Self‐Delivered Supramolecular Nanomedicine with Transformable Shape for Ferrocene‐Amplified Photodynamic Therapy of Breast Cancer and Bone Metastases

Abstract

Although nanomedicines can passively target tumor through the enhanced permeability and retention (EPR) effect, their distribution and retention are limited by complex tumor microenvironment. Herein, a self-delivery supramolecular nanoplatform with shape-transforming capacity (Ce6-CD/ Fc-pep-PEG) is constructed by the host-guest interaction between chlorin e6-conjugated β-cyclodextrin (Ce6-CD) and ferrocene-modified FFVLG 3 C-PEG conjugates (Fc-pep-PEG). Following passive accumulation mediated by the EPR effect, hydrophobic Fc is oxidized to water-soluble Fc + by endogenous ROS in tumor sites. The resulting Fc + -pep-PEG fragment dissociated from Ce6-CD and recombined to nanofibers through the intermolecular hydrogen bonds among FFVLG 3 C peptide chains, thus enhancing the retention. Meanwhile, the Ce6-CD fragment still maintained the form of spherical micelles with a relatively smaller size to penetrate into the deep tumor regions. Moreover, the cascade Fenton reaction catalyzed by Fc generated •OH and O 2 to relieve hypoxia and amplify PDT efficiency. In turn, ROS generated by PDT promoted shape-transformation and continuous occurrence of Fenton reaction. In vitro and in vivo evaluations verify that through the positive feedback loop, Ce6-CD/ Fc-pep-PEG can induce a potent antitumor immune response and achieve ROS-potentiated elimination of primary tumor and bone metastasis.

Stimuli-responsive cyclodextrin-based supramolecular assemblies as drug carriers

“…86 Furthermore, Fenton or Fenton-like reactions are vital in chemodynamic therapy and photodynamic therapy, facilitating synergetic cancer therapy. 87,88…”

“…Yi et al optimized this kind of ROS self-enhanced system by endowing the system with shape-transforming capacity. 88 At the tumor site, the guest moiety, Fc-modified FFVLG 3 C-PEG, dissociated from the host moiety, chlorin e6-conjugated β-CD, thus formed nanofibers in a physiological environment. Meanwhile, the smaller micelles formed by host moieties penetrated to the deeper site of the tumor.…”

“…86 Furthermore, Fenton or Fenton-like reactions are vital in chemodynamic therapy and photodynamic therapy, facilitating synergetic cancer therapy. 87,88 When designing CD-based redox-responsive assemblies for cancer therapy, the huge difference between redox concentrations benefits the fast disassembly of the systems and specific drug release. For instance, celecoxib, a COX-2/PEG 2 inhibitor was conjugated to the mesoporous silica nanoparticles (MSNs) by disulfide bonds with MSNs encapsulating DOX to suppress cancer repopulation because MSNs could act as a carrier base to improve the drug loading efficiency or realize multidrug delivery (Fig.…”

Research progress on self-assembled nanodrug delivery systems

“…In addition, cell-based experiments demonstrated that the constructed self-assembly has effective cytotoxicity and active targeting capability. 55 In Gao's group, many self-assembled nanoplatforms were constructed for multimodal combined treatment of breast cancer. 56,57 For instance, a macrophage membrane covered shape changeable nanomedicine(I-P@NPs@M) was reported for chemotherapy, PDT and immunotherapy of breast cancer.…”

“…In addition, cell-based experiments demonstrated that the constructed self-assembly has effective cytotoxicity and active targeting capability. 55…”