Organic effects of associating paclitaxel with a lipid-based nanoparticle system on a nonhuman primate, Cebus apella

Figures & data

Figure 1 Design of the LDE particle, demonstrating its structure composed by nucleus made of cholesterol esters encapsulated by a monolayer of phospholipids and free cholesterol.

Abbreviation: LDE, cholesterol-rich nanoemulsion.

Figure 2 Tissue biodistribution of LDE in Cebus apella, as represented by tissue capture of intravenously injected [³H]-cholesterol ether after 24 hours. The figure shows the evaluation of the radioactivity measured in percentage, and the data are expressed in columns as mean and in bars as standard deviation.

Abbreviations: CPM, counts per minute; LDE, cholesterol-rich nanoemulsion.

Figure 3 Curve of kinetic decay in plasmatic [³H]-free cholesterol from LDE in Cebus apella. Points represent mean values and bars represent standard deviation.

Abbreviation: LDE, cholesterol-rich nanoemulsion.

Table 1 Average values and SDs obtained in analysis of hematological parameters

Hematological parameters	NC	LDE-PTX175 (175 mg/m^2)	LDE-PTX250 (250 mg/m^2)	PTX175 (175 mg/m^2)	PTX250 (250 mg/m^2)
	Average ± SD	Average ± SD	Average ± SD	Average ± SD	Average ± SD
Hematocrit (%)	42.72±1.69	43.80±2.05	42.80±3.11	38.96±2.26a	41.21±0.49
Red blood cells (×10^6 mm^3)	5.89±0.38	5.75±0.24	5.66±0.35	5.19±0.23a	5.57±0
Hemoglobin (G/DI)	14.2±0	14.46±0.28	14.18±1.06	12.45±0.21b	13.28±0.35
MCH (μg)	24.4±1.69	25.12±0.49	24.98±0.28	24.13±1.62b	23.75±0.70b
RDW	11.2±0.21	11.34±0.91	11.50±1.12	13.38±1.06c	13±1.62c
Leukocytes	7.91±4.22	5.26±1.26d	4.99±1.73d	5.12±3.14	5.45±1.56b
Basophils (%)	0.63±0.13	1.85±2.01d	1.17±1.96	1.28±0.70	1.55±2.26
Neutrophils (%)	57.62±0.84	36.69±8.34d	40.24±9.54d	57.39±17.39b	45.66±20.01
Lymphocytes (%)	30.07±0.07	56±7.28e	54.84±4.45e	36.32±14.56	40.36±13.08
Monocytes (%)	6.66±0.96	5.12±1.08	3.43±3.31	8.40±2.12c	11.52±4.78c
Platelets (×10^3/mm^3)	238.75±91.21	218.72±61.51a	200.93±21.21	224.83±7.77a	275.5±26.16b
MPV (fL)	13.4±0.28	12.32±0.56	12.36±0.77	14.56±0.77f	11.70±0.91

Notes:

a P<0.05 in relation to group LDE-PTX175;

b P<0.05 in relation to groups PTX175 and LDE-PTX250;

c P<0.05 in relation to negative control group and groups LDE-PTX175, and LDE-PTX250;

d P<0.05 in relation to negative control group;

e P<0.05 in relation to negative control group and groups PTX175, and PTX250;

f P<0.05 in relation to groups PTX250, LDE-PTX175, and LDE-PTX250.

Abbreviations: SD, standard deviation; NC, negative control; LDE, cholesterol-rich nanoemulsion; PTX, paclitaxel; MCH, mean corpuscular hemoglobin; RDW, red cell distribution width; MPV, mean platelet volume; g/dL, grams per deciliter.

Table 2 Average values and SDs obtained in analysis of biochemical parameters

Biochemical parameters	NC	LDE-PTX175 (175 mg/m^2)	LDE-PTX250 (250 mg/m^2)	PTX175 (175 mg/m^2)	PTX250 (250 mg/m^2)
	Average ± SD	Average ± SD	Average ± SD	Average ± SD	Average ± SD
Urea (mg/dL)	26.66±16.23	32.61±9.89a	19.94±2.50b	21.25±5.25	28.33±11.31
Glucose	66.66±17.67	63.22±19.79	74.88±35.35c	86.41±45.25c	106.58±83.43d
Cholesterol	113.00±28.99	181.25±23.33	203.08±18.38e	166.91±76.36	152.75±1.41
HDL-C	59.66±5.65	91.30±1.41e	92.25±21.92e	65.66±19.79	75.08±0.70
Triglycerides	58.66±40.30	58.69±7.77	67.27±1.41	77.00±34.64	104.83±40.30f
AST (U/L)	20.32±9.71	18.66±8.65	18.00±8.58	11.41±3.20g	14.17±3.95
ALT (U/L)	14.33±8.02	11.16±8.13	12.56±7.71	6.75±1.76g	6.08±0.29g
GGT (U/L)	38.67±20.55	56.50±26.17	51.47±28.54	32.08±8.67h	67.83±10.59c
Lipase	22.67±11.15	17.69±3.12	19.28±5.09	14.50±4.40i	13.17±3.86g
Alkaline phosphatase	199.33±121.33	277.74±96.85	141.64±53.54j	243.75±98.75	241.67±60.91

Notes:

a P<0.05 in relation to groups LDE-PTX250 and PTX175;

b P<0.05 in relation to group PTX250;

c P<0.05 in relation to group LDE-PTX175;

d P<0.05 in relation to groups LDE-PTX175, LDE-PTX250, and PTX175;

e P<0.05 in relation to group NC;

f P<0.05 in relation to groups LDE-PTX175 and LDE-PTX250;

g P<0.05 in relation to groups NC, LDE-PTX175, and LDE-PTX250;

h P<0.05 in relation to all other groups;

i P<0.05 in relation to groups NC and LDE-PTX250;

j P<0.05 in relation to groups LDE-PTX175, PTX175, and PTX250.

Abbreviations: SD, standard deviation; NC, negative control; LDE, cholesterol-rich nanoemulsion; PTX, paclitaxel; HDL-C, high-density lipoprotein cholesterol; AST, aspartate aminotransferase; ALT, aspartate aminotransferase; GGT, gamma-glutamyl transferase.

Figure 4 Results of histopathological analysis of the stomach. (A) NC – normal mucosa showing mucoid cells, parietal and chief, and scattered vascular congestion. (B) LDE-PTX175 – normal mucosa showing mucoid cells, parietal and chief, and scattered vascular congestion. (C) LDE-PTX250 – normal mucosa showing mucoid cells, parietal and chief, presenting pervasion by some inflammatory mononuclear cells. (D) LDE-PTX250 – presence of intense vascular congestion in the submucosa. Magnification is 400×, and scale bar represents 50 μm.

Abbreviations: NC, negative control; LDE, cholesterol-rich nanoemulsion; PTX, paclitaxel.

Figure 5 Results of histopathological analysis of the liver. (A) NC – cordons of preserved hepatocytes, seen in the portal space and centrilobular vein, and scattered microvesicular steatosis. (B) LDE-PTX175 – cordons of preserved hepatocytes, view of de portal space and centrilobular vein, and sinusoidal hemorrhage. (C) LDE-PTX250 – disorganization of hepatocyte cordons, hydropic and ballooning degeneration of hepatocytes, and inflammatory foci. Magnification is 400×, and scale bar represents 50 μm.

Abbreviations: NC, negative control; LDE, cholesterol-rich nanoemulsion; PTX, paclitaxel.

Figure 6 Results of histopathological analysis of the kidney. (A) NC – preserved glomerulus, unaltered proximal and distal tubules, and glomerular and interstitial hemorrhage. (B) LDE-PTX175 – preserved glomerulus, unaltered proximal and distal tubules, and glomerular and interstitial hemorrhage. (C) LDE-PTX250 – preserved glomerulus, proximal and distal tubes with cellular tumefaction, and glomerular and interstitial hemorrhage, several exhibiting cylinder hyaline. Magnification is 400×, and scale bar represents 50 μm.

Abbreviations: NC, negative control; LDE, cholesterol-rich nanoemulsion; PTX, paclitaxel.