Modular lipid nanoparticle platform technology for siRNA and lipophilic prodrug delivery

Roy van der Meel (Corresponding author), Sam Chen, Josh Zaifman, Jayesh A. Kulkarni, Xu Ran Sabrina Zhang, Ying K. Tam, Marcel B Bally, Raymond M. Schiffelers, Marco A. Ciufolini, Pieter R. Cullis, Yuen Yi C. Tam

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Successfully employing therapeutic nucleic acids, such as small interfering RNA (siRNA), requires chemical modifications or the use of nanocarrier technology to prevent their degradation and facilitate intracellular delivery. Lipid nanoparticles (LNP) are among the most advanced nanocarriers and have facilitated the first siRNA therapeutic's clinical translation and approval. One of LNPs' major advantages is their applicability as modular platform technology due to the interchangeable siRNA payload. In addition, drug derivatization approaches can be used to synthesize lipophilic small molecule prodrugs that stably incorporate in LNPs. This provides ample opportunities to develop combination therapies by co-encapsulating multiple therapeutic agents in a single formulation. Here, we describe how the modular LNP platform can be applied for combined gene silencing and chemotherapy to induce additive anti-cancer effects. We show that various lipophilic taxane prodrug derivatives and siRNA against the androgen receptor, a prostate cancer driver, can be efficiently and stably co-encapsulated in LNPs. In addition, we demonstrate that prodrug incorporation does not affect LNPs' gene silencing ability and that the combination therapy induces additive therapeutic effects in vitro. Using a double-radiolabeling approach, we quantitively determined the LNPs' and prodrugs' pharmacokinetic properties and biodistribution following systemic administration in tumor-bearing mice. Our results indicate that co-encapsulation of siRNA and lipophilic prodrugs into LNPs could be an attractive and straightforward approach for combination therapy development.
Originele taal-2Engels
Aantal pagina's20
TijdschriftbioRxiv
DOI's
StatusGepubliceerd - 16 jan 2020

Vingerafdruk

Prodrugs
Nanoparticles
Small Interfering RNA
Technology
Lipids
Gene Silencing
Therapeutics
Androgen Receptors
Therapeutic Uses
Nucleic Acids
Neoplasms
Prostatic Neoplasms
Pharmacokinetics
Drug Therapy
Pharmaceutical Preparations

Citeer dit

van der Meel, Roy ; Chen, Sam ; Zaifman, Josh ; Kulkarni, Jayesh A. ; Zhang, Xu Ran Sabrina ; Tam, Ying K. ; Bally, Marcel B ; Schiffelers, Raymond M. ; Ciufolini, Marco A. ; Cullis, Pieter R. ; Tam, Yuen Yi C. / Modular lipid nanoparticle platform technology for siRNA and lipophilic prodrug delivery. In: bioRxiv. 2020.
@article{6648cd9168ee42febf78d79361655701,
title = "Modular lipid nanoparticle platform technology for siRNA and lipophilic prodrug delivery",
abstract = "Successfully employing therapeutic nucleic acids, such as small interfering RNA (siRNA), requires chemical modifications or the use of nanocarrier technology to prevent their degradation and facilitate intracellular delivery. Lipid nanoparticles (LNP) are among the most advanced nanocarriers and have facilitated the first siRNA therapeutic's clinical translation and approval. One of LNPs' major advantages is their applicability as modular platform technology due to the interchangeable siRNA payload. In addition, drug derivatization approaches can be used to synthesize lipophilic small molecule prodrugs that stably incorporate in LNPs. This provides ample opportunities to develop combination therapies by co-encapsulating multiple therapeutic agents in a single formulation. Here, we describe how the modular LNP platform can be applied for combined gene silencing and chemotherapy to induce additive anti-cancer effects. We show that various lipophilic taxane prodrug derivatives and siRNA against the androgen receptor, a prostate cancer driver, can be efficiently and stably co-encapsulated in LNPs. In addition, we demonstrate that prodrug incorporation does not affect LNPs' gene silencing ability and that the combination therapy induces additive therapeutic effects in vitro. Using a double-radiolabeling approach, we quantitively determined the LNPs' and prodrugs' pharmacokinetic properties and biodistribution following systemic administration in tumor-bearing mice. Our results indicate that co-encapsulation of siRNA and lipophilic prodrugs into LNPs could be an attractive and straightforward approach for combination therapy development.",
author = "{van der Meel}, Roy and Sam Chen and Josh Zaifman and Kulkarni, {Jayesh A.} and Zhang, {Xu Ran Sabrina} and Tam, {Ying K.} and Bally, {Marcel B} and Schiffelers, {Raymond M.} and Ciufolini, {Marco A.} and Cullis, {Pieter R.} and Tam, {Yuen Yi C.}",
year = "2020",
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doi = "10.1101/2020.01.16.907394",
language = "English",
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van der Meel, R, Chen, S, Zaifman, J, Kulkarni, JA, Zhang, XRS, Tam, YK, Bally, MB, Schiffelers, RM, Ciufolini, MA, Cullis, PR & Tam, YYC 2020, 'Modular lipid nanoparticle platform technology for siRNA and lipophilic prodrug delivery', bioRxiv. https://doi.org/10.1101/2020.01.16.907394

Modular lipid nanoparticle platform technology for siRNA and lipophilic prodrug delivery. / van der Meel, Roy (Corresponding author); Chen, Sam; Zaifman, Josh; Kulkarni, Jayesh A.; Zhang, Xu Ran Sabrina; Tam, Ying K.; Bally, Marcel B; Schiffelers, Raymond M.; Ciufolini, Marco A.; Cullis, Pieter R.; Tam, Yuen Yi C.

In: bioRxiv, 16.01.2020.

Onderzoeksoutput: Bijdrage aan tijdschriftTijdschriftartikelAcademic

TY - JOUR

T1 - Modular lipid nanoparticle platform technology for siRNA and lipophilic prodrug delivery

AU - van der Meel, Roy

AU - Chen, Sam

AU - Zaifman, Josh

AU - Kulkarni, Jayesh A.

AU - Zhang, Xu Ran Sabrina

AU - Tam, Ying K.

AU - Bally, Marcel B

AU - Schiffelers, Raymond M.

AU - Ciufolini, Marco A.

AU - Cullis, Pieter R.

AU - Tam, Yuen Yi C.

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N2 - Successfully employing therapeutic nucleic acids, such as small interfering RNA (siRNA), requires chemical modifications or the use of nanocarrier technology to prevent their degradation and facilitate intracellular delivery. Lipid nanoparticles (LNP) are among the most advanced nanocarriers and have facilitated the first siRNA therapeutic's clinical translation and approval. One of LNPs' major advantages is their applicability as modular platform technology due to the interchangeable siRNA payload. In addition, drug derivatization approaches can be used to synthesize lipophilic small molecule prodrugs that stably incorporate in LNPs. This provides ample opportunities to develop combination therapies by co-encapsulating multiple therapeutic agents in a single formulation. Here, we describe how the modular LNP platform can be applied for combined gene silencing and chemotherapy to induce additive anti-cancer effects. We show that various lipophilic taxane prodrug derivatives and siRNA against the androgen receptor, a prostate cancer driver, can be efficiently and stably co-encapsulated in LNPs. In addition, we demonstrate that prodrug incorporation does not affect LNPs' gene silencing ability and that the combination therapy induces additive therapeutic effects in vitro. Using a double-radiolabeling approach, we quantitively determined the LNPs' and prodrugs' pharmacokinetic properties and biodistribution following systemic administration in tumor-bearing mice. Our results indicate that co-encapsulation of siRNA and lipophilic prodrugs into LNPs could be an attractive and straightforward approach for combination therapy development.

AB - Successfully employing therapeutic nucleic acids, such as small interfering RNA (siRNA), requires chemical modifications or the use of nanocarrier technology to prevent their degradation and facilitate intracellular delivery. Lipid nanoparticles (LNP) are among the most advanced nanocarriers and have facilitated the first siRNA therapeutic's clinical translation and approval. One of LNPs' major advantages is their applicability as modular platform technology due to the interchangeable siRNA payload. In addition, drug derivatization approaches can be used to synthesize lipophilic small molecule prodrugs that stably incorporate in LNPs. This provides ample opportunities to develop combination therapies by co-encapsulating multiple therapeutic agents in a single formulation. Here, we describe how the modular LNP platform can be applied for combined gene silencing and chemotherapy to induce additive anti-cancer effects. We show that various lipophilic taxane prodrug derivatives and siRNA against the androgen receptor, a prostate cancer driver, can be efficiently and stably co-encapsulated in LNPs. In addition, we demonstrate that prodrug incorporation does not affect LNPs' gene silencing ability and that the combination therapy induces additive therapeutic effects in vitro. Using a double-radiolabeling approach, we quantitively determined the LNPs' and prodrugs' pharmacokinetic properties and biodistribution following systemic administration in tumor-bearing mice. Our results indicate that co-encapsulation of siRNA and lipophilic prodrugs into LNPs could be an attractive and straightforward approach for combination therapy development.

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DO - 10.1101/2020.01.16.907394

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JO - bioRxiv

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