Prodrug strategy for PSMA-targeted delivery of TGX-221 to prostate cancer cells.

TGX-221 is a potent, selective, and cell membrane permeable inhibitor of the PI3K p110ß catalytic subunit. Recent studies showed that TGX-221 has antiproliferative activity against PTEN-deficient tumor cell lines including prostate cancers. The objective of this study was to develop an encapsulation system for parenterally delivering TGX-221 to the target tissue through a prostate-specific membrane aptamer (PSMAa10) with little or no side effects. In this study, PEG-PCL micelles were formulated to encapsulate the drug, and a prodrug strategy was pursued to improve the stability of the carrier system. Fluorescence imaging studies demonstrated that the cellular uptake of both drug and nanoparticles was significantly improved by targeted micelles in a PSMA positive cell line. The area under the plasma concentration time curve of the micelle formulation in nude mice was 2.27-fold greater than that of the naked drug, and the drug clearance rate was 6.16-fold slower. These findings suggest a novel formulation approach for improving site-specific drug delivery of a molecular-targeted prostate cancer treatment.

A54 peptide-mediated functionalized gold nanocages for targeted delivery of DOX as a combinational photothermal-chemotherapy for liver cancer.

The combination of photothermal therapy and chemotherapy (photothermal-chemotherapy) is a promising strategy for cancer therapy. Gold nanocages (AuNCs), with hollow and porous structures and unique optical properties, have become a rising star in the field of drug delivery. Here, we designed a novel targeted drug delivery system based on functionalized AuNCs and evaluated their therapeutic effects in vitro and in vivo. We then loaded doxorubicin into this promising system, designated as DHTPAuNCs consisting of hyaluronic acid-grafted and A54 peptide-targeted PEGylated AuNCs. Its formation was corroborated by ultraviolet-visible spectroscopy, transmission electron microscopy and dynamic light scattering. This delivery platform needed hyaluronidase to release encapsulated drugs, meanwhile the acidic pH and near-infrared irradiation could accelerate the release. In addition, the results of cellular uptake demonstrate that this system could bind specifically with BEL-7402 cells. In vitro, we evaluated therapeutic effects of the DHTPAuNCs in BEL-7402 cells by 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyl-tetrazolium bromide assay. Moreover, in BEL-7402 tumor-bearing nude mice, its therapy effect in vivo was also evaluated. As expected, DHTPAuNCs exhibited excellent therapeutic effect by photothermal-chemotherapy, both in vitro and in vivo. In short, DHTPAuNCs with low toxicity showed great potential as a drug delivery system for cancer therapy.

Prostate-targeted biodegradable nanoparticles loaded with androgen receptor silencing constructs eradicate xenograft tumors in mice.

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.