Controlled release of 5-fluorouracil and progesterone from magnetic nanoaggregates

Figures & data

Table 1 Entrapment efficiencies of 5-fluorouracil as a function of different initial drug concentrations and nanoaggregates’ average diameters

Concentration of pluronic F-68	Particle average diameter (nm ± RSD)	Initial drug concentration (mg drug/mg nanoparticles)	Drug loading (%)	Drug entrapment efficiency (%)
				In-situ loading	Freeze-drying loading
0.5	293 ± 14.65	30	10	82.65	83.25
1.0	207 ± 10.35	25	9.5	50.66	63.14
1.5	146 ± 7.30	20	9	48.25	56.90
2	124 ± 6.20	10	5	23.69	31.56
2.5	98.70 ± 4.93	20	3	16.11	19.12
3.0	90.20 ± 4.51	20	2	32.01	46.22

Abbreviation: RSD, relative standard deviation.

Figure 1 Scanning electron micrograph (SEM) images for different magnetic nanoaggregate formulations. Effect of polymeric composition on morphology of nanoaggregates: (A) 0.5 mmol block copolymer and 0 wt% beta-cyclodextrin; (B) 3 mmol block copolymer and 0 wt% beta-cyclodextrin; (C) 3 mmol block copolymer and 5 wt% beta-cyclodextrin; and (D) 3 mmol block copolymer and 25 wt% beta-cyclodextrin.

Figure 2 Effect of block copolymer concentrations on the average primary and aggregated particle diameters.

Figure 3 X-ray diffraction profiles of magnetic nanoaggregates as a function of block copolymer concentration. (A) 0.5 mmol; and (B) 3 mmol of block copolymer (Pluronic F-68).

Abbreviation: CPS, counts per second.

Figure 4 FTIR spectrum of uncoated magnetic nanoaggregates.

Abbreviation: FTIR, fourier transform infrared spectroscopy.

Figure 5 FTIR spectra of different polymer coated magnetic nanoaggregates.

Abbreviation: %T, % Transmittance.

Figure 6 Room temperature (300 K) magnetization curves of magnetic nanoaggregates prepared with 3 mmol of block copolymer and 5 wt% beta-cyclodextrin compared to magnetic nanoparticles prepared by conventional method.

Abbreviation: emu, electro-magnetic unit.

Table 2 Estimated Peppas parameters as a function of drug loading percentages and loading techniques

Drug loading	In-situ drug loading			Freeze-drying drug loading
	Release rate constant (K, day^−1)	Regression coefficient (R^2)	Release index (n)	Release rate constant (K, day^−1)	Regression coefficient (R^2)	Release index (n)
2% 5-FU	58.75 ± 4.32	0.87	0.23 ± 0.03	66.22 ± 2.94	0.91	0.18 ± 0.02
3% 5-FU	56.78 ± 3.80	0.88	0.22 ± 0.03	67.39 ± 1.55	0.95	0.14 ± 0.01
5% 5-FU	64.08 ± 1.93	0.92	0.14 ± 0.01	94.73 ± 1.55	0.96	0.15 ± 0.02

Abbreviation: 5-FU, 5-fluorouracil.

Figure 7 Drug release profiles of 5-fluorouracil nanoaggregates prepared by in situ loading method.

Figure 8 Effect of beta-cyclodextrin mass fraction on the release of progesterone samples loaded by freeze-drying.

Figure 9 Mathematical modeling of 5-fluorouracil release from 146 nm magnetic nanoaggregates.

Figure 10 Mathematical modeling of 5-fluorouracil release from 293 nm magnetic nanoaggregates.

Scheme 1 Chemical structures of beta-cyclodextrin, polypropylene oxide/polypropylene oxide block copolymer (Pluronic F-68, HO (C₂H₄O)_n(C₃H₆O)_m(C₂H₄O)_n OH, m = 80 and n = 27) and the two encapsulated drugs: progesterone and 5-fluorouracil.

Table 3 Release parameters for mathematical modeling of progesterone-loaded magnetic nanoaggregates

Mass fraction of Beta-cyclodextrin	Peppas model			Modified Peppas model with initial burst effect
	Regression coefficient (R^2)	Release index (n)	Regression coefficient (R^2)	Initial release parameter (b)
5% Beta-cyclodextrin	0.83	0.07 ± 0.02	0.86	19.99 ± 0.63
25% Beta-cyclodextrin	0.69	0.03 ± 0.01	0.91	22.53 ± 0.31

Figure S1 Drug release profiles of 5-fluorouracil-loaded nanoaggregates prepared by in-situ loading method.

Figure S2 Effect of particle size and loading procedures on the release profile of 5-fluorouracil-loaded nanoaggregates at constant percentage of drug loading.

Figure S3 Modified Peppas model equation for prediction of initial burst effect of progesterone-loaded nanoaggregates prepared at 0% beta-cyclodextrin.

Figure S4 Modified Peppas model equation for prediction of initial burst effect of progesterone-loaded nanoaggregates sample prepared at (A) 0%; and (B) 25% beta-cyclodextrin.

Figure S5 Effect of drug loading percentages on the viability of cancerous cells.

Figure S6 Effect of drug loading technique on viability of lung cancer cells.

Abbreviation: 5-FU, 5-fluorouracil.

Table S1 Mathematical models describing release rates of 5-fluorouracil and progesterone from the hollow nanoaggregates^14–16

Model	Equation
Zero order	$C=K_{0}t$
First order	$Log\hspace{0.17em}C=Log\hspace{0.17em}{C}_0-Kt/2.303$
Hixson-Crowell	$Q_0^{1/3}-Q_t^{1/3}=Kt$
Higuchi	$Q={Kt}^{0.5}$
Peppas	$Q={kt}^n$
Modified Peppas	$Q={at}^n+b$
Weibull	$Q=1-\text{exp}(-a{t}^b)$
Lonsdale and Baker	$\frac{2}{3}\left(1-{\left\{1-\frac{Q}{100}\right\}}^{\frac{2}{3}}\right)-\left\{\frac{Q}{100}\right\}=Kt$

Notes: where C is the concentration of drug released, C₀ is the initial concentration of drug, K is the release rate constant in units of concentration/time, Q is the amount of drug released in time t, Q₀ is the initial amount of drug loaded into the nanoaggregates, and the release index is symbolized as n.

Table S2 Effect of drug loading on the estimated release rates and release indices according to Peppas model equation

Drug loading	Release rate constant (K, day^−1)	Regression coefficient (R^2)	Release index (n)
9% 5-fluorouracil	40.43 ± 0.47	0.97	0.075 ± 0.005
9.5% 5-fluorouracil	35.29 ± 0.39	0.92	0.069 ± 0.002
10% 5-fluorouracil	32.76 ± 0.32	0.98	0.071 ± 0.004

Note: The samples are all loaded by the in-situ method.

Table S3 Effect of beta-cyclodextrin mass fraction on the release parameters of progesterone and 5-fluorouracil freeze-dried loaded samples

Drug loading	Release rate constant (K, day^−1)	Regression coefficient (R^2)	Release index (n)
Progesterone, 0% beta-cyclodextrin	64.08 ± 0.14	0.92	0.14 ± 0.01
Progesterone, 5% beta-cyclodextrin	67.67 ± 1.72	0.83	0.07 ± 0.01
Progesterone, 15% beta-cyclodextrin	65.94 ± 0.05	0.78	0.05 ± 0.01
Progesterone, 25% beta-cyclodextrin	61.76 ± 1.42	0.70	0.03 ± 0.01
5-Fluorouracil, 0% beta-cyclodextrin	66.22 ± 2.94	0.91	0.18 ± 0.02
5-Fluorouracil, 5% beta-cyclodextrin	44.29 ± 1.81	0.93	0.19 ± 0.02
5-Fluorouracil, 15% beta-cyclodextrin	39.13 ± 1.34	0.95	0.21 ± 0.01
5-Fluorouracil, 25% beta-cyclodextrin	33.13 ± 1.18	0.94	0.17 ± 0.02

Table S4 Results for the curve fitting parameters of different model functions for 5-fluorouracil release profiles

Model function	% 5-FU loading	Release rate constant (K, day^−1)	Regression coefficient (R^2)	Release index (n)	Probability (P)
Lonsdale model	9% 5-FU	0.01 ± 0.002	0.01	–	0.003
Peppas model	9% 5-FU	40.43 ± 0.47	0.97	0.075 ± 0.005	<0.001
Hixson model	9% 5-FU	0.02 ± 0.004	0.03	–	<0.001
Higuchi model	9% 5-FU	16.82 ± 1.71	0.01	–	<0.001
First order model	9% 5-FU	0.08 ± 0.02	0.02	–	<0.001
Lonsdale model	9.5% 5-FU	0.004 ± 0.0001	0.79	–	<0.001
Peppas model	9.5% 5-FU	35.29 ± 0.39	0.92	0.069 ± 0.002	<0.001
Hixson model	9.5% 5-FU	0.02 ± 0.003	0.03	–	<0.001
Higuchi model	9.5% 5-FU	14.67 ± 1.42	0.09	–	<0.001
First order model	9.5% 5-FU	0.06 ± 0.01	0.02	–	<0.001
Lonsdale model	10% 5-FU	0.04 ± 0.01	0.01	–	0.004
Peppas model	10% 5-FU	32.76 ± 0.32	0.98	0.071 ± 0.004	<0.001
Hixson model	10% 5-FU	0.02 ± 0.002	0.03	–	<0.001
Higuchi model	10% 5-FU	13.48 ± 1.41	0.01	–	<0.001
First order model	10% 5-FU	0.06 ± 0.01	0.02	–	<0.001

Abbreviation: 5-FU, 5-Fluorouracil.

Controlled release of 5-fluorouracil and progesterone from magnetic nanoaggregates.

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