Folic acid-targeted disulfide-based cross-linking micelle for enhanced drug encapsulation stability and site-specific drug delivery against tumors

Abstract

Although the shortcomings of small molecular antitumor drugs were efficiently improved by being entrapped into nanosized vehicles, premature drug release and insufficient tumor targeting demand innovative approaches that boost the stability and tumor responsiveness of drug-loaded nanocarriers. Here, we show the use of the core cross-linking method to generate a micelle with enhanced drug encapsulation ability and sensitivity of drug release in tumor. This kind of micelle could increase curcumin (Cur) delivery to HeLa cells in vitro and improve tumor accumulation in vivo. We designed and synthesized the core cross-linked micelle (CCM) with polyethylene glycol and folic acid-polyethylene glycol as the hydrophilic units, pyridyldisulfide as the cross-linkable and hydrophobic unit, and disulfide bond as the cross-linker. CCM showed spherical shape with a diameter of 91.2 nm by the characterization of dynamic light scattering and transmission electron microscope. Attributed to the core cross-linking, drug-loaded CCM displayed higher Nile Red or Cur-encapsulated stability and better sensitivity to glutathione than noncross-linked micelle (NCM). Cellular uptake and in vitro antitumor studies proved the enhanced endocytosis and better cytotoxicity of CCM-Cur against HeLa cells, which had a high level of glutathione. Meanwhile, the folate receptor-mediated drug delivery (FA-CCM-Cur) further enhanced the endocytosis and cytotoxicity. Ex vivo imaging studies showed that CCM-Cur and FA-CCM-Cur possessed higher tumor accumulation until 24 hours after injection. Concretely, FA-CCM-Cur exhibited the highest tumor accumulation with 1.7-fold of noncross-linked micelle Cur and 2.8-fold of free Cur. By combining cross-linking of the core with active tumor targeting of FA, we demonstrated a new and effective way to design nanocarriers for enhanced drug encapsulation, smart tumor responsiveness, and elevated tumor accumulation.

Dual Interactions of Amphiphilic Gelatin Copolymer and Nanocurcumin Improving the Delivery Efficiency of the Nanogels

“…The emergence of micelle packing with well-design at the higher level complex formulation, which comes from the approaching the concept of biological macromolecules as protein, have proven to be an excellent candidate in drug delivery system field of amphiphilic block copolymer [5,6]. Various supramolecular micelles as the large complex micelles [7,8,9], multicompartment micelles [10,11] and large compound micelles/vesicles [12] have been received via the modification of amphiphilic block copolymer. Among these, we have developed several approaches to obtain complex self-assemblies of amphiphilic block copolymer [4,8], in which specific interactions, mainly hydrophobic–hydrophobic interactions connect the core and shell.…”

“…Self-assemble offers tremendous potential as a method to fabricate the complex micelles in the form of multicore [7,8,9,10,11,12]. In particular, the self-assembled process, the uniform structure with the controllable size of these particles are still the remaining problem [9].…”

“…In particular, the self-assembled process, the uniform structure with the controllable size of these particles are still the remaining problem [9]. These can be solved by modification the amphiphilic copolymer to improve the thermodynamics of the assembling molecules as the introduction of another component [3,6,11,12] through the control of the natural interaction of each component in solution. However, the co-assembly of this approach is still random and difficult to apply to the general system.…”

Development and evaluation of a new modular nanotransporter for drug delivery into nuclei of pathological cells expressing folate receptors

“…This includes mainly FA conjugated either to cytotoxic or imaging agents: Vinca alkaloid alone ( ClinicalTrials.gov identifiers: NCT00308269; NCT01577654), 25 and its combination with mitomycin 26 as a therapeutic approach; indium-111 ( ClinicalTrials.gov Identifier: NCT00003763) 27 and technecium-99m ( ClinicalTrials.gov Identifier: NCT01689766) 28 for subsequent SPECT imaging; fluorescent infrared dye ( ClinicalTrials.gov Identifier: NCT02317705) 29 for intraoperative imaging, and some other variants. Besides these molecules, there are a large number of delivery systems targeted at FR currently in in vitro/preclinical stages of development, mainly FA-decorated liposomes, 30 micelles, 31 and nanoparticles 32 demonstrating promising potency, which shows the perspectives of FR-targeted therapeutics and diagnostics approaches. They usually deliver the carried cargo into cells via FR-mediated endocytosis with subsequent cargo entrapment or active release 33 from the lysosomes, sometimes followed by passive transport to an intracellular compartment mediated by the properties of the cargo (eg, doxorubicin accumulating in the nucleus due to its binding to DNA).…”

Sol-gel zinc oxide nanoparticles: advances in synthesis and applications

“…Additionally, the use of this system allowed real-time imaging of gene delivery [19,118,119]. Different articles have used different oxides of metal nanoparticles as a suitable carrier for gene silencing and gene delivery [120][121][122][123]. However, further studies are required in this area.…”