Abstract
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.
Highlights
Prostate cancer (PCa) is the second most common cancer in men worldwide with 1.3 million new cases in 2018
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Because the PC-3 cells are the cells mostly used as an experimental model for CRPa [38,39], they were considered as a fully suitable model for evaluating the usefulness of transporting ASOs with immunoliposomes in prostate cancer, especially because we have demonstrated previously that higher efficacy with trastuzumab-grafted liposomes was not necessarily correlated to a high level of Her2 expression
Summary
Prostate cancer (PCa) is the second most common cancer in men worldwide with 1.3 million new cases in 2018. The overexpression of the TCTP protein plays an important role in PCa and most in CRPCa [6] This protein is involved in progression of the disease and therapeutic failure. Antisense technology has emerged as a promising strategy in cancer [9] The principle of this approach is the sequence-specific binding of an antisense oligonucleotide (ASO) to target mRNA, preventing gene translation [10]. Our study is based upon this double trend of encapsulation and use of therapeutic monoclonal antibodies to improve the specificity of nanoparticles against tumors. The conjunction of these two concepts results in a new nanoparticle, the antibody nanoconjugate (ANC), more commonly called the immunoliposome [20,21]. For ASO in MeOH, 100 μL of sample was evaporated to dryness; the sample was resuspended in water, and 90 μL was injected
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