<p>PSMA-Targeting Reduction-Cleavable Hyperbranched Polyamide-Amine Gene Delivery System to Treat the Bone Metastases of Prostate Cancer</p>

Abstract

This study aimed to develop aptamer-anchored hyperbranched poly(amido amine) (HPAA) for the systemic delivery of miRNA-133a-3p and to evaluate its therapeutic potential against bone metastasis of prostate cancer in vivo and in vitro. Methods: A glutathione (GSH)-responsive cationic HPAA was prepared by the Michael addition reaction. Furthermore, HPAA-PEG was produced by PEGylation, and then the aptamer targeted to prostate-specific membrane antigen (PSMA) was conjugated to the HPAA-PEG. The obtained HPAA-PEG-APT could form nanocomplexes with miRNA-133a-3p through electrostatic adsorption. Results: The results of immunocytochemistry indicated that the complexes could target PSMA-expressing LNCaP cells. The ability of HPAA-PEG-APT to facilitate the delivery of miRNA-133a-3p into LNCaP cells was proven, and HPAA-PEG-APT/miRNA-133a-3p demonstrated enhanced antitumor activity, lower cytotoxicity and better biocompatibility in vitro. Moreover, in a mouse tibial injection tumor model, the intravenous injection of the HPAA-PEG-APT/miRNA-133a-3p complex significantly inhibited cancer growth and extended the survival time. Conclusion: This study provided an aptamer-anchored HPAA-loaded gene system to deliver miRNA-133a-3p for better therapeutic efficacy of bone metastasis of prostate cancer.

MicroRNAs as Epigenetic Determinants of Treatment Response and Potential Therapeutic Targets in Prostate Cancer

“…A major constraint is related to the need for safe and efficient delivery systems able to guarantee an enhanced cell type-specific delivery. Different miRNA delivery systems have been proposed thus far, and some of them have demonstrated the ability to inhibit tumor growth in in vivo models of PCa [ 65 , 165 , 166 , 167 , 168 ]. Additional challenges in developing miRNA-based therapeutics are related to the need for a more detailed understanding of the functions exerted by specific miRNAs and the precise identification of their key targets relevant to PCa.…”

Therapeutic potential of targeting mirnas to prostate cancer tumors: using psma as an active target

“…Furthermore, in an in vivo mouse model of PC, systemic injection of the APT-HPAA-PEG/miRNA-133a-3p compound inhibited tumor growth and prolonged animal survival. 96 …”

“… 122 In the attempts to use miRNA in cancer treatment, PSMA is being tested as a reliable and specific target for developing a targeted delivery system with potential application in PC, one of the most common cancers worldwide. 95 , 96 As targeted miRNA therapy systems mediated through PSMA may increase the efficacy and prevent toxic effects on other human cells, new treatment strategies for using PSMA in PC treatment will be valuable for further studies. Furthermore, future works are needed for designing and optimizing an effective delivery system for miRNAs targeting PSMA and potential combinations of these therapies, along with other therapeutic strategies, for the long-term treatment of PC.…”

miRNAs as Therapeutic Tools and Biomarkers for Prostate Cancer

“…Another polymer proposed for nucleic acid delivery is hyperbranched poly(amido amine) (HPAA). HPAA-nanovectors escaped endolysososml pathway and showed rapid cargo release [ 140 ]. Specific targeting of PCa cells was achieved by engineering a PEG-modified HPAA conjugated with an aptamer recognizing the prostate-specific membrane antigen (HPAA-PEG-APT).…”

“…LNCap cells treated with miR-133-3p-loaded HPAA-PEG-APT showed reduced cell viability and decreased expression of miR-133-3p target proteins, including MET and EGFR. The antitumor potency of HPAA-PEG-APT/miR-133a-3p in vivo was demonstrated in mice bearing LNCap xenograft tumors [ 140 ].…”