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Synthetic polymers are characterised by RMN-1H in CDCl3 and Gel Permeation
Chromatography (GPC) in THF/NEt3. Conversion rates are between 88,5% and 94%.
Polydispersities are between 1,3 and 1,46. These results prove the well-controlled ROP.
The on-going step is the synthesis of the fourth part of the polymer – “clickable” group for
fixing muscular cell targeting agents.
Conclusions
Synthesis of aliphatic polycarbonate for transport of
AO’s and targeted delivery in gene therapy
A. Baronia,b, J. Diricqa, P. Duboisa, L. Mespouillea, B. Blankertb
aLaboratory of Polymeric and Composite Materials (LPCM), Center of Innovation and Research in Materials and Polymers (CIRMAP)
bLaboratory of Pharmaceutical Analysis, Research Institute for Health and Science Technology
University of Mons (UMONS), 23 Place du Parc, 7000 Mons Belgium
Gene therapy has attracted increasing attention worldwide as prominent strategy to treat diseases at the gene level. The use of antisense oligomers (AO’s) therapeutics is a promising
therapeutic strategy to treat neuromuscular disorder as FSHD (Facio-Scapulo-Humeral muscular Distrophy). While these therapeutics hold high promises, the administration of
oligonucleotides as a drug is very challenging because of their rapid clearance from the bloodstream and the lack of tissue selectivity. Synthetic polymers have attracted attention in
the field of gene therapy owing to the ease of synthesis and modification, allowing the design of polymer vectors safer than viral ones and presenting some advantageous
characteristics enabling overcoming obstacles met in gene therapy.
Herein, the use of tailor-made aliphatic poly(carbonate)s (APCs) synthetized by ring-opening polymerization (ROP) using a metal-free and non-toxic catalyst1 is reported. This family of
polymers is biocompatible and biodegradable2,3 which is really advantageous compared to the highly toxic golden standard poly(ethylenimine) (PEI)4. In a preliminary study5, the
presence of hydrophobic tail of polytrimethylene carbonate (PTMC) as well as the introduction of guanidinum and morpholino groups in the composition of the polymer vector led to
powerful carrier for siRNA delivery. In order to promote cell targeting to muscle cells, introduction of efficient click coupling functionality will be investigated in next vector generation.
Finally the cytotoxicity and the efficacy of the vector will be evaluated. First results and work plan are presented.
INTRODUCTION
REFERENCES
1A. Nachtergael et al., Biomacromolecules, 2015, accepted, DOI 10.1021/bm5015443
2 S. Tempelaar et al. Chem. Soc. Rev., 2013, 42, 1312-1336
3 L. Mespouille et al. Prog.
4 J. Zhou et al. Nature Mater. 2012, 11, 82
5 A. Frere et al., Biomacromolecules, 2015, accepted, DOI 10.1021/bm501676
Synthetic Polymer Vector
It is an Aliphatic PolyCarbonate
• Safe: non immunogenic response nor mutation
• No leaking of their content
• Biocompatible
• Low toxicity
• Biodegradable
• Functional
WHYis it a good one
by Ring Opening Polymerization
Controlled Mn, Ɖ, topology – mild conditions
Using a Green Catalyst
DBU
HOWis it synthetized
NEEDTo reach the target!
Synthesisof
• Functional cyclic monomers
• Based on commercially available BIS-MPA
Biological challenges
1
2
3
4
5
1 Good gene loading and serum stability
2 Cell targeting (a) and cellular uptake (b)
3 Cytoplasmic mobility
4 Endosomal escape
5 Unpacking
The polymer’s …
…Charge density
… Molecular weight
… Architecture
… Hydrophilic-lipophilic balance
… Amount and type of amine groups
Trimethylene carbonate (TMC)
Hydrophobic tail for 2b
Synthesis conditions
[M]/[C]/[I] = 32 / 0,01 / 1
Ambient – 8 hours – CH2Cl2
Guanidinium carbonate (MTC-G)
Polycation for
Synthesis conditions
[M]/[C]/[I] = 20 / 1 / 1
Ambient – 3 hours - CH2Cl2
1
Morpholino carbonate (MTC-Mo)
Buffer segment for
Synthesis conditions
[M]/[C]/[I] = 20 / 1 / 1
Ambient – 3 hours - CH2Cl2
4
Chemicalsolutions(preliminaryresults)
Time-line
Synthesis and
characterization of
polymer nanoparticles
loaded with AO
(LPCM – L. Mespouille)
Biological
investigations
(Lab. of Pharma. Analysis – B. Blankert)
Nanoparticles
decoration with muscle-
specific ligands
(LPCM – Lab. of Pharma. Analysis)
Oct. 2014
Oct. 2018
- Monomers, copolymers
vector, polyplexes
synthesis and
degradation in various
buffer aqueous solution
- Cytotoxicity on human
myoblast
- AO complexation and
nanoformulation
- AO release in various media
(analytical method
development)
- Transfection efficiency and
silencing investigation
- Click linking of targeting
agents onto
nanoparticles
- Evaluation of targeting
efficiency toward specific
muscular cell line
- Cytotoxic studies of
ligand-decorated NPs
- Transfection efficiency
and silencing
investigation of I would like to thanks the Molecular Biology department of UMONS, more particularly A.
Belayew, for giving me the opportunity to have this enriching subject. Also, it was a
pleasure to work with J. Diricq and his results are fundamentals for this work.
A. Baroni is a FNRS Research Fellow
A. Baroni and J. Diricq are grateful to the ABMM for their financial support
Acknowledgement
Clickable group for
On-going research
Planed click reactions for
fixing targeting agents
2a
Synthesis of P[TMC32-b-G9-b-Mo8,5]
triblock copolymer
by ROP using DBU as catalyst in CDCl3 at room r.t.
Macro-initiator P[TMC]32 -OH
DPGUAN 8
DPMORPH 8,5
𝑀 𝑛( 𝑁𝑀𝑅
a
)
9.700 g.mol-1
𝑀 𝑛( 𝐺𝑃𝐶
𝑏
)
5.700 g.mol-1
𝑀 𝑤( 𝐺𝑃𝐶
𝑏
)
7.900 g.mol-1
Ɖ 1,4
a 1H-NMR 500 MHz in CDCl3
b GPC in THF/NEt3 at r.t.

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2015 mdc poster rev02_a baroni

  • 1. Synthetic polymers are characterised by RMN-1H in CDCl3 and Gel Permeation Chromatography (GPC) in THF/NEt3. Conversion rates are between 88,5% and 94%. Polydispersities are between 1,3 and 1,46. These results prove the well-controlled ROP. The on-going step is the synthesis of the fourth part of the polymer – “clickable” group for fixing muscular cell targeting agents. Conclusions Synthesis of aliphatic polycarbonate for transport of AO’s and targeted delivery in gene therapy A. Baronia,b, J. Diricqa, P. Duboisa, L. Mespouillea, B. Blankertb aLaboratory of Polymeric and Composite Materials (LPCM), Center of Innovation and Research in Materials and Polymers (CIRMAP) bLaboratory of Pharmaceutical Analysis, Research Institute for Health and Science Technology University of Mons (UMONS), 23 Place du Parc, 7000 Mons Belgium Gene therapy has attracted increasing attention worldwide as prominent strategy to treat diseases at the gene level. The use of antisense oligomers (AO’s) therapeutics is a promising therapeutic strategy to treat neuromuscular disorder as FSHD (Facio-Scapulo-Humeral muscular Distrophy). While these therapeutics hold high promises, the administration of oligonucleotides as a drug is very challenging because of their rapid clearance from the bloodstream and the lack of tissue selectivity. Synthetic polymers have attracted attention in the field of gene therapy owing to the ease of synthesis and modification, allowing the design of polymer vectors safer than viral ones and presenting some advantageous characteristics enabling overcoming obstacles met in gene therapy. Herein, the use of tailor-made aliphatic poly(carbonate)s (APCs) synthetized by ring-opening polymerization (ROP) using a metal-free and non-toxic catalyst1 is reported. This family of polymers is biocompatible and biodegradable2,3 which is really advantageous compared to the highly toxic golden standard poly(ethylenimine) (PEI)4. In a preliminary study5, the presence of hydrophobic tail of polytrimethylene carbonate (PTMC) as well as the introduction of guanidinum and morpholino groups in the composition of the polymer vector led to powerful carrier for siRNA delivery. In order to promote cell targeting to muscle cells, introduction of efficient click coupling functionality will be investigated in next vector generation. Finally the cytotoxicity and the efficacy of the vector will be evaluated. First results and work plan are presented. INTRODUCTION REFERENCES 1A. Nachtergael et al., Biomacromolecules, 2015, accepted, DOI 10.1021/bm5015443 2 S. Tempelaar et al. Chem. Soc. Rev., 2013, 42, 1312-1336 3 L. Mespouille et al. Prog. 4 J. Zhou et al. Nature Mater. 2012, 11, 82 5 A. Frere et al., Biomacromolecules, 2015, accepted, DOI 10.1021/bm501676 Synthetic Polymer Vector It is an Aliphatic PolyCarbonate • Safe: non immunogenic response nor mutation • No leaking of their content • Biocompatible • Low toxicity • Biodegradable • Functional WHYis it a good one by Ring Opening Polymerization Controlled Mn, Ɖ, topology – mild conditions Using a Green Catalyst DBU HOWis it synthetized NEEDTo reach the target! Synthesisof • Functional cyclic monomers • Based on commercially available BIS-MPA Biological challenges 1 2 3 4 5 1 Good gene loading and serum stability 2 Cell targeting (a) and cellular uptake (b) 3 Cytoplasmic mobility 4 Endosomal escape 5 Unpacking The polymer’s … …Charge density … Molecular weight … Architecture … Hydrophilic-lipophilic balance … Amount and type of amine groups Trimethylene carbonate (TMC) Hydrophobic tail for 2b Synthesis conditions [M]/[C]/[I] = 32 / 0,01 / 1 Ambient – 8 hours – CH2Cl2 Guanidinium carbonate (MTC-G) Polycation for Synthesis conditions [M]/[C]/[I] = 20 / 1 / 1 Ambient – 3 hours - CH2Cl2 1 Morpholino carbonate (MTC-Mo) Buffer segment for Synthesis conditions [M]/[C]/[I] = 20 / 1 / 1 Ambient – 3 hours - CH2Cl2 4 Chemicalsolutions(preliminaryresults) Time-line Synthesis and characterization of polymer nanoparticles loaded with AO (LPCM – L. Mespouille) Biological investigations (Lab. of Pharma. Analysis – B. Blankert) Nanoparticles decoration with muscle- specific ligands (LPCM – Lab. of Pharma. Analysis) Oct. 2014 Oct. 2018 - Monomers, copolymers vector, polyplexes synthesis and degradation in various buffer aqueous solution - Cytotoxicity on human myoblast - AO complexation and nanoformulation - AO release in various media (analytical method development) - Transfection efficiency and silencing investigation - Click linking of targeting agents onto nanoparticles - Evaluation of targeting efficiency toward specific muscular cell line - Cytotoxic studies of ligand-decorated NPs - Transfection efficiency and silencing investigation of I would like to thanks the Molecular Biology department of UMONS, more particularly A. Belayew, for giving me the opportunity to have this enriching subject. Also, it was a pleasure to work with J. Diricq and his results are fundamentals for this work. A. Baroni is a FNRS Research Fellow A. Baroni and J. Diricq are grateful to the ABMM for their financial support Acknowledgement Clickable group for On-going research Planed click reactions for fixing targeting agents 2a Synthesis of P[TMC32-b-G9-b-Mo8,5] triblock copolymer by ROP using DBU as catalyst in CDCl3 at room r.t. Macro-initiator P[TMC]32 -OH DPGUAN 8 DPMORPH 8,5 𝑀 𝑛( 𝑁𝑀𝑅 a ) 9.700 g.mol-1 𝑀 𝑛( 𝐺𝑃𝐶 𝑏 ) 5.700 g.mol-1 𝑀 𝑤( 𝐺𝑃𝐶 𝑏 ) 7.900 g.mol-1 Ɖ 1,4 a 1H-NMR 500 MHz in CDCl3 b GPC in THF/NEt3 at r.t.