Folate-Decorated and Reduction-Sensitive Micelles Assembled from Amphiphilic Polymer–Camptothecin Conjugates for Intracellular Drug Delivery

Abstract

It is one of the challenges for a wide clinical application of polymer micelles to address the structure disintegration and premature drug release before reaching a pathological site. In the current study, folic acid (FA)-decorated polymer-drug conjugates (FSC) were synthesized with disulfide linkages between camptothecin (CPT) and amphiphilic poly(ethylene glycol)-b-poly(ε-caprolactone) (PECL) copolymers. FSC conjugates were proposed to assemble into micelles with a hydrophobic core of PCL segments and CPT and a hydrophilic corona of PEG segments. The addition of hexadecanol during micelle formation (FSC-16) was proposed to modulate the interactions of hydrophobic segments in micelles and enhance the reductive sensitivity. FSC-16 micelles were obtained with critical micelle concentration of around 2 μg/mL and an average size of around 200 nm, and the conjugated CPT was rapidly released out in response to glutathione. The reductive sensitivity was also demonstrated with respect to the changes of micelle size and morphologies as well as the fluorescent intensity of pyrene loaded in micelles. Benefiting from the FA receptor-mediated uptake and the reduction-sensitive release of CPT, significant cytotoxicity and cell apoptosis were identified for FSC-16 micelles against SKOV-3 cells with strong expressions of FA receptors. Flow cytometry and confocal laser scanning microscopy analyses demonstrated that CPT was distributed into nuclei after cellular uptake and intracellular release from FSC-16 micelles. Thus, the FA-decorated and reduction-sensitive micelles assembled from polymer-drug conjugates show advantages in inhibiting premature release during circulation, enhancing cellular uptake at the tumor tissues, and promoting intracellular release and nuclei location of the active moieties.

Bacillus-Shape Design of Polymer Based Drug Delivery Systems with Janus-Faced Function for Synergistic Targeted Drug Delivery and More Effective Cancer Therapy

“…45 On the other hand, it was proven that targeting ligand could enter the cells by the receptor-mediated endocytosis even when coupled with a variety of small molecules. 45,46 Therefore, the functionalization of the cancer cell-specific targeting/diseasespecific cytotoxic MTX as a Janus-like agent on the drug carriers could not only avoid its premature release in the circulation system to reduce the toxicity of chemotherapy but also keep its accessibility to the FA receptor site to keep the selective targeting ability. 41,42 In vitro and in vivo studies were then systematically investigated.…”

Redox-Responsive Tumor Targeted Dual-Drug Loaded Biocompatible Metal-Organic Frameworks for Enhancing Anticancer Cytotoxicity

“…According to the previous literature in Fig. S4, 3,3'-dithiodipropionic acid anhydride (DTDPA) was obtained by acylation of 3,3'-dithiodipropionic (DTDP) acid with acetyl chloride [31]. The resonance at δ = 12.35 ppm corresponded to the carboxyl proton of the DTDP, and the peak disappeared after re uxing in acetyl chloride, which indicated the successful formation of DTDPA in 1 H NMR in Fig.…”

Investigation of the Therapeutic Potential of a Synergistic Delivery System through Dual Controlled Release of Camptothecin–Doxorubicin

“…The release of CPT from HBP/DOX/CPT conjugates was investigated using three glutathione concentrations: 20 × 10 −6 m , 10 × 10 −3 m, and 40 × 10 −3 m which were representative of the reductive microenvironment of extracellular space, cytoplasm of healthy cells and tumor cells, respectively. [ 30,46 ] As shown in Figure 1A, CPT conjugation was stable in the presence of 2 × 10 −6 m of GSH which mimics the glutathione concentration in the blood. [ 47 ] For example, less than 10% of CPT was released from HBP/CPT/DOX after 108 h at 2 × 10 −6 m GSH, which based on known pharmacokinetic profiles of similar nanomedicines indicates that release of CPT during blood circulation should be minimal under these conditions.…”