Enhanced Antisense Oligonucleotide Delivery Using Cationic Liposomes Grafted with Trastuzumab: A Proof-of-Concept Study in Prostate Cancer
Prostate cancer (PCa) is the second most common cancer in men worldwide and the fifth leading cause of death by cancer. The overexpression of TCTP protein plays an important role in castration resistance. Over the last decade, antisense technology has emerged as a rising strategy in oncology. Using...
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| Format: | Article |
| Language: | English |
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MDPI AG
2020-11-01
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| Series: | Pharmaceutics |
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| Online Access: | https://www.mdpi.com/1999-4923/12/12/1166 |
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| author | Guillaume Sicard Clément Paris Sarah Giacometti Anne Rodallec Joseph Ciccolini Palma Rocchi Raphaëlle Fanciullino |
| author_facet | Guillaume Sicard Clément Paris Sarah Giacometti Anne Rodallec Joseph Ciccolini Palma Rocchi Raphaëlle Fanciullino |
| author_sort | Guillaume Sicard |
| collection | DOAJ |
| description | Prostate cancer (PCa) is the second most common cancer in men worldwide and the fifth leading cause of death by cancer. The overexpression of TCTP protein plays an important role in castration resistance. Over the last decade, antisense technology has emerged as a rising strategy in oncology. Using antisense oligonucleotide (ASO) to silence TCTP protein is a promising therapeutic option—however, the pharmacokinetics of ASO does not always meet the requirements of proper delivery to the tumor site. In this context, developing drug delivery systems is an attractive strategy for improving the efficacy of ASO directed against TCTP. The liposome should protect and deliver ASO at the intracellular level in order to be effective. In addition, because prostate cancer cells express Her2, using an anti-Her2 targeting antibody will increase the affinity of the liposome for the cell and optimize the intratumoral penetration of the ASO, thus improving efficacy. Here, we have designed and developed pegylated liposomes and Her2-targeting immunoliposomes. Mean diameter was below 200 nm, thus ensuring proper enhanced permeation and retention (EPR) effect. Encapsulation rate for ASO was about 40%. Using human PC-3 prostate cancer cells as a canonical model, free ASO and ASO encapsulated into either liposomes or anti-Her2 immunoliposomes were tested for efficacy in vitro using 2D and 3D spheroid models. While the encapsulated forms of ASO were always more effective than free ASO, we observed differences in efficacy of encapsulated ASO. For short exposure times (i.e., 4 h) ASO liposomes (ASO-Li) were more effective than ASO-immunoliposomes (ASO-iLi). Conversely, for longer exposure times, ASO-iLi performed better than ASO-Li. This pilot study demonstrates that it is possible to encapsulate ASO into liposomes and to yield antiproliferative efficacy against PCa. Importantly, despite mild Her2 expression in this PC-3 model, using a surface mAb as targeting agent provides further efficacy, especially when exposure is longer. Overall, the development of third-generation ASO-iLi should help to take advantage of the expression of Her2 by prostate cancer cells in order to allow greater specificity of action in vivo and thus a gain in efficacy. |
| first_indexed | 2024-03-10T14:27:39Z |
| format | Article |
| id | doaj.art-e0a55ff105ca4193996df2263157e9d7 |
| institution | Directory Open Access Journal |
| issn | 1999-4923 |
| language | English |
| last_indexed | 2024-03-10T14:27:39Z |
| publishDate | 2020-11-01 |
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| series | Pharmaceutics |
| spelling | doaj.art-e0a55ff105ca4193996df2263157e9d72023-11-20T22:53:39ZengMDPI AGPharmaceutics1999-49232020-11-011212116610.3390/pharmaceutics12121166Enhanced Antisense Oligonucleotide Delivery Using Cationic Liposomes Grafted with Trastuzumab: A Proof-of-Concept Study in Prostate CancerGuillaume Sicard0Clément Paris1Sarah Giacometti2Anne Rodallec3Joseph Ciccolini4Palma Rocchi5Raphaëlle Fanciullino6SMARTc Unit, CRCM Inserm U1068, Aix Marseille University, 13007 Marseille, FranceCNRS, INSERM, Institut Paoli-Calmettes, CRCM, Aix Marseille University, 13007 Marseille, FranceSMARTc Unit, CRCM Inserm U1068, Aix Marseille University, 13007 Marseille, FranceSMARTc Unit, CRCM Inserm U1068, Aix Marseille University, 13007 Marseille, FranceSMARTc Unit, CRCM Inserm U1068, Aix Marseille University, 13007 Marseille, FranceCNRS, INSERM, Institut Paoli-Calmettes, CRCM, Aix Marseille University, 13007 Marseille, FranceSMARTc Unit, CRCM Inserm U1068, Aix Marseille University, 13007 Marseille, FranceProstate cancer (PCa) is the second most common cancer in men worldwide and the fifth leading cause of death by cancer. The overexpression of TCTP protein plays an important role in castration resistance. Over the last decade, antisense technology has emerged as a rising strategy in oncology. Using antisense oligonucleotide (ASO) to silence TCTP protein is a promising therapeutic option—however, the pharmacokinetics of ASO does not always meet the requirements of proper delivery to the tumor site. In this context, developing drug delivery systems is an attractive strategy for improving the efficacy of ASO directed against TCTP. The liposome should protect and deliver ASO at the intracellular level in order to be effective. In addition, because prostate cancer cells express Her2, using an anti-Her2 targeting antibody will increase the affinity of the liposome for the cell and optimize the intratumoral penetration of the ASO, thus improving efficacy. Here, we have designed and developed pegylated liposomes and Her2-targeting immunoliposomes. Mean diameter was below 200 nm, thus ensuring proper enhanced permeation and retention (EPR) effect. Encapsulation rate for ASO was about 40%. Using human PC-3 prostate cancer cells as a canonical model, free ASO and ASO encapsulated into either liposomes or anti-Her2 immunoliposomes were tested for efficacy in vitro using 2D and 3D spheroid models. While the encapsulated forms of ASO were always more effective than free ASO, we observed differences in efficacy of encapsulated ASO. For short exposure times (i.e., 4 h) ASO liposomes (ASO-Li) were more effective than ASO-immunoliposomes (ASO-iLi). Conversely, for longer exposure times, ASO-iLi performed better than ASO-Li. This pilot study demonstrates that it is possible to encapsulate ASO into liposomes and to yield antiproliferative efficacy against PCa. Importantly, despite mild Her2 expression in this PC-3 model, using a surface mAb as targeting agent provides further efficacy, especially when exposure is longer. Overall, the development of third-generation ASO-iLi should help to take advantage of the expression of Her2 by prostate cancer cells in order to allow greater specificity of action in vivo and thus a gain in efficacy.https://www.mdpi.com/1999-4923/12/12/1166liposomesimmunoliposomesantisense oligonucleotidesprostate cancer |
| spellingShingle | Guillaume Sicard Clément Paris Sarah Giacometti Anne Rodallec Joseph Ciccolini Palma Rocchi Raphaëlle Fanciullino Enhanced Antisense Oligonucleotide Delivery Using Cationic Liposomes Grafted with Trastuzumab: A Proof-of-Concept Study in Prostate Cancer Pharmaceutics liposomes immunoliposomes antisense oligonucleotides prostate cancer |
| title | Enhanced Antisense Oligonucleotide Delivery Using Cationic Liposomes Grafted with Trastuzumab: A Proof-of-Concept Study in Prostate Cancer |
| title_full | Enhanced Antisense Oligonucleotide Delivery Using Cationic Liposomes Grafted with Trastuzumab: A Proof-of-Concept Study in Prostate Cancer |
| title_fullStr | Enhanced Antisense Oligonucleotide Delivery Using Cationic Liposomes Grafted with Trastuzumab: A Proof-of-Concept Study in Prostate Cancer |
| title_full_unstemmed | Enhanced Antisense Oligonucleotide Delivery Using Cationic Liposomes Grafted with Trastuzumab: A Proof-of-Concept Study in Prostate Cancer |
| title_short | Enhanced Antisense Oligonucleotide Delivery Using Cationic Liposomes Grafted with Trastuzumab: A Proof-of-Concept Study in Prostate Cancer |
| title_sort | enhanced antisense oligonucleotide delivery using cationic liposomes grafted with trastuzumab a proof of concept study in prostate cancer |
| topic | liposomes immunoliposomes antisense oligonucleotides prostate cancer |
| url | https://www.mdpi.com/1999-4923/12/12/1166 |
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