Thailandepsin A-loaded and octreotide-functionalized unimolecular micelles for targeted neuroendocrine cancer therapy

Abstract

Due to the overexpression of somatostatin receptors in neuroendocrine (NE) cancers, drug nanocarriers conjugated with somatostatin analogs, such as octreotide (OCT), for targeted NE cancer therapy may offer increased therapeutic efficacies and decreased adverse effects. In this study, OCT-functionalized unimolecular micelles were prepared using individual hyperbranched polymer molecules consisting of a hyperbranched polymer core (Boltorn® H40) and approximately 25 amphiphilic polylactide-poly(-ethlyene glycol) (PLA-PEG) block copolymer arms (H40-PLA-PEG-OCH3/OCT). The resulting micelles, exhibiting a uniform core-shell shape and an average hydrodynamic diameter size of 66 nm, were loaded with thailandepsin-A (TDP-A), a relatively new naturally produced histone deacetylase (HDAC) inhibitor. In vitro studies using flow cytometry and confocal laser scanning microscopy (CLSM) demonstrated that OCT conjugation enhanced the cellular uptake of the unimolecular micelles. Consequently, TDP-A-loaded and OCT-conjugated micelles exhibited the highest cytotoxicity and caused the highest reduction of NE tumor markers. Finally, the in vivo studies on NE cancer bearing nude mice demonstrated that TDP-A-loaded and OCT-conjugated micelles possessed superior anticancer activity in comparison with other TDP-A formulations or drug alone, while showing no detectable systemic toxicity. Thus, these TDP-A-loaded and OCT-conjugated micelles offer a promising approach for targeted NE cancer therapy.

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

“…1 (C)) [18, 19]. In addition, we previously reported that TDP-A-loaded octreotide-conjugated unimolecular micelles induced 74% of tumor reduction compared to the control, also measured 20 days after the first injection using the same TDP-A dosage, same treatment schedule, and same tumor model [48]. This may be another indication that KE108 was more effective than octreotide as an NE tumor-targeting ligand for drug nanocarriers.…”

“…Figure 5 shows the SSTR 1–5 expression levels in BON and MZ–CRC–1 cells. Our previous studies demonstrated that octreotide—which has a high affinity for SSTR2 and a moderate affinity for SSTR5—increased the cellular uptake of the micelles about 4-fold compared with non-targeted micelles in BON cells [48]. The KE108 peptide—which displays high affinity for all 5 subtypes of SSTRs (SSTR 1–5)—should exhibit much higher cellular uptake than octreotide.…”

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

“…small molecules, peptides, antibodies, and aptamers) and imaging probes (e.g., dyes, radioisotopes, etc.) 27–30 .…”

Application of the Fuzzy Oil Drop Model Describes Amyloid as a Ribbonlike Micelle

“…Other models oriented on micellar organization deal with dynamic forms [11], including micellar aggregates studied in the context of membrane proteins [12,13]. Studies of micellar forms and their applications in drug transport can be found in [14][15][16][17][18][19]. Notably, the ability to construct a co-micelle (i.e., …”