Enhancing Drug Delivery with Supramolecular Amphiphilic Macrocycle Nanoparticles: Selective Targeting of CDK4/6 Inhibitor Palbociclib to Melanoma

Abstract

Drug delivery systems based on amphiphilic supramolecular macrocycles have garnered increased attention over the past two decades due to their ability to successfully formulate nanoparticles. Macrocyclic (MC) materials can self-assemble at lower concentrations without the need for surfactants and polymers, but surfactants are required to form and stabilize nanoparticles at higher concentrations. Using MCs to deliver both hydrophilic and hydrophobic guest molecules is advantageous. We developed two novel types of amphiphilic macrocycle nanoparticles (MC NPs) capable of delivering either Nile Red (NR) (a hydrophobic model) or Rhodamine B (RhB) (a hydrophilic model) fluorescent dyes. We extensively characterized the materials using various techniques to determine size, morphology, stability, hemolysis, fluorescence, loading efficiency (LE), and loading capacity (LC). We then loaded the CDK4/6 inhibitor Palbociclib (Palb) into both MC NPs using a solvent diffusion method. This yielded Palb-MC NPs in the size range of 65-90 nm. They exhibited high stability over time and in fetal bovine serum with negligible toxicity against erythrocytes. Cytotoxicity was minimal when tested against RAW macrophages, human fibroblast HDFn, and adipose stromal cells (ASCs) at higher concentrations of MC NPs. Cell viability studies were conducted with different concentrations of MC NPs, Palb-MC NPs, and free Palb against RAW macrophages, human U-87 GBM, and human M14 melanoma cell lines in vitro. Flow cytometry experiments revealed that blank MC NPs and Palb-MC NPs were selectively targeted to melanoma cells, resulting in cell death compared to the other two cell lines. Future work will focus on studying the biological effect of MC NPs including their binding affinity with molecules/receptors expressed on the M14 and other melanoma cell surface by molecular docking simulations. Subsequently, we will evaluate the MCs as a component of combination therapy in a murine melanoma model. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=154 SRC="FIGDIR/small/567974v1_ufig1.gif" ALT="Figure 1"> View larger version (39K): org.highwire.dtl.DTLVardef@5cddb9org.highwire.dtl.DTLVardef@e0c4e0org.highwire.dtl.DTLVardef@9d6838org.highwire.dtl.DTLVardef@2556b2_HPS_FORMAT_FIGEXP M_FIG C_FIG