DM1 Loaded Ultrasmall Gold Nanoparticles Display Significant Efficacy and Improved Tolerability in Murine Models of Hepatocellular Carcinoma

Abstract

Hepatocellular carcinoma (HCC) is the sixth most common cancer worldwide with poor prognosis and limited options for treatment. Life expectancy after diagnosis is short; the currently available treatments are not well tolerated and have limited clinical benefit. There is a clear unmet clinical need for the development of new treatments. In this study, ultrasmall, 2 nm gold core nanoparticles (MidaCore) conjugated with the potent maytansine analogue DM1 (MTC-100038) were assessed as a systemic nanomedicine for the treatment of hepatocellular carcinoma. The platform improved overall tolerability of DM1, permitting ∼3fold higher levels of drug to be administered compared to free drug. Dose for dose, MTC-100038 also facilitated delivery of ∼2.0-fold higher (p = 0.039) levels of DM1 to the tumor compared to free DM1. MTC-100038 produced significant efficacy (tumor growth index ∼102%; p = <0.0001), in several murine xenograft models of HCC, and was superior to both free DM1 and the current standard of care, sorafenib. Furthermore, MTC-100038 displayed potent (nM) in vitro activity in various HCC primary patient derived cell lines and across various other different cancer cell types. These data demonstrate the potential of MidaCore nanoparticles to enhance tumor delivery of cytotoxic drugs and indicate MTC-100038 is worthy of further investigation as a potential treatment for HCC and other cancer types.

Oral delivery of protein and peptide drugs: from non-specific formulation approaches to intestinal cell targeting strategies

“…Studies demonstrated that incorporating TNF-α onto the gold platform improved systemic tolerability. In phase I studies, the safety profile showed the GNPs were well tolerated for patients with advanced cancer 78 . Ultrasmall GNPs, with size of only 2-3 nm, have also showed great potential in a wide variety of therapeutic applications.…”

Biomolecular interactions of ultrasmall metallic nanoparticles and nanoclusters

“…So far, usNPs have been developed as self-therapeutic agents, 325 drug delivery vehicles, 326 radiosensitizers for cancer radiotherapy, 6,327,328 among other applications in cancer nanomedicine. However, despite promising results so far, commonly encountered limitations such as restricted tumor uptake and off-target localization may hamper the clinical applications of usGNPs.…”

Gold nanoparticle‑mediated delivery of paclitaxel and nucleic acids for cancer therapy (Review)

“…Furthermore, TnF-carrying aunPs have been indicated to be more effective against tumor cells compared with naive TnF (41). Studies have also been performed on aunPs featuring optimization of either the particle or the drug payload (42,43). dM1, which is a maytansine analogue, was developed as a microtubulin inhibitor with the same mechanism of action as paclitaxel, but its toxicity and narrow therapeutic window limited its clinical development.…”

“…dM1, which is a maytansine analogue, was developed as a microtubulin inhibitor with the same mechanism of action as paclitaxel, but its toxicity and narrow therapeutic window limited its clinical development. conjugation of dM1 with ultra-small (diameter, 2 nm) aunPs prolonged the half-life of dM1, increased its cytotoxicity in Bel7404 and HepG2 cells and also improved its tolerability and efficacy in ectopic xenograft models of hepatocellular carcinoma (42). The conjugation of kaempferol, a flavonoid that damages dna in malignant cells, to 2-nm gold nanoclusters decreases toxicity to normal cells, enhances toxicity to cancer cells and decreases proliferation, colony formation and migration of a549 lung cancer cells (43).…”