Patient‐Derived Prostate Cancer Explants: A Clinically Relevant Model to Assess siRNA‐Based Nanomedicines

Abstract

Over the last thirty years, research in nanomedicine has widely been focused on applications in cancer therapeutics. However, despite the plethora of reported nanoscale drug delivery systems that can successfully eradicate solid tumor xenografts in vivo, many of these formulations have not yet achieved clinical translation. This issue particularly pertains to the delivery of small interfering RNA (siRNA), a highly attractive tool for selective gene targeting. One of the likely reasons behind the lack of translation is that current in vivo models fail to recapitulate critical elements of clinical solid tumors that may influence drug response, such as cellular heterogeneity in the tumor microenvironment. This study incorporates a more clinically relevant model for assessing siRNA delivery systems; ex vivo culture of prostate cancer harvested from patients who have undergone radical prostatectomy, denoted patient‐derived explants (PDE). The model retains native human tissue architecture, microenvironment, and cell signaling pathways. Porous silicon nanoparticles (pSiNPs) behavior in this model is investigated and compared with commonly used 3D cancer cell spheroids for their efficacy in the delivery of siRNA directed against the androgen receptor (AR), a key driver of prostate cancer.

Targeting autophagy in prostate cancer: preclinical and clinical evidence for therapeutic response

“…A variety of molecular pathways and mechanisms can result in drug resistance development such as activation of tumor-promoting factors and inhibition of tumor-suppressor factors [ 152 – 154 ]. In respect to emergence of genetic tools such as small interfering RNA (siRNA), short-hairpin RNA (shRNA) and the CRISPR-Cas9 system for gene regulation, molecular mechanisms involved in drug resistance can be targeted in providing cancer sensitization to chemotherapy [ 155 – 158 ]. Autophagy, owing to its dual role, can either suppress or induce chemoresistance [ 159 ].…”

Harnessing the Utility of Ex Vivo Patient Prostate Tissue Slice Cultures

“…Finally, while TS are optimal for assessing therapeutic responses, overexpression and knockdown tools needed for mechanistic studies need to be carefully optimized to penetrate into explant tissue cultures. This includes delivery of siRNAs, as reported in localized PCa PDE cultures by Tieu et al ( 31 ).…”

Overcoming Barriers: Clinical Translation of siRNA Nanomedicines

“…[ 133 ] Furthermore, PAMAM‐functionalised pSiNPs loaded with siRNA targeting the androgen receptor (AR) have been studied in a clinically relevant ex vivo prostate cancer model, denoted patient‐derived explants (PDE). [ 135 ] The explant model elucidates information on how a nanoparticle/siRNA complex behaved in a human tumor architecture. PDE retains the structural complexities and heterogeneity of human tumors, providing clinical insight into how the nanoparticles interact within a solid tumor environment.…”

“…[ 136 ] The pSiNPs inhibited AR expression by 56% with no visible toxicity, demonstrating efficacy against clinical‐grade patient tissue. [ 135 ]…”