Modification of polyethylene glycol onto solid lipid nanoparticles encapsulating a novel chemotherapeutic agent (PK-L4) to enhance solubility for injection delivery

Figures & data

Table 1 Composition of the sold lipid nanoparticles (SLNs) grafting with or without polyethylene glycol (PEG)

Formulations	Lipid phase (mg, %)						Aqueous phase (μL)
	Trimyristin	Gelucire^® 53/10	Hydrogenated SPC	Stearylamine	PEG monostearate	PK-L4	1% F-68
SLNs without PEG	60 (2%)	60 (2%)	30 (1%)	1.5 (0.05%)	–	4.5 (0.15%)	2820
SLNs with PEG	60 (2%)	60 (2%)	30 (1%)	1.5 (0.05%)	30 (1%)	4.5 (0.15%)	2820

Abbreviations: F-68, Pluronic^® F 68; PK-L4, 3-Chloro-4-[(4-methoxyphenyl)amino]furo[2,3-b]quinoline; SPC, soybean phosphatidylcholine.

Table 2 Characterization of 3-Chloro-4-[(4-methoxyphenyl)amino]furo[2,3-b]quinoline-loaded solid lipid nanoparticles (SLNs) with or without polyethylene glycol (PEG) in terms of the diameter of particle size (d), polydispersity index (PDI), zeta potential, and entrapment efficiency (EE%), and stability changes following storage at room temperature (25°C) for 1 month

Formulation	d (nm)		PDI		Zeta potential (mV)		EE%
	0 day	1 month	0 day	1 month	0 day	1 month	0 day	1 month
SLNs without PEG	47.3 ± 0.5	42.4 ± 0.4	0.18 ± 0.01	0.18 ± 0.01	22.5 ± 1.5	20.9 ± 1.8	99.69 ± 0.12	80.59 ± 1.20
SLNs with PEG	28.0 ± 0.6	28.7 ± 0.3	0.13 ± 0.02	0.20 ± 0.01	27.8 ± 6.4	25.4 ± 3.3	99.98 ± 0.00	91.63 ± 2.36

Note: Each value represents the mean ± standard deviation (n = 3).

Figure 1 (A and B) Transmission electron microscopy images of 3-Chloro-4-[(4- methoxyphenyl)amino]furo[2,3-b]quinoline (PK-L4)-loaded solid lipid nanoparticles (SLNs) with polyethylene glycol (PEG)-monostearate: (A) macro view, original magnification (50,000×); (B) microscopic view (70,000×). (C) Schematic depiction of a PK-L4-loaded SLN system.

Notes: The PK-L4 (yellow particle) entrapped in the inner cores of the SLNs (light blue) with Gelucire^® 53/10 (black), hydrogenated soybean phosphatidylcholine (HSPC) (purple), and the positive charge of stearylamine chelated in the core-shell, Pluronic^® F 68 (F-68) (pink), connected to those of the surfactant, and functionalized with PEG (blue) (left), followed by the assembly of those of the surfactant on the core shells of the SLNs (right). The fully assembled PK-L4-loaded SLN system is shown on the right.

Figure 2 Differential scanning calorimetry thermograms of solid lipid nanoparticle (SLN) ingredients and 3-Chloro-4-[(4-methoxyphenyl)amino]furo[2,3-b]quinoline (PK-L4) at increasing scanning periods at 80°C–180°C.

Abbreviations: HSPC, hydrogenated soybean phosphatidylcholine; PEG, polyethylene glycol; SA, stearylamine; TM, trimyristin.

Figure 3 In vitro release of 3-Chloro-4-[(4-methoxyphenyl)amino]furo[2,3-b] quinoline (PK-L4) from solid lipid nanoparticles (SLNs) with and without polyethylene glycol (PEG) monostearate.

Notes: Phosphate-buffered saline (pH 7.4) containing 1% Pluronic^® F 127 was used as the receptor medium. Each value represents the mean ± standard deviation (n = 4).

Table 3 The half-maximal inhibitory concentrations (IC₅₀) of the 3-Chloro-4-[(4-methoxyphenyl)amino]furo[2,3-b]quinoline (PK-L4) solution and PK-L4-loaded solid lipid nanoparticles (SLNs) with and without polyethylene glycol (PEG) monostearate

Formulations	IC50 (μg/mL) on cell lines
	A549	HepG2	MCF7	MDA-MB-231	Ca9-22
PK-L4 solution	0.11	0.04	8.47	2.14	0.04
SLNs without PEG	0.06	0.09	0.10**	0.11**	0.03
SLNs with PEG	0.04*	0.04	0.10**	0.12**	0.03
Doxorubicin solution	0.40*	0.11*	0.43**	0.51**	0.14*

Notes: A doxorubicin solution was used as the comparison group. Each value represents the mean ± standard deviation (n = 6).

* P < 0.05;

** P < 0.01 as compared with the data of PK-L4 control solution. Note that doxorubicin solution was a free aqueous solution – this drug has commercial potential as an anticancer drug.

Abbreviations: A549, human lung carcinoma cell line; HepG2, human hepatocellular liver carcinoma cell line; MCF7, human breast adenocarcinoma with estrogen receptor cell line; MDA-MB-231, human breast adenocarcinoma cell line; Ca9-22, human oral squamous cell carcinoma cell line.

Table 4 Pharmacokinetic parameters of 3-Chloro-4-[(4-methoxyphenyl)amino]furo[2,3-b]quinoline (PK-L4) (4.7 mg/kg) after intravenous administration of the control (PK-L4 solution) and solid lipid nanoparticles (SLNs) with and without polyethylene glycol (PEG) to rats for 12 hours

Parameters	Control (PK-L4 solution)	SLNs without PEG	SLNs with PEG
t1/2β (h)	0.078 ± 0.023	0.118 ± 0.009*	0.136 ± 0.046*
t1/2β (h)	0.994 ± 0.138	1.042 ± 0.118	1.026 ± 0.658
Cl (L/h/kg)	4.075 ± 0.323	4.148 ± 0.265	4.296 ± 0.134
Vss (L/kg)	4.118 ± 0.395	4.457 ± 0.065	2.878 ± 0.970*
AUC0→∞ (h · μg/mL)	1.158 ± 0.087	1.136 ± 0.071	1.095 ± 0.034
MRT (h)	1.016 ± 0.145	1.078 ± 0.081	0.674 ± 0.244*

Note: Each value represents the mean ± standard deviation (n = 3).

Abbreviations: AUC_0–∞, area under the plasma concentration–time curve from time zero to infinity; Cl, clearance; MRT, mean residence time; t_1/2α, half-life of the distribution phase; t_1/2β, half-life of the elimination phase; Vss, volume of distribution at steady state.

Figure 4 Tissue distribution of 3-Chloro-4-[(4-methoxyphenyl)amino]furo[2,3-b]quinoline (PK-L4) concentrations from a control PK-L4 solution and one loaded into solid lipid nanoparticles (SLNs) with or without polyethylene glycol (PEG) after intravenous administration to Wistar rats at a dose of 4.7 mg/kg for 30 minutes.

Notes: Each value represents the mean and SD (n = 3). *P < 0.05 as compared with the data of the PK-L4 control solution.