bimodal immunoradiotherapy polysaccharide-based … · bimodal immunoradiotherapy using...
Post on 09-Sep-2018
251 Views
Preview:
TRANSCRIPT
Bimodal immunoradiotherapy
using thermoresponsive
polysaccharide-based polymers:
Are they able to promote
immune system?
Lenka Loukotová (Ph.D. student)
Institute of Macromolecular Chemistry, Prague, Czech Republic
ChemotherapyRadiotherapy
Immunotherapy
Hormone Therapy
Stem Cell Transplant
Current types of cancer treatment
Surgery
ChemotherapyRadiotherapy
Immunotherapy
Hormone Therapy
Stem Cell Transplant
Current types of cancer treatment
Surgery
Immuno-radiotherapy
Treatment principle of immunoradiotherapy
• polymer forms a depot at the injection site - thermoresponsivity
• radiation kills tumor cells (including cells protecting tumor from immune
response)
• immunomodulator enhances following immune response against remaining
tumor cells and metastasis
Polymer drug design
20 °C 37 °C
– therapeutic radiation – yttrium-90(III)β– decay, T1/2 = 64.1 hDOTA = 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid
– thermoresponsivity – poly(2-isopropyl-2-oxazoline) graftsbiocompatibility, radioresistivity1
– immunomodulatory polysaccharidenon-specific immune activation, biodegradable
1 O. Sedlacek, P. Cernoch, J. Kucka, R. Konefal, P. Stepanek, M. Vetrik, T.P. Lodge, M. Hruby, Thermoresponsive polymers for nuclear medicine: Which polymer is the best?, Langmuir 32 (2016) 6115–6122.
β-Glucan from Auricularia auricula-judae
1. Synthesis- extraction of β-glucan from Auricula auricula-judae
- anticancer properties1
- grafting of β-glucan by polyoxazoline, chemical modification
- radiolabeling with yttrium-90(III)
Auriculaauricularia-judae
1 M. Zhaocheng, J. Wang, L. Zhang, Structure and chain conformation of β‐glucan isolated from Auricularia auricula‐judae, Biopolymers 89 (2008) 614–622.
β-Glucan-graft-POX
2. Physico-chemical characterization
- dynamic light scattering – cloud point temperature –tuned to be appropriate for the depot formation
- β-glucan-graft-polyoxazoline (Mn,graft = 2500 Da, maximum achievable grafting density),c = 1 mg/mL in PBS
T = ?
10 20 30 40
0
500
1000
1500
2000
2500
Rh
(nm
)
temperature (°C)
CPT
L. Loukotova et al., Thermoresponsive β-glucan-based polymers for bimodal immunoradiotherapy–Are they able to promote the immunesystem?, J. Control. Release 267 (2017) 78–91.
3. In vivo experiments - prior successful and promising in vitro experiments
(cellular uptake, oxidative burst of the leukocytes, production of TNF-α…)
Antitumor efficiency - C57BL/6N mice with murine lymphoma EL4- groups:1) Control
- no treatment
2) IMMUNO- β-glucan-graft-POX
1 mg/mouse
3) RADIO- POX with 90Y
0.7 mg/4 MBq/mouse
4) IMMUNORADIO- β-glucan-graft-POX with 90Y
1 mg/4 MBq/mouse
β-Glucan-graft-POX
L. Loukotova et al., Thermoresponsive β-glucan-based polymers for bimodal immunoradiotherapy–Are they able to promote the immunesystem?, J. Control. Release 267 (2017) 78–91.
3. In vivo experiments
Antitumor efficiency
0 15 30 45 60
0
20
40
60
80
100
su
rviv
ing
mic
e (
%)
days after application
control group
IMMUNO
RADIO
IMMUNORADIO
0 5 10 15 20
0
2
4
6
8
control group
IMMUNO
RADIO
IMMUNORADIO
Va
ve
rag
e (
mL
)
days after application
IMMUNO – β-glucan-graft-POXRADIO – POX with 90YIMMUNORADIO – β-glucan-graft-POX with 90Y
β-Glucan-graft-POX
L. Loukotova et al., Thermoresponsive β-glucan-based polymers for bimodal immunoradiotherapy–Are they able to promote the immunesystem?, J. Control. Release 267 (2017) 78–91.
Study design
– therapeutic radiation – yttrium-90(III)
– thermoresponsivity – polyoxazoline grafts
– immunomodulatory polysaccharide
1. Influence of various polysaccharides on the treatment success in vivo
2. Detailed study of the synergistic effect of both therapies
κ-Carrageenan from Kappaphycus alvarezii
1. Physico-chemical characterization
- dynamic light scattering – κ-carrageenan-graft-POX (Mn,graft = 1950 Da),c = 1 mg/mL
Kappaphycusalvarezii
κ-carrageenan
10 20 30 40 50 60
102
103
104
105
106
in 0.15 M NaCl
in PBS
De
rive
d C
ou
nt
Ra
te (
a.u
.)
Temperature (°C)
κ-Carrageenan-graft-POX
1. Physico-chemical characterization
- dynamic light scattering – κ-carrageenan-graft-POX (Mn,graft = 1950 Da),c = 1 mg/mL
gel solution
10 20 30 40 50 60
102
103
104
105
106
in 0.15 M NaCl
in PBS
De
rive
d C
ou
nt
Ra
te (
a.u
.)
Temperature (°C)
κ-Carrageenan-graft-POX
1. Physico-chemical characterization
- dynamic light scattering – κ-carrageenan-graft-POX (Mn,graft = 1950 Da),c = 1 mg/mL
gel solution above CPT
10 20 30 40 50 60
102
103
104
105
106
in 0.15 M NaCl
in PBS
De
rive
d C
ou
nt
Ra
te (
a.u
.)
Temperature (°C)
top related