Ratiometric theranostic nanoprobe for pH imaging-guided photodynamic therapy.

An abnormal pH microenvironment results from the development of tumors, and also affects the therapeutic efficiency of anti-tumor drugs. In this work, a Förster resonance energy transfer (FRET)-based theranostic fluorescent nanoprobe was constructed for simultaneous ratiometric pH sensing and tumor-targeted photodynamic therapy. Based on the FRET process between rhodamine B and protoporphyrin IX (PpIX), the fabricated nanoprobe exhibited excellent pH responsiveness in both solutions and live cells with the ratiometric fluorescence changes. Moreover, this ratiometric pH fluorescent nanoprobe also possessed the capability for pH-responsive singlet oxygen (1O2) generation under light irradiation, guiding robust photodynamic therapy in a pH-dependent manner. Benefiting from the enhanced permeability and retention (EPR) effect, the nanoprobe could significantly inhibit tumor growth and metastasis via targeted photodynamic therapy in vivo. This work presents a novel paradigm for precise tumor theranostics by ratiometric pH fluorescence imaging-guided photodynamic therapy.

A Theranostic Nanoprobe for Hypoxia Imaging and Photodynamic Tumor Therapy.

Hypoxia is a common feature for most malignant tumors, which was also closely related to the oxygen-dependent photodynamic therapy. Based on Förster resonance energy transfer (FRET), a smart nanoprobe (designated as H-Probe) was designed in this paper for hypoxia imaging and photodynamic tumor therapy. Due to the FRET process, H-Probe could respond to hypoxia with a significant fluorescence recovery. Moreover, abundant in vitro investigations demonstrated that the photosensitizer of PpIX in H-Probe could generate large amounts of singlet oxygen to kill cancer cells in the presence of oxygen and light with appropriate wavelength. Also, intravenously injected H-Probe with light irradiation achieved an effective tumor inhibition in vivo with a reduced side effect. This original strategy of integrating hypoxia imaging and tumor therapy in one nanoplatform would promote the development of theranostic nanoplatform for tumor precision therapy.

Chimeric peptide engineered exosomes for dual-stage light guided plasma membrane and nucleus targeted photodynamic therapy.

Targeted delivery of the drug to its therapeutically active site with low immunogenicity and system toxicity is critical for optimal tumor therapy. In this paper, exosomes as naturally-derived nano-sized membrane vesicles are engineered by chimeric peptide for plasma membrane and nucleus targeted photosensitizer delivery and synergistic photodynamic therapy (PDT). Importantly, a dual-stage light strategy is adopted for precise PDT by selectively and sequentially destroying the plasma membrane and nucleus of tumor cells. Briefly, plasma membrane-targeted PDT of chimeric peptide engineered exosomes (ChiP-Exo) could directly disrupt the membrane integrity and cause cell death to some extent. More interestingly, the photochemical internalization (PCI) and lysosomal escape triggered by the first-stage light significantly improve the cytosolic delivery of ChiP-Exo, which could enhance its nuclear delivery due to the presence of nuclear localization signals (NLS) peptide. Upon the second-stage light irradiation, the intranuclear ChiP-Exo would activate reactive oxygen species (ROS) in situ to disrupt nuclei for robust and synergistic PDT. Based on exosomes, this dual-stage light guided subcellular dual-targeted PDT strategy exhibits a greatly enhanced therapeutic effect on the inhibition of tumor growth with minimized system toxicity, which also provides a new insight for the development of individualized biomedicine for precise tumor therapy.

A Self-Delivery Chimeric Peptide for Photodynamic Therapy Amplified Immunotherapy.

In this paper, a self-delivery chimeric peptide PpIX-PEG8 -KVPRNQDWL is designed for photodynamic therapy (PDT) amplified immunotherapy against malignant melanoma. After self-assembly into nanoparticles (designated as PPMA), this self-delivery system shows high drug loading rate, good dispersion, and stability as well as an excellent capability in producing reactive oxygen species (ROS). After cellular uptake, the ROS generated under light irradiation could induce the apoptosis and/or necrosis of tumor cells, which would subsequently stimulate the anti-tumor immune response. On the other hand, the melanoma specific antigen (KVPRNQDWL) peptide could also activate the specific cytotoxic T cells for anti-tumor immunity. Compared to immunotherapy alone, the combined photodynamic immunotherapy exhibits significantly enhanced inhibition of melanoma growth. Both in vitro and in vivo investigations confirm that PDT of PPMA has a positive effect on anti-tumor immune response. This self-delivery system demonstrates a great potential of this PDT amplified immunotherapy strategy for advanced or metastatic tumor treatment.

Mitochondria and plasma membrane dual-targeted chimeric peptide for single-agent synergistic photodynamic therapy.

Mitochondria and cell membrane play important roles in maintaining cellular activity and stability. Here, a single-agent self-delivery chimeric peptide based nanoparticle (designated as M-ChiP) was developed for mitochondria and plasma membrane dual-targeted photodynamic tumor therapy. Without additional carrier, M-ChiP possessed high drug loading efficacy as well as the excellent ability of producing reactive oxygen species (ROS). Moreover, the dual-targeting property facilitated the effective subcellular localization of photosensitizer protoporphyrin IX (PpIX) to generate ROS in situ for enhanced photodynamic therapy (PDT). Notably, plasma membrane-targeted PDT would enhance the membrane permeability to improve the cellular delivery of M-ChiP, and even directly disrupt the cell membrane to induce cell necrosis. Additionally, mitochondria-targeted PDT would decrease mitochondrial membrane potential and significantly promote the cell apoptosis. Both in vitro and in vivo investigations indicated that this combinatorial PDT in mitochondria and plasma membrane could achieve the therapeutic effect maximization with reduced side effects. The single-agent self-delivery system with dual-targeting strategy was demonstrated to be a promising nanoplatform for synergistic tumor therapy.

Epigenetics-inspired photosensitizer modification for plasma membrane-targeted photodynamic tumor therapy.

In recent years, epigenetics has attracted great attentions in the field of biomedicine, which is used to denote the heritable changes in gene expression without any variation in DNA sequence, including DNA methylation, histone modification and so on. Inspired by it, a simple and versatile amino acids modification strategy is proposed in this paper to regulate the subcellular distribution of photosensitizer for plasma membrane targeted photodynamic therapy (PDT). Particularly, the plasma membrane anchoring ability and photo toxicity of the photosensitizer against different cell lines could be effectively manipulated at a single amino acid level. Systematic researches indicate that the number and variety of amino acids have a significant influence on the plasma membrane targeting effect of the photosensitizer. Furthermore, after self-assembling into nanoparticles, the obtained nano photosensitizers (NPs) also exhibit a good biocompatibility and plasma membrane targeting ability, which are conducive to enhancing the PDT therapeutic effect under light irradiation. Both in vitro and in vivo investigations confirm a robust tumor inhibition effect of NPs with a good biocompatibility. This epigenetics-inspired photosensitizer modification strategy would contribute to the development of structure-based drug design for tumor precision therapy.