A Self‐Transformable pH‐Driven Membrane‐Anchoring Photosensitizer for Effective Photodynamic Therapy to Inhibit Tumor Growth and Metastasis

Abstract

Poor tumor selectivity and short life span of reactive oxygen species (ROS) are two major challenges in photodynamic therapy (PDT). In this study, a self‐transformable pH‐driven membrane anchoring photosensitizer (pHMAPS) is used to realize tumor‐specific accumulation and in situ PDT on tumor cell membrane to maximize the therapeutic potency. It is found that pHMAPS was able to form α‐helix structure under acidic condition (pH 6.5 or 5.5), while remain random coil at normal pH of 7.4. This pH‐driven secondary structure switch enables the successful insertion of pHMAPS into membrane lipid bilayer, especially for cancerous cell membrane in the acidic tumor microenvironment. Under laser irradiation, cytotoxic ROS is generated in the immediate vicinity of cell membrane, resulting in superior cell killing effect in vitro and significant inhibition of tumor growth in vivo. Importantly, benefited from this membrane‐specific PDT, tumor growth‐induced hepatic, pulmonary, as well as osseous metastases of breast cancer cells are also retarded after PDT treatment. Thus, the membrane localized PDT by pHMAPS provides a simple but effective strategy to enhance the medical performance of photosensitizing agents in cancer therapy.

A Chimeric Peptide Logic Gate for Orthogonal Stimuli‐Triggered Precise Tumor Therapy

“…Pep‐DMA showed good water solubility as validated by the UV–vis spectrum ( Figure A). Free protoporphyrin (PpIX) had a significantly broadened split Soret band with two peaks at 361 and 450 nm, while Pep‐DMA showed a peak around 400 nm, demonstrating the little aggregation in Pep‐DMA. Meanwhile, UV–vis spectrum of Pep‐DMA still kept stable and Pep‐DMA showed well solubility, when Pep‐DMA was lyophilized and then redissolved in water, suggesting the well storage ability and potential clinical application.…”

Recent Advances in Subcellular Targeted Cancer Therapy Based on Functional Materials

“…However, it is extremely difficult to develop an effective strategy for long‐term anchoring of PSs on the cell membranes, mainly due to the direct cellular uptake and rapid cellular endocytosis. To overcome this dilemma, we carefully designed a pH‐driven membrane‐anchoring photosensitizer (pHMAPS) by employing a pH low insertion peptide (pHLIP), which had been demonstrated to be able to insert across a lipid bilayer at acidic conditions (pH < 7.0) via the conformational self‐transformation, with no requirement for complicated design and synthesis . By taking advantage of pHLIP, pHMAPS was proposed to undergo random‐to‐α‐helix structure change in a pH‐dependent manner, which was ideal for targeting acidic tumors (pH value: 6.1–7.0) for specifically inserting into cancer cell membranes ( Figure a).…”

“…c) Tumor‐growth curves of 4T1 tumor after different treatments. a–c) Adapted with permission . Copyright 2017, Wiley‐VCH.…”

Photodynamic Therapy and the Biophysics of the Tumor Microenvironment

“…The low pH of tumors has also been exploited in the development of functionally targeted PSs. For example, Luo et al developed a self‐transformable pH‐driven membrane anchoring photosensitizer (pHMAPS) for acidic selectivity. The pHMAPS incorporates pH low insertion peptide (pHLIP), which adopts a random coil configuration in neutral physiological pH (~7.4), but changes conformation in a more acidic pH to an α‐helix structure.…”