Addressable Peptide Self‐Assembly on the Cancer Cell Membrane for Sensitizing Chemotherapy of Renal Cell Carcinoma

Abstract

Chemotherapy has been validated unavailable for treatment of renal cell carcinoma (RCC) in clinic due to its intrinsic drug resistance. Sensitization of chemo‐drug response plays a crucial role in RCC treatment and increase of patient survival. Herein, a recognition‐reaction‐aggregation (RRA) cascaded strategy is utilized to in situ construct peptide‐based superstructures on the renal cancer cell membrane, enabling specifically perturbing the permeability of cell membranes and enhancing chemo‐drug sensitivity in vitro and in vivo. First, P1‐DBCO can specifically recognize renal cancer cells by targeting carbonic anhydrase IX. Subsequently, P2‐N3 is introduced and efficiently reacts with P1‐DBCO to form a peptide P3, which exhibits enhanced hydrophobicity and simultaneously aggregates into a superstructure. Interestingly, the superstructure retains on the cell membrane and perturbs its integrity/permeability, allowing more doxorubicin (DOX) uptaken by renal cancer cells. Owing to this increased influx, the IC50 is significantly reduced by nearly 3.5‐fold compared with that treated with free DOX. Finally, RRA strategy significantly inhibits the tumor growth of xenografted mice with a 3.2‐fold enhanced inhibition rate compared with that treated with free DOX. In summary, this newly developed RRA strategy will open a new avenue for chemically engineering cell membranes with diverse biomedical applications.

Chemical Reactions Trigger Peptide Self‐Assembly in vivo for Tumor Therapy

“…In addition to the use of tumor‐related chemical factors in physical to stimulate the self‐assembly of peptide materials, the self‐assembly process of peptides promoted by bio‐orthogonal reactions has higher reaction and assembly efficiency [13,31] . At the same time, the types of bio‐orthogonal reactions are more diverse, making the process of peptide self‐assembly promoted by bio‐orthogonal reactions have a wider application prospect in the treatment of tumors [32] …”

“…Bio‐orthogonal reactions commonly used in organisms include Staudinger ligation, click reactions, and the inverse electron‐demand Diels‐Alder reaction (IEDDA), cyanobenzothiazole‐cysteine condensation reaction among others [24,33–34] . The use of bio‐orthogonal reaction as the triggering factor for peptide assembly is more selective and time‐sensitive, and we can control the occurrence of the reaction to a certain extent [13,31] . If other in vivo stimuli are combined during this process, our control over the assembly of peptides will be further enhanced.…”

2D Nanoarchitectonics: Soft Interfacial Media as Playgrounds for Microobjects, Molecular Machines, and Living Cells

“…Nanoarchitectonic supramolecular assembly of molecular components on the cell membranes can improve chemotherapy for drug‐resistant cells, as reported by Wang, Xu, and co‐workers . Therapy for renal cell carcinoma with high drug resistance is not easy with conventional chemotherapy.…”

Peptide-Decorated Supramolecules for Subcellular Targeted Cancer Therapy: Recent Advances

“…Consequently, it can lead to enhanced cellular uptake of therapeutic agents for improved therapeutic efficacy, or even cell death (see Figure 1). Hence, cell membrane-localized PTT , PDT (Ma et al, 2019), chemotherapy Wang et al, 2019), and non-drug-loaded supramolecular nanoassemblies (Hu et al, 2017) can be used to address MDR, avoid cell barriers, and enhance therapeutic efficacy in STCT.…”

“…Upon arriving at tumor sites, the chimeric peptides anchored onto the cell membrane and generated self-assembled networks in situ, which strictly limited DOX efflux to obtain 49-fold greater anti-MDR ability than free DOX. Similarly but different, Xu's group perturbed the cell membrane to cause permeability enhancement of DOX through the recognition-reaction-aggregation (RRA) strategy (Wang et al, 2019).…”