Prostate-Targeted Biodegradable Nanoparticles Loaded with Androgen Receptor Silencing Constructs Eradicate Xenograft Tumors in Mice

Abstract

Background Prostate cancer is the major cause of cancer death in men and the androgen receptor (AR) has been shown to play a critical role in the progression of the disease. Our previous reports showed that knocking down the expression of the AR gene using a siRNA-based approach in prostate cancer cells led to apoptotic cell death and xenograft tumor eradication. In this study, we utilized a biodegradable nanoparticle to deliver the therapeutic AR shRNA construct specifically to prostate cancer cells. Materials & methods The biodegradable nanoparticles were fabricated using a poly(dl-lactic-co-glycolic acid) polymer and the AR shRNA constructs were loaded inside the particles. The surface of the nanoparticles were then conjugated with prostate-specific membrane antigen aptamer A10 for prostate cancer cell-specific targeting. Results A10-conjugation largely enhanced cellular uptake of nanoparticles in both cell culture- and xenograft-based models. The efficacy of AR shRNA encapsulated in nanoparticles on AR gene silencing was confirmed in PC-3/AR-derived xenografts in nude mice. The therapeutic property of A10-conjugated AR shRNA-loaded nanoparticles was evaluated in xenograft models with different prostate cancer cell lines: 22RV1, LAPC-4 and LNCaP. Upon two injections of the AR shRNA-loaded nanoparticles, rapid tumor regression was observed over 2 weeks. Consistent with previous reports, A10 aptamer conjugation significantly enhanced xenograft tumor regression compared with nonconjugated nanoparticles. Discussion These data demonstrated that tissue-specific delivery of AR shRNA using a biodegradable nanoparticle approach represents a novel therapy for life-threatening prostate cancers.

Generation 2.5 Antisense Oligonucleotides Targeting the Androgen Receptor and Its Splice Variants Suppress Enzalutamide-Resistant Prostate Cancer Cell Growth

“…Although, AR targeting approaches with ASOs or siRNA have been reported previously (16,45,46), no study so far has reported on pharmacologic AR inhibition in vivo in the context of ENZ-resistant disease. ASOs are chemically modified stretches of single stranded DNA complementary to an mRNA region in a target gene that inhibit gene expression by forming RNA/DNA duplexes that are then degraded (15).…”

siRNA Lipid Nanoparticle Potently Silences Clusterin and Delays Progression When Combined with Androgen Receptor Cotargeting in Enzalutamide-Resistant Prostate Cancer

“…(14) to deliver CLU-siRNA and knockdown CLU in in vivo ENZresistant MR49F cells. Our in vitro data indicate that LNP CLUsiRNA reduces CLU and PSA protein levels, as well as the phosphorylation of AKT and extracellular signal-regulated kinase (35) in ENZ-R MR49F and parental LNCaP cells (Fig. 3A and B).…”

“…Although monotargeting of AR or CLU with ASO or siRNA has been reported previously (16,24,35), and combinatorial cotargeting the AR and CLU in ENZ-R CRPC with nucleotide-based therapeutics is biologically rational, combining two antisense drugs in vivo is precluded by toxicity induced by doubling the dose of the oligonucleotide backbone. To circumvent this backbone toxicity limitation, we combined the AR-ASO with a CLU LNP-siRNA formulation.…”

Aptamer Nanomedicine for Cancer Therapeutics: Barriers and Potential for Translation

“…95 This study is the first to show significant regression of tumors by intraperitoneal treatment ( Figure 5D). K Besides the aptamerÀtherapeutic nucleic acid chimera, aptamerÀPEGÀPLGA 96 and aptamerÀPEGÀ liposome 97 nanoparticles have also been used to deliver nucleic acids for the treatment of prostate cancer. In the PEGÀPLGA system (A10-Nano-ARHP8), 96 the aptamer A10 and plasmid-encoding shRNA (ARHP8) served as the ligand for PSMA targeting and the payload for silencing the expression of androgen receptor, respectively.…”

“…K Besides the aptamerÀtherapeutic nucleic acid chimera, aptamerÀPEGÀPLGA 96 and aptamerÀPEGÀ liposome 97 nanoparticles have also been used to deliver nucleic acids for the treatment of prostate cancer. In the PEGÀPLGA system (A10-Nano-ARHP8), 96 the aptamer A10 and plasmid-encoding shRNA (ARHP8) served as the ligand for PSMA targeting and the payload for silencing the expression of androgen receptor, respectively. Compared with the control group, the A10-Nano-ARHP8 nanoparticle intravenously administered prevented tumor growth in three different tumor models established by LNCaP, 22RV1, and LAPAC-4 prostate cancer cells.…”