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G. Li et al. / Journal of Molecular Liquids 313 (2020) 113451
is favored by many researchers. Zhao et al. [15] developed a new strat-
egy for the self-coated interfacial layer on drug-loaded mesoporous sil-
ica nanoparticles (MSNs) based on mussel-mimetic catecholamine
polymer (polydopamine, PDA) layer between inorganic and organic
matrix for controlling drug release. When the interface PDA was coated
and MSNs encapsulated in electrospun poly(L-lactide) (PLLA) fibers, the
release rates of drugs located inside/outside the interfacial layer could
be finely controlled. The short-term anti-inflammation Ibuprofen (IBF)
could release for 30 days in the absence of interfacial interactions and
sustained long-term doxorubicin (DOX) could release for 90 days in
the presence of interfacial interactions, which was helpful to inhibit po-
tential tumor recurrence. Cole and Pierce et al. [16,17] explained the
way of long-term anti-cancer drug delivery along with short-term
anti-inflammatory drug release inhibited a tumor reappearance after
surgery and the tumor resection site. In this system, the anti-
inflammatory drug may decrease the risk of inflammation and cancer
recurrence by inhibiting inflammatory cell growth, and the anticancer
drug destroys the tumor cells. Moreover, biodegradable scaffolds pro-
vide a suitable microenvironment for healthy cell growth and so sup-
port tissue regeneration. These studies showed how important the
multi-agents delivery system was for drug delivery.
This study was aimed to establish a versatile and general methodol-
ogy for improving the efficiency of the delivery system. We have devel-
oped a novel nano-sized multidrug delivery system based on drug-
surfactant interaction. The physicochemical interaction between the
drug molecule and the surfactant system significantly improves the sol-
ubility of the drug, avoids the drug from forming a precipitate in the so-
lution during the injection process, and reduces side effects [18,19].
Considering the physio-chemical interactions between drugs and sur-
factants, the appearance of surfactants may increase the absorption of
drugs. Therefore, a systematic study was proposed to describe the inter-
actions of drugs with a variety of surfactants.
aggregates on DOX was examined by dialysis experiments. Finally, the cy-
totoxicity of mixed aggregates on MCF-7 cell lines was tested to verify the
application effect of the prepared aggregate which simultaneously encap-
sulate two different drugs and have a sustained release function. The
structure of CL and IBF was shown in Fig. 1(A & B).
2. Experimental
Materials and Methods was representing in the electronic support-
ive information (ESI) from 2.1 to 2.6 sections.
2.7. Synthesis of cationic lipid (CL), 2,3-bis(dodecyloxy)-N-ethyl-N,N-
dimethylpropane-1-aminium chloride
2.7.1. Synthesis of 1-dimethylamino-2,3-propanediol
70.9 g (520 mmol L−1) of a 33% dimethylamine aqueous solution
was added and stirred in a 250 mL three-necked flask. Weigh 6 g of so-
dium hydroxide and arranged it as a 40% aqueous solution. When it was
cooled to room temperature, add it into a three-necked bottle. 44 g
(400 mmol L−1) of 1-chloro-2,3-propanediol was weigh into a
dropping funnel and added slowly into the bottle. In the three-necked
bottle, the control acceleration was 1–2 drops/s. After the addition
was completed, the reaction was performed at 30 °C for 24 h. Then a dis-
tillation apparatus was installed, and the temperature was gradually in-
creased to 105 °C to distill off the excess dimethylamine. After
distillation, the distillation apparatus was removed, and the three bot-
tles were heated and stirred opened until the evolved gas had no
amine taste. The water was removed under reduced pressure, and
after completion, the fraction of 102–104 °C/2 mmHg was collected by
distillation under reduced pressure. 60% yield was observed. The reac-
tion scheme was shown in the Fig. 2(1).
Mixed aggregates with high encapsulating efficiency and controlled
release have received much attention for the drug delivery system [20].
In this work we have used Gemini cationic lipids (CL), which have low
cmc and are increasingly reported as multipurpose materials like gene
therapy [21–25] and drug encapsulation [26–30], capturing the interest
of the scientific communities. Due to the size, biocompatibility, and pro-
tective effect of CLs on the degradation of encapsulating substances, CLs
are suitable for the administration of drugs and diagnostic agents re-
gardless of the route taken (oral, injectable, parenteral or lung). Our pre-
vious studies described the efficiency of CL encapsulated DNA for gene
delivery [21]. The variable length of carbon chains and the quaternary
ammonium or neutral tertiary amine heads of CL allowed us to find
the structure-function relationship of how these factors affect cationic
lipids on gene delivery performance. CL gene vectors in the condition
of carbamate as connection bond and hydroxyalkyl group as a head
group may improve the gene therapy transfection efficiency and
lower cytotoxicity [24].
In the current system, Ibuprofen (IBF) and doxorubicin (DOX) are
used, in which the former contains a carboxylic group and hydrophobic
moiety, and the latter contains liposoluble anthraquinone ligand, phe-
nolic hydroxyl, and basic amino groups. It used as a clinically common
combination drug in tumor treatment which could offer the advantages
of increasing the tumoricidal efficacy and reducing the side effects
caused by the high-dose of a single medication. The IBF and DOX were
expected to bind into the inner core through ionic interaction and hy-
drophobic effect [31].
2.7.2. Synthesis of dodecyl p-toluenesulfonate
124.9 mmol L−1 of lauryl alcohol and 39.5 g of pyridine were added
to a 250 mL three-necked bottle, and the flask was immersed in an ice-
water bath to make the temperature of the mixture 0 °C. 26.25 g
(138.1 mmol L−1) of p-toluenesulfonyl chloride are added to the bottle
in portions within 20–30 min at this temperature. The mixture was
stirred for 12 h under 20 °C. and diluted with a solution of 100 mL of hy-
drochloric acid (specific gravity 1.19) and 300 mL of ice water. The crys-
tallized ester was filtered through a chilled Buchner funnel and blotted
as dry as possible. The solid was transferred to a 500 mL beaker, and add
100 mL of methanol, then the mixture was heated in a water bath until
the ester melted. It was cooled in an ice-water bath with constant stir-
ring, and the ester precipitated very finely. It is filtered on a frozen fun-
nel and dried in air (preferably below 20 °C). The crude product was
recrystallized from petroleum ether (30–60 °C) and the solution was
cooled to 0 °C. The resulting ester was filtered through a frozen funnel
to give the product. 70–80% yield was observed. The reaction scheme
was shown in the Fig. 2(2).
2.7.3. Synthesis of N, N-dimethyl-dodecyloxypropylamine
N,N-dimethylaminopropylene(2.4 g, 20 mmol), p-toluenesulfonate
(60 mmolL−1), potassium tert-butoxide (6.72 g), and xylene were
added to a 100 mL single-mouth flask equipped with a reflux condenser
and a three-way charge/discharge valve. After pumping vacuum with a
In this work, we have prepared mixed aggregates of CL and IBF using
mole fraction based formulation (C*(αCL + αIBF)). The physicochemical
properties of CL-IBF mixed aggregate were determined using surface ten-
sion and conductance experiments methods. The interaction parameter
and thermodynamic interfacial parameters was evaluated by Clint's,
Rubingh, and Motumura's equations. The applicability of prepared
mixed aggregate was used to enhance the binding properties and encap-
sulation of DOX. After encapsulating DOX, the slow-release effect of these
Fig. 1. (A) The structure of 2,3-bis(dodecyloxy)-N-ethyl-N,N-dimethylpropane-1-
aminium chloride(CL)and (B) Ibuprofen sodium salt.