KE108-conjugated unimolecular micelles loaded with a novel HDAC inhibitor thailandepsin-A for targeted neuroendocrine cancer therapy

Abstract

Neuroendocrine (NE) cancers can cause significant patient morbidity. Besides surgery, there are no curative treatments for NE cancers and their metastases, emphasizing the need for the development of other forms of therapy. In this study, multifunctional unimolecular micelles were developed for targeted NE cancer therapy. The unimolecular micelles were formed by multi-arm star amphiphilic block copolymer poly(amidoamine)–poly(valerolactone)–poly(ethylene glycol) conjugated with KE108 peptide and Cy5 dye (abbreviated as PAMAM–PVL–PEG–KE108/Cy5). The unimolecular micelles with a spherical core–shell structure exhibited a uniform size distribution and excellent stability. The hydrophobic drug thailandepsin-A (TDP-A), a recently discovered HDAC inhibitor, was physically encapsulated into the hydrophobic core of the micelles. KE108 peptide, a somatostatin analog possessing high affinity for all five subtypes of somatostatin receptors (SSTR 1–5), commonly overexpressed in NE cancer cells, was used for the first time as an NE cancer targeting ligand. KE108 exhibited superior targeting abilities compared to other common somatostatin analogs, such as octreotide, in NE cancer cell lines. The in vitro assays demonstrated that the TDP-A-loaded, KE108-targeted micelles exhibited the best capabilities in suppressing NE cancer cell growth. Moreover, the in vivo near-infrared fluorescence imaging on NE-tumor-bearing nude mice showed that KE108-conjugated micelles exhibited the greatest tumor accumulation due to their passive targeting and active targeting capabilities. Finally, TDP-A-loaded and KE108-conjugated micelles possessed the best anticancer efficacy without detectable systemic toxicity. Thus, these novel TDP-A-loaded and KE108-conjugated unimolecular micelles offer a promising approach for targeted NE cancer therapy.

AB3-loaded and tumor-targeted unimolecular micelles for medullary thyroid cancer treatment

“…The s27 primer sequences were as follows: forward, 5′-TCTTTAGCCATGCACAAACG-3′ and reverse, 5′-TTTCAGTGCTGCTTCCTCCT-3′. The mRNA expression levels of the SSTRs in MZ–CRC–1 cells were measured following a similar procedure 34 . Both TT and MZ–CRC–1 are human MTC cell lines.…”

“…KE108 peptide is a somatostatin analog displaying strong binding affinities to all five subtypes of SSTRs. Our recent report demonstrated, for the first time, that KE108, a true pansomatostatin synthetic nonapeptide, can be used as an efficient SSTR-targeting ligand for targeted carcinoid cancer therapy 34 . In this study, we aimed to develop multifunctional unimolecular micelles for targeted MTC treatment (Figure 1 (A)).…”

Role of tumor microenvironment in tumorigenesis

“…IL-2 was more specific than any marker other than Ki-67 in detecting gastroenteropancreatic NE tumors 235, even though some other targeting markers were promising for use in clinical treatment. Novel TDP-A-loaded and KE108-conjugated unimolecular micelles exhibited the best potential in suppressing NE cancer cell growth both in vitro and in vivo 236. There also have also been some achievements in the fields of prostate, lung, pancreas, and gastrointestinal tracts.…”

Octanoyl galactose ester-modified microemulsion system self-assembled by coix seed components to enhance tumor targeting and hepatoma therapy

“…Cy5, a commonly used near-infrared dye, was encapsulated into various microemulsions for visualization of distribution in vivo. 25,26 At 8 h post-intragastric administration of free Cy5, the fluorescence signal of HepG2 tumor-bearing mice mainly accumulated in the intestinal tract and was eliminated rapidly from 8 to 24 h. Due to nanoparticle-mediated EPR effect, Cy5/C-MEs presented a potential of tumor targeting after crossing the enterocytes, especially at the initial 4 h. In sharp contrast, Cy5/ Gal(oct)-C-MEs displayed the most obvious fluorescence signal in the tumor site, which was retained for 48 h ( Figure 6A). For further confirming the accumulation of the tumor, ex vivo imaging was observed immediately after harvest of the tumor tissues from HepG2 tumor-bearing mice.…”