Targeted Chemoradiotherapy of Prostate Cancer Using Gold Nanoclusters with Protease Activatable Monomethyl Auristatin E

Abstract

Combined radiotherapy (RT) and chemotherapy are prescribed to patients with advanced prostate cancer (PCa) to increase their survival; however, radiation-related side effects and systematic toxicity caused by chemotherapeutic drugs are unavoidable. To improve the precision and efficacy of concurrent RT and chemotherapy, we have developed a PCa-targeted gold nanocluster radiosensitizer conjugated with a highly potent cytotoxin, monomethyl auristatin E, PSMA-AuNC-MMAE, for RT and chemotherapy of PCa. This approach resulted in enhanced uptake of NCs by PSMA-positive cancer cells, targeted chemotherapy, and increased efficacy of RT both in vitro and in vivo. In addition, the combination of gold and MMAE further increased the efficacy of either of the agents delivered alone or simultaneously but not covalently linked. The PSMA-AuNC-MMAE conjugates improve the specificity and efficacy of radiation and chemotherapy, potentially reducing the toxicity of each therapy and making this an attractive avenue for clinical treatment of advanced PCa.

Engineering Gold Nanostructures for Cancer Treatment: Spherical Nanoparticles, Nanorods, and Atomically Precise Nanoclusters

“…In another report, Li and co-workers demonstrated a transformable AuNC aggregate-based synergistic strategy, which can improve the tumor retention/penetration of the nano-radiosensitizers and weaken the radio-resistance of cancer cells [ 83 ]. In a quite recent study, Burda’s group and Basilion’s group reported that when conjugating AuNCs with protease activatable monomethyl auristatin E, the specificity and efficacy of radiation and chemotherapy can be significantly improved [ 84 ]. Both in vitro and in vivo results showed selective tumor cell uptake, excellent anti-tumor activity, and prolonged chemotherapeutic effect [ 84 ].…”

“…In a quite recent study, Burda’s group and Basilion’s group reported that when conjugating AuNCs with protease activatable monomethyl auristatin E, the specificity and efficacy of radiation and chemotherapy can be significantly improved [ 84 ]. Both in vitro and in vivo results showed selective tumor cell uptake, excellent anti-tumor activity, and prolonged chemotherapeutic effect [ 84 ].…”

Antibody-Drug Conjugates Containing Payloads from Marine Origin

“…Although it is out of the scope of the present review, it is important to mention alternative tactics that are being explored with the auristatins with the objective of targeting cancer cells in a highly selective manner by means of platforms different from antibodies recognized by tumor antigens. Among these alternative devices, it is worth highlighting low-molecular-weight ligands for antigens such as the prostate-specific membrane antigen (PSMA) [ 129 ] or integrin ανβ 3 [ 130 ], aptamers [ 131 ], gold nanoclusters [ 132 ] or radiolabeled proteins [ 133 ].…”

Tumor protease-activated theranostic nanoparticles for MRI-guided glioblastoma therapy

“…Major challenges in achieving effective GBM therapy responses are tumor-specific drug delivery and off-target side effects. Preclinical and clinical studies have investigated potent tubulin polymerization inhibitors from the monomethyl auristatin family conjugated to antibodies (known as antibody-drug conjugates or ADCs) as potential treatments for a wide variety of cancers including GBM 5 , 6 , 22 . This ADC approach can successfully deliver cytotoxic drugs but often leads to inadequate retention in tumors due to substantial intertumoral and intratumoral variation in antibody accumulation 23 , 24 .…”

“…Moreover, in a GBM U87ΔEGFR-luc xenograft model, the heterogeneous drug/antibody ratio failed to reach a satisfying therapeutic outcome 14 , 25 . As an alternative to antibodies, researchers have developed nanoparticles with reductive-sensitive linkers or prostate-specific membrane antigen (PSMA)-targeting plus cathepsin B (Cat B)-activatable linkers to deliver tubulin inhibitors to tumors 5 , 7 .…”