Effects of Surface Characteristics of Polymeric Nanocapsules on the Pharmacokinetics and Efficacy of Antimalarial Quinine

Figures & data

Table 1 Physico-Chemical Characterization of Unloaded and Quinine-Loaded Polymeric Nanocapsules and Nanospheres

Parameter	NCP80	UNCP80	NSP80	UNSP80	NCEUD	UNCEUD	NSEUD	UNSEUD
Diameter (nm) ± SD	180 ± 0.4^c	184 ± 1.0	200 ± 29.0	201 ± 23.0	141 ± 2.0 ^c	146 ± 0.4	138 ± 3.8	148 ± 5.5
pH ± SD	7.5 ± 0.04^c	6.4 ± 0.01	7.2 ± 0.02	6.8 ± 0.03	8.3 ± 0.02 ^c	7.1 ± 0.13	8.4 ± 0.01	7.7 ± 0.02
Zeta potential (mV) ± SD	−33.1 ± 0.7^a,c	−30.5 ± 1	−25.5 ± 1^a	−20 ± 0.3	4.61 ± 1^b,c	14.1 ± 0.9	2.86 ± 0.3^b	2.84 ± 0.6
Drug content (%) ± SD	101.7± 1.6^a	–	81.5 ± 4.9^a		102.9 ± 1.1 ^b	–	89.5 ± 4.9^b
EE (%) ± SD	81.0 ± 0.8^a,c	–	72.4 ± 3^a		71.4± 0.2 ^bc	–	41.6 ± 3^b

Notes: ^aSignificant difference between NCP80 and NSP80; ^bSignificant difference between NCEUD and NSEUD; ^cSignificant difference between NCP80 and NCEUD (p > 0.05, ANOVA).

Abbreviations: SD, standard deviation (n = 3); NC, nanocapsules; NS, nanospheres; U, unloaded nanoparticles; P80, P80-coated nanoparticles prepared with PCL; EUD, nanoparticles Prepared with EUD.

Table 2 Mathematical Modeling of QN Photodegradation Profiles

Sample	Reaction Order	R	MSC	K (h^−1)	T1/2 (h) ± SD	Photodegradation (%) ± SD
Free QN	Bioexponential	0.9822	3.2	0.00037	1754 ± 37	27.1± 0.2
NCP80	Zero	0.9830	4.3	0.0002	2413±13^a,b,d	9.9 ± 0.4^a,b,d
NSP80	Bioexponential	0.9834	4.1	0.002	299 ± 13^a,b	12.4±0.9^a,b
NCEUD	Zero	0.9940	4.7	0.0001	3450 ± 16^a,d	13.3 ± 0.6^a,c,d
NSEUD	Monoexponential	0.9968	4.0	0.002	343 ± 22^a	15.7±0.6^a,c

Notes: ^aSignificant difference of free QN; ^bSignificant difference between NCP80 and NSP80; ^cSignificant difference between NCEUD and NSEUD; ^dSignificant difference between NCP80 and NCEUD (p > 0.05, ANOVA).

Abbreviations: SD, standard deviation (n = 3); R, correlation coefficient; MSC, model selection criteria; K, constant for the reaction speed; T_1/2, half-life time degradation.

Figure 1 Images obtained by the AFM for NCP80 (A), UNCP80 (B), NCEUD (C), and UNCEUD (D).

Table 3 QN Pharmacokinetic Parameters in Plasma After 20 mg/kg i.v. Bolus Dosing to Plasmodium berghei-Infected Rats

PK Parameters	Non-Compartmental			Two-Compartmental Model
	Free (n=5)	NCP80 (n=4)	NCEUD (n=6)	Free (n=5)	NCP80 (n=4)	NCEUD (n=6)
AUC0–t (µg.h/mL)	32.4 ± 5.0	55.9 ± 41.1	58.8 ± 21.0	-	-	-
AUC0–∞(µg.h/mL)	33.8 ± 4.8	61.1 ± 41.2	59.8 ± 22.2	32.13	30.54	55.13
AUMC0–t (µg.h^2/mL)	67.7 ± 12.5	156.4 ± 65.7^a	73.6 ± 41.3	-	-	-
CLTot (L/h)	0.09 ± 0.01	0.08 ± 0.05	0.06 ± 0.02	0.09	0.10	0.06
t½ (h)	1.68 ± 0.33	16.14 ± 13.21^a	7.11 ± 3.90^a	1.76	10.06	4.87
Ke (h^−1) or β (h^−1)	0.43 ± 0.09	0.07 ± 0.04^a,b	0.14 ± 0.10^a,b	0.39	0.06	0.14
MRT (h^−1)	2.10 ± 0.47	6.20 ± 2.46^a,b	1.48 ± 0.62^b	-	-	-
Vdss (mL/kg)	0.198 ± 0.070	0.570 ± 0.418^a,b	0.077 ± 0.011^a,b	0.183	0.502	0.06

Notes: ^aSignificant difference of free QN; ^bSignificant difference between NCP80 and NCEUD (p <0.05, ANOVA).

Abbreviations: Ke, elimination rate constant; t_1/2, half-life; AUC_0–∞, area under the curve; MRT, mean residence time; CL_total, total plasma clearance; Vd_ss, volume of distribution at steady state.

Figure 2 (A) POP pk fit mean (± standard deviation) plasma–time profiles of free quinine, NCP80, and NCEUD after a single 20 mg/kg intravenous dose in Wistar rats infected with P. berghei. (B) Visual predictive check.

Table 4 Parameter Estimates of the Final Quinine Population Pharmacokinetic Model

Parameter	Estimate	RSE (%)	Interindividual Variability	RSE (%)
V1 (L)	0.611	18.4	0.268	30.6
β_V1_CATNCEUD	-1.29	18	NA	NA
CL (L/h)	0.453	9.01	0.330	20.7
Q pop	1.98	44.1	0.751	20.4
β_Q_CATNCP80	-1.71	32.3	NA	NA
β_Q_CATNCEUD	-3.59	15.5	NA	NA
V2 pop	0.956	42	0.965	19.3
β_V2_NCP80	1.91	32.3	NA	NA
K12_pop (h^−1) *	3.24
K12_NCP80 (h^−1)	0.58
K12_NCEUD (h^−1)	0.324
K21_pop (h^−1) *	2.07
K21_NCP80 (h^−1)	0.055
K21_NCEUD (h^−1)	0.056
Residual variability
Proportional model	0.39	6.08
log-likelihood estimate	692.98
AIC	728.98

Abbreviations: NA, not applicable; RSE, relative standard error (standard error of estimate/estimate × 100); V1, central volume compartment; V2, peripheral compartment volume; Q, intercompartmental clearance.

Table 5 Efficacy of Different Treatments in Swiss Mice Experimentally Infected with Plasmodium Berghei

Groups	Survival (Days)		Parasitemia (%)		Supression (%)
	Mean	SD	Mean	SD
Saline	10.3	1.0^c,d	5.7	2.0^d	–
Free QN	13.0	1.8^a,c,d	3.5	0.3^d	41
NCP80	13.8	1.1^a,d	4.5	2.8^d	46
UNCP80	8.7	3.4^d	6.2	3.6^d	19
NCEUD	19.5	1.9^a,b,c	2.9	0.2^a,c	59
UNCEUD	11.7	3.0^d	5.1	2.1^d	26
Chloroquine	19.7	1.6^a,c	0.4	0.5^a,c	88

Notes: ^aSignificant difference versus saline; ^bSignificant difference of free QN; ^cSignificant difference between NCP80 and NCEUD (p <0.05, ANOVA); ^dSignificant difference versus chloroquine.

Abbreviation: SD, standard deviation (n = 6).

Figure 3 Profile of Parasitemia for evaluation of the antimalarial efficacy of the groups in P. berghei-infected Wistar rats (n = 6 per group).