrapment efficiency levels (62.3% to 99.8%) with a good drug

loading in the range of 1.58%–4.19% (Table 1), a favorable

parameter for increasing efficacy of targeted drug delivery.

Dynamic light scattering (DLS) measurements of the particle size of

CXB-loaded polymeric NPs are presented in Table 1. The size of NPs

ranged from 176.4 to 265.2 nm.

from DLS measurements. The DLS method gives the hydrodynamic

diameter, and the nanoparticles may shrink during the sample

36

drying and preparation for TEM.

The FTIR spectra of the CXB-loaded polymeric NPs, CXB-26, CXB-43,

CXB-44, CXB-45, CXB-46, exhibited two characteristic absorbance

−1

peaks at the range of υ 3397-3282 cm corresponding to the

symmetric and asymmetric stretching of NH group of CXB.

2

−1

Moreover, two bands at the range of υ 1378-1084 cm were

Table 1: Physicochemical properties of CXB-loaded polymeric NPs.

assigned to the symmetric and asymmetric stretching of the drug

Polymer Entrapment Drug

Particle PDI

Zeta

2

SO group. Thus, the FT IR spectra of CXB-loaded polymeric NPs

Efficiency,

EE (% w/w)

71.3

68.2

98.3

Loading, DL size

potential

(mV)

indicate the successful entrapment of the drug within the

nanoparticles. The in vitro cumulative release profiles of CXB from

different polymeric NPs are shown in (Figure 4). It was found that

after 48 h, 46.9%, 64.20%, 57.81%, 53.95%, and 49.43% of CXB was

released from polymeric NPs CXB-26, CXB-43, CXB-44, CXB-45 and

CXB-46 respectively. This result showed that the nanocarrier cannot

only solubilize the poorly soluble drug, CXB, but also sustain its

(% w/w)

1.58

(nm)

CXB-26

CXB-43

CXB-44

CXB-45

CXB-46

209.1

183.9

245.7

176.4

265.2

0.219 -31.2

0.257 -24.2

0.258 -37.9

0.280 -32.9

0.304 -27.0

3.25

2.32

62.3

99.8

2.97

4.19

As a prototype, Figure 2a shows a representative particle size

distribution of CXB-loaded polymeric NPs of CXB-46. A unimodal

particle size distribution was observed where the particles have a

size of 265.2 nm with polydispersity of 0.304-0.338. Such small size

of the prepared nanoparticles leads to a reduction in the rate of

clearance by the RES and thus an extended plasma circulation

release. A sustained-release pattern is

a key issue in the

development of colloidal drug delivery systems used in the field of

nanomedicine. Drugs must be released slowly from polymeric NPs

because fast release of drugs from NPs causes precipitation of the

5

7

hydrophobic drug in the systemic circulation.

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(a)

(b)

Figure 2: Particle size (a) and zeta potential (b) distribution of CXB-loaded polymeric NPs (CXB-46).

Figure 3: Transmission electron micrograph (TEM) of CXB-loaded polymeric NPs CXB-46.

8

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Figure 4: The in vitro release behavior of CXB from different polymeric NPs in PBS (pH 7.4) at 37°C.

A cytotoxic study was performed in order to assess the potential was lower than free drug solution (IC50 of 29.95 µg/mL) after 24 hr

benefit of the polymeric NPs for enhancing the cytotoxic activity of incubation period. The lower cytotoxicity demonstrated by NPs over

CXB. The cytotoxicity of free CXB, and CXB-loaded polymeric NPs 24 hr may be explained by the slow release of CXB from the

CXB-43, CXB-45, and CXB-46 were assessed on human breast formulated NPs which could be due to the hydrophobic-

5

9

cancer cells, MCF-7, using MTT assay, a dye-based assay that hydrophobic interaction between the drug and polymer. Actually,

depends on the metabolic activity of viable cells. In MTT assay, only the gradual slow release of CXB was confirmed by the results of in

metabolically active viable cells are able to convert the yellow MTT vitro drug release conducted in our study. Conclusively, CXB-loaded

(3-(4,5-dimethylthiozol-2-yl)-2,5-diphenyl tetrazolium bromide) dye polymeric NPs developed in this study are expected to have high

to purple MTT-formazan crystals which is further dissolved in accumulation in tumor sites via the EPR effect and enhanced

5

8

solvent and analyzed spectrophotometrically. Notably, free CXB, cellular uptake by nonspecific internalization into cells via

and CXB-loaded polymeric NPs CXB-43, CXB-45, and CXB-46 endocytosis or phagocytosis.

demonstrated considerable reduction in cell viability in a dose-

dependent manner (Figure 5). Questionably, the observed cytotoxic

potential of CXB-loaded polymeric NPs CXB-43, CXB-45, and CXB-46

(

IC , 50% growth inhibition, 120, 100, and 52.5 µg/mL, respectively,

50

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Figure 5: Cytotoxicity analysis of free CXB, and CXB-loaded polymeric NPs CXB-43, CXB-45, and CXB-46on MCF-7 cells at the concentration

of 0-500µg/mL after 24 hr.

Biopolymeric nanoparticles based on the synthesized polyamides

and loaded with the poorly soluble drug, CXB, were successfully

Conclusions

developed. The nanoparticles exhibited small size and good

The design of suitable polymeric materials is an increasingly

colloidal stability together with a sustained drug release. Moreover,

important research area due to demands for applications in

the nanoparticles were cytotoxic against breast cancer cells.

medicine as drug delivery systems. A new library of s-triazine

Overall, these nanoparticles hold a great promise as drug delivery

polyamides, based on the reaction of s-triazine glycine and

systems and are expected to accumulate significantly in tumor

thioglycolic acid derivatives with ethylenediamine, benzidine,

tissues via the EPR effect showing enhanced anti-tumor efficacy

piperazine or p-phenylenediamine, was prepared. Structure-

through maximizing the drugs anti-tumor efficacy and reducing

thermal property correlation based on changing the diacid residue

systemic toxicity.

as well as the amine residue at the triazine moiety, revealed the

Experimental

prepared polyamides with comparable thermal stabilities.

Thermal decomposition results revealed the thermal stability of the Chemistry

newly synthesized polyamides. In addition, all the polymers possess

Solvents and reagents were purchased from Sigma-Aldrich. Unless

high activation energy values assigning their high stability. Most of

otherwise stated, the normal workup from organic solvent involved

the prepared polyamides exhibited a melting and glass transition

2 4

drying over Na SO and rotary evaporation. TLC was performed

peak indicating that most of the polymers are amorphous. The

melting temperature, T , of all polymers ranged from 505°C to

43°C, which is an additional indication for the high stability of the

polymers.

using aluminum-backed Merck Silica Gel 60 F-254 plates using

suitable solvent systems and spots being visualized by a Spectroline

m

6

2

UV Lamp (254 or 365 nm) or I vapor. Melting points were obtained

in open capillary tubes using a MEL-Temp II melting point apparatus

and are uncorrected. Infrared spectra (IR) were recorded on a

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-1 1

Perkin-Elmer 1600 series Fourier transform instrument as KBr 2700 (br, OH, acid), 3324 (NH, amine), 1754 (C=O, acid) cm . H-

pellets. The absorption bands (υmax) are given in wave numbers NMR (500 MHz: DMSO-d ): δ 3.53-3.55 (m, 8 H, 2 CH -N, 2 CH -O),

-NH), 6.73-7.03 (m, 2 H, 2 NH, D

6

2

-

1

(

cm ). Nuclear magnetic resonance (NMR) spectra ( H-NMR and 3.74-3.83 (m, 4 H, 2 CH

2

O

1

3

C-NMR) were recorded on a JEOL 500 MHz spectrometer at exchangeable), 12.25 (br s, 2 H, 2 COOH, D

O exchangeable).

2

ambient temperature. Chemical shifts are reported in parts per Elemental analysis Calc. for C11

million (ppm) and are referenced relative to residual solvent (e.g. Found: C, 42.47; H, 4.99; N, 26.67.

CHCl at δ 7.26 ppm for CDCl , DMSO at δ 2.50 ppm for DMSO-d ).

16 6 5

H N O : C, 42.31; H, 5.16; N, 26.91.

3

6

2

,2'-(6-Morpholino-1,3,5-triazine-2,4-diyl)bis(sulfanediyl)diacetic

Thermogravimetry (TG) and differential thermal analysis (DTA) and

differential scanning calorimetry (DSC) analyses were carried out in

the temperature range from 20°C to 700°C by LINSEIS STA PT1000

thermal analyzer. The experimental conditions were: alumina

crucible, air atmosphere and heating rate 10°C/min. Elemental

analyses were performed on a Perkin-Elmer 2400 elemental

analyzer, and the values found were within ±0.3% of the theoretical

values.

acid 10. The product was obtained as a white powder, mp 190-

1

92°C. Method A: 91% yield. IR (KBr): 3459-2500 (br, OH, acid),

-1

1

718 (C=O, acid) cm . H-NMR (500 MHz: DMSO-d

O, CH -S), 3.63-3.65 (m, 4 H, 2 CH N), 3.72 (s, 2 H,

-S), 12.43 (br s, 2 H, 2 COOH, D O exchangeable). Elemental

: C, 38.14; H, 4.07; N, 16.17. Found:

6

): δ 3.54-3.56

(

m, 6 H, 2 CH

2

CH

2

analysis: Calc. for C11

C, 37.98; H, 4.21; N, 16.04.

,2'-(6-(Piperidin-1-yl)-1,3,5-triazine-2,4-diyl)bis(azanediyl)diacetic

acid 11. The product was obtained as a white powder, mp 248-

50°C. Method A: 87% yield. IR (KBr): 3500-2500 (br, OH, acid),

14 4 5 2

H N O S

2

General Procedure of the preparation of triazine dicarboxylic acid

monomers 9-14

2

-1 1

Method A: A solution of cyanuric chloride 1 (1.84g, 10 mmol) in 3290 (NH, amine), 1745 (C=O, acid) cm . H-NMR (500 MHz: DMSO-

acetone (20 mL) was added dropwise to an ice-cold mixture of

): δ 1.39 (s, 4 H, 2 CH ), 1.54 (s, 2 H, CH ), 3.77-3.79 (m, 8 H, 2 CH

glycine 2, thioglycolic acid 3 (20 mmol) and Na CO

(4.24 g, 40 N, 2 CH -NH), 6.75-6.91 (m, 2H, 2NH, D O exchangeable), 12.11 (br

mmol) in water (30 mL) during 30 min. The reaction mixture was s, 2 H, 2 COOH, D O exchangeable). C-NMR (125 MHz: DMSO-d ):

stirred overnight at room temperature. The reaction mixture was δ 24.83, 25.82, 42.66, 43.93, 164.29, 165.92, 166.20, 172.69,

neutralized with concentrated hydrochloric acid and filtered off, 172.75. Elemental analysis Calc. for C12 : C, 46.45; H, 5.85; N,

d

6

2

-

2

3

2

1

3

2

6

H N O

18 6 4

washed with cold water and dried to afford 2-chloro-4,6- 27.08. Found: C, 46.21; H, 6.01; N, 27.19.

disubstituted-1,3,5-triazine derivatives 4 and 5.

2

,2'-(6-(Piperidin-1-yl)-1,3,5-triazine-2,4-diyl)bis(sulfanediyl)

diacetic acid 12. The product was obtained as a white powder, mp

solution (0.95 g, 9 mmol) in water (40 mL), morpholine 6, piperidine 155-157°C. Method A: 85% yield. IR (KBr): 3440-2500 (br, OH, acid),

2 3

To a stirred mixture of the crude 4 or 5 (3 mmol) and Na CO

-1 1

7

or aniline 8 (4.5mmol) in dioxane (20 mL) was added dropwise. 1716 (C=O, acid) cm . H-NMR (500 MHz: DMSO-d

The reaction mixture was stirred at 70-80°C for 8 h. The progress of 2 CH ), 1.55 (br s, 2 H, CH ), 3.60-3.68 (m, 4 H, 2 CH

the reaction was monitored by TLC. After the completion of the CH -S), 3.78 (s, 2 H, CH -S), 12.59 (br s, 2 H, 2 COOH, D

reaction, the reaction mixture was neutralized with hydrochloric exchangeable). C-NMR (125 MHz: DMSO-d ): δ 24.53, 25.60,

acid. The product was filtered off, washed with cold water and 33.10, 44.52, 162.66, 170.91, 171.01, 177.78, 177.85. Elemental

6

): δ 1.42 (s, 4 H,

2

), 3.69 (s, 2 H,

2

O

1

3

6

recrystallized from ethanol to afford the triazine derivatives.

16 4 4 2

analysis Calc. for C12H N O S : C, 41.85; H, 4.68; N, 16.27. Found: C,

4

1.59; H, 4.98; N, 16.34.

Method B: A solution of morpholine, piperidine or aniline (9 mmol)

in dry CH Cl was added dropwise to an ice-cold mixture of cyanuric 2,2'-(6-(Phenylamino)-1,3,5-triazine-2,4-diyl)bis(azanediyl)diacetic

2

chloride 1 (1.84 g, 10 mmol) and Na

CH Cl

during 30 min. The reaction mixture was stirred for 30 min. 260°C. Method B: 90% yield. IR (KBr): 3500-2700 (br, OH, acid),

The solid phase was filtered off, washed with CH Cl . The solvent 3451 (NH, amine), 1638 (C=O, acid) cm . H-NMR (500 MHz: DMSO-

2 3

CO

(0.95 g, 9 mmol) in dry acid 13. The product was obtained as a white powder, mp258-

2

-1 1

2

was evaporated under vacuum to dryness. The product was

obtained as white solid and recrystallized from ethanol to afford (m, 2 H, 2 NH, D

,4-dichloro-6-substituted-1,3,5-triazine 12-14.

7.65-7.69 (m, 2 H, 2 Ar-H), 8.98-9.04 (m, 1 H, NH, D

exchangeable), 12.44 (br s, 2 H, 2 COOH, D O exchangeable).

d

6

): δ 3.88 (br s, 4 H, 2 CH

2

), 6.87 (t, 1 H, J = 7.7 Hz, Ar-H), 6.93-7.14

2

O exchangeable), 7.17 (t, 2 H, J = 7.7 Hz, 2 Ar-H),

2

O

2

To a stirred solution of 3crude 12-14 (8 mmol) in dioxane (20 mL), a

mixture of glycine 2, or thioglycolic acid 3 (24 mmol) and Na CO

5.08 g, 48 mmol) in water (40 mL) was added dropwise. The

Elemental analysis Calc. for C13

14 6 4

H N O : C, 49.06; H, 4.43; N, 26.40.

2

3

Found: C, 49.15; H, 4.22; N, 26.17.

(

o

reaction mixture was stirred at 70-80 C for 24 h. The progress of the 2,2'-(6-(Phenylamino)-1,3,5-triazine-2,4-diyl)bis(sulfanediyl)

reaction was monitored by TLC. After the completion of the diacetic acid 14. The product was obtained as a white powder, mp

reaction, the reaction mixture was neutralized with hydrochloric 257-258°C. Method B: 90% yield. IR (KBr): 3500-2600 (br, OH, acid),

-1 1

acid. The product was filtered off, washed with cold water and 3449 (NH, amine), 1752 (C=O, acid) cm . H-NMR (500 MHz: DMSO-

recrystallized from ethanol to afford the corresponding products.

): δ 3.93 (s, 4 H, 2 CH ), 6.99-7.08 (m, 1 H, Ar-H), 7.25-7.36 (m, 2

H, 2 Ar-H), 7.56 (d, 2H, J = 6.9 Hz, 2 Ar-H), 9.72 (s, 1 H, NH, D

d

6

2

O

2

,2'-(6-Morpholino-1,3,5-triazine-2,4-diyl)bis(azanediyl)diacetic

exchangeable), 10.68 (br. s, 2 H, 2 COOH, D O exchangeable).

2

acid 9. The product was obtained as a white powder, mp 258-

60°C. Method A: 70% yield; Method B: 90% yield. IR (KBr): 3500-

2

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Elemental analysis Calc. for C H N O S : C, 44.31; H, 3.43; N, ethylenediamine 21 and 2,2'-(6-(piperidin-1-yl)-1,3,5-triazine-2,4-

1

3 12 4 4 2

1

5.90. Found: C, 44.53; H, 3.39; N, 15.75.

diyl)bis(sulfanediyl)diacetyl chloride 18, yield 68%; mp over 300°C.

3

-1

IR (KBr): 3385 (NH), 2931, 2855 (sp -CH), 1652 (C=O, amide) cm .

Synthesis of (6-substituted-1,3,5-triazin-2,4-yl)bissubstituted

diacetyl chloride derivatives 15-20

Elemental analysis: Calculated for C H N O S : C, 45.63; H, 5.47; N,

1

4 20 6 2 2

2

2.81. Found: C, 45.35; H, 5.56; N, 22.63.

Poly[2-(4-(2-(2-aminoethylamino)-2-oxoethylamino)-6-

phenylamino)-1,3,5-triazin-2-ylamino)acetic acid] 29. The polymer

9 was obtained as dark brown solid from copolymerization of

A mixture of (1.0 mmol) (6-substituted-1,3,5-triazin-2,4-yl)bis-

substituted diacetic acid derivatives9-14 and (5 mL) thionyl chloride

in 10 mL dichloromethane was stirred continuously where the

temperature was maintained at 10°C for 30 min. The reaction

mixture temperature was raised to 80°C and refluxed for 8 h. The

solvent and volatiles were removed under reduced pressure and

the crude residue was washed thoroughly with hexane to produce

(

2

ethylenediamine 21 and 2,2'-(6-(phenylamino)-1,3,5-triazine-2,4-

diyl)bis(azanediyl)diacetyl chloride 19, yield 70%; mp over 300°C. IR

3

-1

(

KBr): 3379 (NH), 2927, 2850 (sp -CH), 1641 (C=O, amide) cm .

Elemental analysis: Calculated for C15 : C, 52.62; H, 5.30; N,

2.73. Found: C, 52.28; H, 5.37; N, 32.47.

Poly[2-(4-(2-(2-aminoethylamino)-2-oxoethylthio)-6-

phenylamino)-1,3,5-triazin-2-ylthio)acetic acid] 30. The polymer

0 was obtained as yellow solid from copolymerization of

18 8 2

H N O

the

desired

(6-substituted-1,3,5-triazin-2,4-yl)bis-substituted

3

diacetyl chloride derivatives 15-20. The crude residue was used

directly to the next step.

(

General method of polymerization

3

To a stirred cold (ice-bath) solution of (1.0 mmol) diamine

ethylenediamine 21 and 2,2'-(6-(phenylamino)-1,3,5-triazine-2,4-

diyl)bis(sulfanediyl)diacetyl chloride 20, yield 77%; mp over 300°C.

(ethylenediamine21,

benzidine22,

piperazine23

or

p-

phenylenediamine24) in

3

mL DMF, (0.41 mL,

3

mmol)

3

-1

IR (KBr): 3410 (NH), 2925, 2857 (sp -CH), 1683 (C=O, amide) cm .

triethylamine was added. A solution of (1.0 mmol) of the previously

prepared (6-substituted-1,3,5-triazin-2,4-yl)bis-substituted diacetyl

chloride derivatives 15-20 in (3 mL) DMF was added dropwise for 30

min. The reaction mixture was stirred overnight and was then

poured into ice cold water. The formed polymer was filtered,

washed thoroughly with water, ethanol, and air dried.

Elemental analysis: Calculated for C H N O S : C, 47.86; H, 4.28; N,

1

5 16 6 2 2

2

2.32. Found: C, 47.51; H, 4.32; N, 22.02.

Poly[2-(4-(2-(4'-aminobiphenyl-4-ylamino)-2-oxoethylamino)-6-

morpholino-1,3,5-triazin-2-ylamino)acetic acid] 31. The polymer 31

was obtained as black solid from copolymerization of benzidine 22

and 2,2'-(6-morpholino-1,3,5-triazine-2,4-diyl)bis(azanediyl)diacetyl

chloride 15, yield 80%; mp over 300°C. IR (KBr): 3431 (NH), 2956,

Poly[2-(4-(2-(2-aminoethylamino)-2-oxoethylamino)-6-

morpholino-1,3,5-triazin-2-ylamino)acetic acid] 25. The polymer 25

was obtained as brown solid from copolymerization of

3

-1

2

924, 2858 (sp -CH), 1652 (C=O, amide)cm . Elemental analysis:

Calculated for C23 : C, 59.99; H, 5.25; N, 24.33. Found: C,

9.61; H, 5.32; N, 24.01.

24 8 3

H N O

ethylenediamine21

and

2,2'-(6-morpholino-1,3,5-triazine-2,4-

5

diyl)bis(azanediyl)diacetyl chloride 15, yield 86%; mp over 300°C. IR

3

-1

Poly[2-(4-(2-(4'-aminobiphenyl-4-ylamino)-2-oxoethylthio)-6-

morpholino-1,3,5-triazin-2-ylthio)acetic acid] 32. The polymer 32

was obtained as black solid from copolymerization of benzidine22

(KBr): 3389 (NH), 2965, 2860 (sp -CH), 1674 (C=O, amide) cm .

Elemental analysis: Calculated for C H N O : C, 46.42; H, 5.99; N,

1

3

20

8

3

3.31. Found: C, 46.10; H, 6.11; N, 32.99.

Poly[2-(4-(2-(2-aminoethylamino)-2-oxoethylthio)-6-morpholino-

,3,5-triazin-2-ylthio)acetic acid] 26. The polymer 26 was obtained

as black solid from copolymerization of ethylenediamine 21 and

,2'-(6-morpholino-1,3,5-triazine-2,4-diyl)bis(sulfanediyl)diacetyl

chloride 16, yield 76%; mp over 300°C. IR (KBr): 3433 (NH), 2922,

and

2,2'-(6-morpholino-1,3,5-triazine-2,4-

diyl)bis(sulfanediyl)diacetyl chloride 16, yield 73%; mp over 300°C.

1

3

IR (KBr): 3445 (NH), 2963, 2911, 2855 (sp -CH), 1637 (C=O, amide)

-1

cm .Elemental analysis: Calculated for C23

H

22

N

6

3

O S

2

: C, 55.85; H,

2

4

.48; N, 16.99. Found: C, 55.51; H, 4.54; N, 16.61.

Poly[2-(4-(2-(4'-aminobiphenyl-4-ylamino)-2-oxoethylamino)-6-

piperidin-1-yl)-1,3,5-triazin-2-ylamino)acetic acid] 33. The

3

-1

2

857 (sp -CH), 1652 (C=O, amide) cm .Elemental analysis:

Calculated for C13 : C, 42.15; H, 4.90; N, 22.69. Found: C,

1.85; H, 4.97; N, 22.37.

Poly[2-(4-(2-(2-aminoethylamino)-2-oxoethylamino)-6-(piperidin-

-yl)-1,3,5-triazin-2-ylamino)acetic acid] 27. The polymer 27 was

obtained as brown solid from copolymerization of ethylenediamine

and 2,2'-(6-(piperidin-1-yl)-1,3,5-triazine-2,4-

diyl)bis(azanediyl)diacetyl chloride 17, yield 87%; mp over 300°C. IR

(

18 6 3 2

H N O S

polymer 33 was obtained as greenish yellow solid from

copolymerization of benzidine22 and 2,2'-(6-(piperidin-1-yl)-1,3,5-

triazine-2,4-diyl)bis(azanediyl)diacetyl chloride 17, yield 74%; mp

4

1

3

over 300°C. IR (KBr): 3425 (NH), 2964, 2856 (sp -CH), 1674 (C=O,

-1

amide) cm . Elemental analysis: Calculated for C24

H

26

N

8

O

2

: C, 62.87;

21

H, 5.72; N, 24.44. Found: C, 62.53; H, 5.82; N, 24.13.

Poly[2-(4-(2-(4'-aminobiphenyl-4-ylamino)-2-oxoethylthio)-6-

piperidin-1-yl)-1,3,5-triazin-2-ylthio)acetic acid] 34. The polymer

4 was obtained as greenish yellow solid from copolymerization of

benzidine22 and 2,2'-(6-(piperidin-1-yl)-1,3,5-triazine-2,4-

diyl)bis(sulfanediyl)diacetyl chloride 18, yield 77%; mp over 300°C.

3

-1

(

KBr): 3418 (NH), 2933, 2858 (sp -CH), 1663 (C=O, amide) cm .

(

Elemental analysis: Calculated for C H N O : C, 50.29; H, 6.63; N,

1

4

22

8

2

3

33.51. Found: C, 49.96; H, 6.68; N, 33.23.

Poly[2-(4-(2-(2-aminoethylamino)-2-oxoethylthio)-6-(piperidin-1-

yl)-1,3,5-triazin-2-ylthio)acetic acid] 28. The polymer 28 was

obtained as dark brown solid from copolymerization of

3

-1

IR (KBr): 3432 (NH), 2931, 2853 (sp -CH), 1688 (C=O, amide) cm .

1

2 | J. Name., 2012, 00, 1-3

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ARTICLE

Elemental analysis: Calculated for C H N O S : C, 58.52; H, 4.91; N, obtained as brown solid from copolymerization of piperazine 23

24

6

2 2

1

7.06. Found: C, 58.20; H, 4.97; N, 16.88.

Poly[2-(4-(2-(4'-aminobiphenyl-4-ylamino)-2-oxoethylamino)-6-

phenyl amino)-1,3,5-triazin-2-ylamino)acetic acid] 35. The

polymer 35 was obtained as black solid from copolymerization of

benzidine22 and 2,2'-(6-(phenylamino)-1,3,5-triazine-2,4-

diyl)bis(azanediyl)diacetyl chloride 19, yield 73%; mp over 300°C. IR Poly[2-(4-(2-oxo-2-(piperazin-1-yl)ethylthio)-6-(phenylamino)-

and

2,2'-(6-(phenylamino)-1,3,5-triazine-2,4-

diyl)bis(azanediyl)diacetyl chloride 19, yield 79%; mp over 300°C. IR

3

-1

(

KBr): 3388 (NH), 2975, 2925 (sp -CH), 1615 (C=O, amide) cm .

Elemental analysis: Calculated for C17 : C, 55.43; H, 5.47; N,

0.42. Found: C, 55.18; H, 5.52; N, 30.13.

(

20 8 2

H N O

3

-1

(KBr): 3374 (NH), 2975, 2950 (sp -CH), 1613 (C=O, amide) cm . 1,3,5-triazin-2-ylthio)acetic acid] 42. The polymer 42 was obtained

Elemental analysis: Calculated for C25

H

22

N

8

O

2

: C, 64.37; H, 4.75; N, as brown solid from copolymerization of piperazine 23 and 2,2'-(6-

(phenylamino)-1,3,5-triazine-2,4-diyl)bis(sulfanediyl)diacetyl

24.02. Found: C, 64.03; H, 4.87; N, 23.91.

chloride 20, yield 80%; mp over 300°C. IR (KBr): 3414 (NH), 2925,

Poly[2-(4-(2-(4'-aminobiphenyl-4-ylamino)-2-oxoethylthio)-6-

phenyl amino)-1,3,5-triazin-2-ylthio)acetic acid] 36. The polymer

was obtained as brown solid from copolymerization of

benzidine22 and 2,2'-(6-(phenylamino)-1,3,5-triazine-2,4-

diyl)bis(sulfanediyl)diacetyl chloride 20, yield 78%; mp over 300°C. Poly[2-(4-(2-(4-aminophenylamino)-2-oxoethylamino)-6-

3

-1

2

857 (sp -CH), 1622 (C=O, amide) cm . Elemental analysis:

Calculated for C17 : C, 50.73; H, 4.51; N, 20.88. Found: C,

0.44; H, 4.61; N, 20.53.

(

18 6 2 2

H N O S

36

5

3

-1

IR (KBr): 3403 (NH), 2926, 2850 (sp -CH), 1733 (C=O, amide) cm . morpholino-1,3,5-triazin-2-ylamino)acetic acid] 43. The polymer 43

Elemental analysis: Calculated for C H N O S : C, 59.98; H, 4.03; N, was obtained as black solid from copolymerization of p-

25

20

6

2 2

1

6.79. Found: C, 59.62; H, 4.12; N, 16.46.

Poly[2-(4-morpholino-6-(2-oxo-2-(piperazin-1-yl)ethylamino)-

,3,5-triazin-2-ylamino)acetic acid] 37. The polymer 37 was

phenylenediamine 24 and 2,2'-(6-morpholino-1,3,5-triazine-2,4-

diyl)bis(azanediyl)diacetyl chloride 15,yield 75%; mp over 300°C. IR

3

-

(

1

KBr): 3425 (NH), 2968, 2859 (sp -CH), 1601 (C=O, amide) cm

1

.

Elemental analysis: Calculated for C17

H

20

N

8

O

3

: C, 53.12; H, 5.24; N,

obtained as brown solid from copolymerization of piperazine 23

and 2,2'-(6-morpholino-1,3,5-triazine-2,4-diyl)bis(azanediyl)diacetyl

2

9.15. Found: C, 52.80; H, 5.28; N, 28.86.

chloride 15, yield 77%; mp over 300°C. IR (KBr): 3434 (NH), 2924, Poly[2-(4-(2-(4-aminophenylamino)-2-oxoethylthio)-6-

3

-1

2

857 (sp -CH), 1620 (C=O, amide) cm .Elemental analysis: morpholino-1,3,5-triazin-2-ylthio)acetic acid] 44. The polymer 44

Calculated for C15

H

22

N

8

O

3

: C, 49.71; H, 6.12; N, 30.92. Found: C, was obtained as greenish brown solid from copolymerization of p-

phenylenediamine 24 and 2,2'-(6-morpholino-1,3,5-triazine-2,4-

49.42; H, 6.18; N, 30.64.

diyl)bis(sulfanediyl)diacetyl chloride 16, yield 76%; mp over 300°C.

Poly[2-(4-morpholino-6-(2-oxo-2-(piperazin-1-yl)ethylthio)-1,3,5-

triazin-2-ylthio)acetic acid] 38. The polymer 38 was obtained as

greenish yellow solid from copolymerization of piperazine 23 and

3

-1

IR (KBr): 3437 (NH), 2916, 2858 (sp -CH), 1674 (C=O, amide) cm .

Elemental analysis: Calculated for C17 : C, 48.79; H, 4.34; N,

0.08. Found: C, 48.41; H, 4.46; N, 19.87.

chloride 16, 0.29 g (73%) yield; mp over 300°C. IR (KBr): 3439 (NH), Poly[2-(4-(2-(4-aminophenylamino)-2-oxoethylamino)-6-

18 6 3 2

H N O S

2

2,2'-(6-morpholino-1,3,5-triazine-2,4-diyl)bis(sulfanediyl)diacetyl

3

-1

2

964, 2919, 2857 (sp -CH), 1652 (C=O, amide) cm .Elemental (piperidin-1-yl)-1,3,5-triazin-2-ylamino)acetic acid] 45. The

analysis Calculated for C15

H

20

N

6

O

3

S

2

: C, 45.44; H, 5.08; N, 21.20. polymer 45 was obtained as brown solid from copolymerization of

p-phenylenediamine 24 and 2,2'-(6-(piperidin-1-yl)-1,3,5-triazine-

Found: C, 45.08; H, 5.17; N, 20.94.

2

3

,4-diyl)bis(azanediyl)diacetyl chloride 17, yield 86%; mp over

Poly[2-(4-(2-oxo-2-(piperazin-1-yl)ethylamino)-6-(piperidin-1-yl)-

,3,5-triazin-2-ylamino)acetic acid] 39. The polymer 39 was

obtained as buff solid from copolymerization of piperazine 23 and

,2'-(6-(piperidin-1-yl)-1,3,5-triazine-2,4-diyl)bis(azanediyl)diacetyl

chloride 17, 0.30 g (83%) yield; mp over 300°C. IR (KBr): 3428 (NH), Poly[2-(4-(2-(4-aminophenylamino)-2-oxoethylthio)-6-(piperidin-

3

00°C. IR (KBr): 3365 (NH), 2932, 2857 (sp -CH), 1605 (C=O, amide)

1

-1

cm .Elemental analysis: Calculated for C18

22 8 2

H N O : C, 56.53; H,

5

.80; N, 29.30. Found: C, 56.21; H, 5.86; N, 28.98.

2

3

-1

2

971, 2931, 2860 (sp -CH), 1641 (C=O, amide) cm . Elemental 1-yl)-1,3,5-triazin-2-ylthio)acetic acid] 46. The polymer 46 was

analysis: Calculated for C16

H

24

N

8

O

2

C, 53.32; H, 6.71; N, 31.09. obtained as yellow solid from copolymerization of p-

phenylenediamine 24 and 2,2'-(6-(piperidin-1-yl)-1,3,5-triazine-2,4-

Found: C, 53.01; H, 6.79; N, 30.83.

diyl)bis(sulfanediyl)diacetyl chloride 18, yield 86%; mp over 300°C.

Poly[2-(4-(2-oxo-2-(piperazin-1-yl)ethylthio)-6-(piperidin-1-yl)-

,3,5-triazin-2-ylthio)acetic acid] 40. The polymer 40 was obtained

as brown solid from copolymerization of piperazine 23 and 2,2'-(6-

piperidin-1-yl)-1,3,5-triazine-2,4-diyl)bis(sulfanediyl)diacetyl

chloride 18, yield 71%; mp over 300°C. IR (KBr): 3440 (NH), 2931, Poly[2-(4-(2-(4-aminophenylamino)-2-oxoethylamino)-6-

3

-1

IR (KBr): 3424 (NH), 2931, 2853 (sp -CH), 1698 (C=O, amide) cm .

Elemental analysis: Calculated for C H N O S : C, 51.90; H, 4.84; N,

1

8 20 6 2 2

2

0.18. Found: C, 51.69; H, 4.87; N, 19.92.

(

3

-1

2853 (sp -CH), 1630 (C=O, amide) cm .Elemental analysis: (phenylamino)-1,3,5-triazin-2-ylamino)acetic acid] 47. The polymer

Calculated for C16

H

22

N

6

O

2

S

2

: C, 48.71; H, 5.62; N, 21.30. Found: C, 47 was obtained as dark brown solid from copolymerization of p-

phenylenediamine 24 and 2,2'-(6-(phenylamino)-1,3,5-triazine-2,4-

48.34; H, 5.66; N, 20.97.

diyl)bis(azanediyl)diacetyl chloride 19, yield 69%; mp over 300°C. IR

Poly[2-(4-(2-oxo-2-(piperazin-1-yl)ethylamino)-6-(phenylamino)-

,3,5-triazin-2-ylamino)acetic acid] 41. The polymer 41 was

3

-1

(

KBr): 3348 (NH), 2950, 2875 (sp -CH), 1614 (C=O, amide) cm .

1

J. Name., 2013, 00, 1-3 | 13

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ARTICLE

Journal Name

Elemental analysis: Calculated for C H N O : C, 58.45; H, 4.65; N, was measured and the zeta potential was calculated by the

1

9

18

8

2

28.70. Found: C, 58.12; H, 4.78; N, 28.42.

Dispersion Technology Software provided by Malvern.

Poly[2-(4-(2-(4-aminophenylamino)-2-oxoethylthio)-6-

Morphological analysis: Transmission electron microscopy (TEM,

(phenylamino)-1,3,5-triazin-2-ylthio)acetic acid] 48. The polymer JEM-100 CX, JEOL, Japan) was performed to elucidate the

48 was obtained as dark brown solid from copolymerization of p- morphology of CXB-loaded polymeric NPs. A 50-fold diluted

phenylenediamine 24 and 2,2'-(6-(phenylamino)-1,3,5-triazine-2,4- dispersion of NPs in distilled water was deposited onto a carbon

diyl)bis(sulfanediyl)diacetyl chloride 20, yield 68%; mp over 300°C. grid. After 30 s, the dispersion was stained with uranyl acetate

3

-1

IR (KBr): 3358 (NH), 2950, 2900 (sp -CH), 1609 (C=O, amide) cm . solution for 1 min. The excess solution was drawn off with a filter

Elemental analysis: Calculated for C19

9.80. Found: C, 53.45; H, 3.98; N, 19.59.

Biology

H

16

N

6

O

2

S

2

: C, 53.79; H, 3.80; N, paper, and the sample was dried at room temperature.

1

Fourier Transform Infrared (FTIR) Spectroscopy: The FTIR spectra

of free CXB, and CXB-loaded polymeric nanoparticles were recorded

using a Spectrum RXI FTIR spectrometer (Perkin Elmer, USA).

Preparation of drug-loaded polymeric nanoparticles

Samples were finely grounded with IR grade KBr and then pressed

into pellet, and IR spectra were taken in transmission over the

Celecoxib (CXB)-loaded polymeric NPs were prepared by

5

1

nanoprecipitation (solvent displacement) method. In brief, 50 mg

-1

range of 4000–500 cm at ambient temperature

polymer and 10 mg CXB were dissolved in 3 mL dimethyl sulfoxide

In vitro drug release: The in vitro release of CXB from polymeric

NPs was performed using dialysis bag. Freshly prepared

nanosuspension (equivalent to 2 mg/mL of CXB) was placed in a

dialysis bag (cut-off 12–14 kDa, Spectrum Laboratories, Inc, Rancho

Dominguez, CA, USA). The bag was then suspended in a beaker

containing 100 mL of phosphate buffered saline (PBS, pH 7.4) with

SLS (0.5% w/v). This assembly was kept in an oscillating

thermostatic water bath (Julabo, Germany) maintained at 100 rpm

and 37°C±0.5°C. At regular time intervals, 2 mL of CXB releasing

media was withdrawn and replaced with an equal volume of fresh

releasing medium to maintain sink conditions. All the samples were

(

DMSO). The organic solvent containing drug and polymer was

injected dropwise into 50 mL water consisting 1 % w/v pluronic F-68

under bath sonication for 30 min. The resultant nanosuspension

was centrifuged at 17000 rpm at 4°C for 30 min (Sigma laboratory

refrigerated centrifuge, model 3K-30, Germany) in order to

separate the NPs. The sedimented NPs were washed with distilled

water, reconstituted in 5 mL distilled water and then freeze-dried

(CRYODOS-50 Freeze-drier, Telstar, Spain). Blank NPs were also

prepared in the same method omitting CXB.

Physicochemical characterization of nanoparticles

Drug content: The amount of CXB encapsulated in the polymeric filtered through 0.45 µm membrane filter and analyzed for CXB

NPs was determined by both direct and indirect methods. In the content using HPLC method.

direct method, 10 mg lyophilized NPs were dissolved in 5 mL

In vitro cytotoxicity: Cytotoxicity was determined by classic MTT

methanol with the aid of ultrasonication for 10 min, then filtered

assay. Briefly, MCF-7 breast cancer cells were seeded in 96-well

through 0.45 µm membrane filter and analyzed for free CXB via

HPLC. In the indirect method, after ultracentrifugation of the bulk

suspension at 17,000 rpm for 30 min, the supernatant was analyzed

for free CXB concentration via HPLC. All the analysis was performed

in triplicate.

3

plate at concentration of 5×10 cells/well in Dulbecco‘s modified

eagle medium (DMEM) enriched with 10% fetal bovine serum and

cultured overnight. Free drug solution and drug loaded polymeric

NPs CXB-43, CXB-45, and CXB-46 were added to reach a final

concentration of 500 μg/mL, and incubated for 24 hr. Measurement

6

0

A reverse phase HPLC method was used for quantifying CXB. HPLC was performed in microplate reader (Model 550, Bio-Rad, USA).

analysis was carried out with Agilent 1200 chromatograph using an

Eclipse plus C18 column (3.5 µm 4.6 x 100 mm), and PDA detector.

Acknowledgements

An isocratic solvent system consisting of 70:30 (v/v) methanol–

acidified water (phosphoric acid, pH = 4) was used at a flow rate of

The

authors

thank

Alexandria

University-Research

1.0 mL/min and an injection volume of 10 µL, and the peaks were

Enhancement Program (ALEXREP), for funding this work

detected at 250 nm.

through the Research Project (HLTH-13 ،BASC-13).

Particle size distribution and zeta potential: The NPs size

distribution and zeta potential were determined using dynamic light

scattering (DLS) technique with a NanoZS/ZEN3600 Zetasizer

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Graphical abstract

The feasibility of s-triazine polyamides to fabricate celecoxib-loaded nanoparticles

.

Article Doi

Design and synthesis of new s-triazine polymers and their application as nanoparticulate drug delivery systems

DOI: 10.1039/c6nj02539k

Source and publish data:

Authors:

Article abstract of DOI:10.1039/c6nj02539k

Full text of DOI:10.1039/c6nj02539k

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