Cooperatively Responsive Peptide Nanotherapeutic that Regulates Angiopoietin Receptor Tie2 Activity in Tumor Microenvironment To Prevent Breast Tumor Relapse after Chemotherapy

Abstract

Expressed in macrophages and endothelial cells, the receptor for angiopoietin, tyrosine kinase with immunoglobulin and epidermal growth factor homology-2 (Tie2), is required for the reconstruction of blood vessels in tumor recurrence after chemotherapy. Thus, small therapeutic peptides that target and block Tie2 activity are promising as a therapeutic for the prevention of tumor relapse after chemotherapy. However, such small peptides often have low bioavailability, undergo rapid enzymatic degradation, and exhibit a short circulation half-life, making them ineffective in cancer therapy. Herein, we designed a dual-responsive amphiphilic peptide (mPEG1000-K­(DEAP)-AAN-NLLMAAS) to modify the small peptide T4 (NLLMAAS) as a Tie2 inhibitor, endowing it with the ability to endure in circulation and specifically target tumor tissue. The ultimate nanoformulation (P-T4) releases T4 in response to the combination of the acidic tumor microenvironment and the presence of legumain, which is commonly overexpressed in tumor tissue. Compared with free T4, P-T4 decreases vessel density significantly (free T4: 2.44 ± 1.20%, P-T4: 0.90 ± 0.75%), delays tumor regrowth after chemotherapy (free T4: 43.2 ± 11.8%, P-T4: 63.6 ± 13.9%), and reduces distant metastasis formation (free T4: 4.50 ± 2.40%, P-T4: 0.67 ± 0.32%). These effects of P-T4 are produced by the local blockage of Tie2 signals in Tie2-positive macrophages and endothelial cells. In addition to describing a potential strategy to enhance circulation half-life and the accumulation of an active peptide at tumor sites, our approach exemplifies the successful targeting of multiple cell types that overexpress a key molecule in conditions associated with tumors.

Tie2‐expressing monocytes as a novel angiogenesis‐related cellular biomarker for non‐small cell lung cancer

“…Our published work has shown that blockade of Tie2 activity may be a viable therapeutic target for the prevention of tumor relapse after chemotherapy 25 . In the present study, circulating TEMs signature was preferentially detected in patients with original and recurrent NSCLC; in addition, tumor presence and recurrence correlated with the accumulation of these cells.…”

Enzyme-Responsive Nanoparticles for Anti-tumor Drug Delivery

“…In the presence of PLGLAG-sensitive MMP-2/9, the PEG layer fell off and the resulting exposure of positive charges promoted the uptake of NPs by the tumor cells. In another study, NPs fabricated in a similar way was reported by Zhang et al (2019). In this approach, fragile hydrophobic therapeutic small peptides T4 (NLLMAAS) were rationally modified with PEG via an enzyme-responsive linker of amino acid sequence AAN, as illustrated in Figure 11.…”

“…For this reason, the same group artfully designed and prepared an outer-frame-degradable nanovehicle by coupling upconversion nanoparticles (UNCPs) with fluorophore-doped macroporous silica (DS). It was finally coated with enzyme-responsive HA crown, as illustrated in Figure 8B (Zhang et al, 2019 ). As expected, in vitro and in vivo evaluation demonstrated that both biodistribution of nanovehicles and the HAase-induced release of protein could be visually monitored at different NIR fluorescence channels.…”

Tumor Microenvironment Sensitive Nanocarriers for Bioimaging and Therapeutics

“…prepared pH and enzyme dual‐responsive micelles for the delivery of a small therapeutic peptide T4 (NLLMAAS), which acts as a tyrosine kinase with immunoglobulin and epidermal growth factor homology‐2 (Tie2) inhibitor. [ 96 ] These micelles were prepared using an amphiphilic PEG‐polypeptide, which was synthesized by conjugating PEG to the peptide T4 through legumain cleavable AAN peptide. To endow pH sensitivity, a DEAP moiety was also inserted between the PEG and AAN peptide.…”