Conventional photodynamic therapy (PDT) has limited applications in clinical cancer therapy due to the insufficient O2 supply, inefficient reactive oxygen species (ROS) generation, and low ...penetration depth of light. In this work, a multifunctional nanoplatform, upconversion nanoparticles (UCNPs)@TiO2@MnO2 core/shell/sheet nanocomposites (UTMs), is designed and constructed to overcome these drawbacks by generating O2 in situ, amplifying the content of singlet oxygen (1O2) and hydroxyl radical (•OH) via water‐splitting, and utilizing 980 nm near‐infrared (NIR) light to increase penetration depth. Once UTMs are accumulated at tumor site, intracellular H2O2 is catalyzed by MnO2 nanosheets to generate O2 for improving oxygen‐dependent PDT. Simultaneously, with the decomposition of MnO2 nanosheets and 980 nm NIR irradiation, UCNPs can efficiently convert NIR to ultraviolet light to activate TiO2 and generate toxic ROS for deep tumor therapy. In addition, UCNPs and decomposed Mn2+ can be used for further upconversion luminescence and magnetic resonance imaging in tumor site. Both in vitro and in vivo experiments demonstrate that this nanoplatform can significantly improve PDT efficiency with tumor imaging capability, which will find great potential in the fight against tumor.
Enhanced and amplified photodynamic therapy: A multifunctional nanoplatform, UCNPs@TiO2@MnO2 core/shell/sheet nanocomposites, is designed to overcome the drawbacks of photodynamic therapy by generating O2 in situ, amplifying the content of singlet oxygen (1O2) and hydroxyl radical (•OH) via water‐splitting, and utilizing 980 nm near‐infrared light to increase penetration depth, which significantly improves PDT efficiency as well as reduces the side effects.
During the last decade, peptide‐based nanomaterials are recognized as upcoming biomedical materials for tumor imaging and therapy. The rapid expansion of peptides and peptide derivatives is almost ...owing to their excellent biocompatibility, diverse bioactivity, potential biodegradability, specific biological recognition ability, and easy chemical modification characteristic. The present review outlines the development up to now concerning the design and biomedical applications of peptide‐based multifunctional nanomaterials, with an emphasis on their variegated therapeutic methods.
Peptide‐based multifunctional nanomaterials are promising for tumor diagnosis and therapy. This review is divided into three parts based on the major functions of peptides, and developments concerning the design and biomedical applications of peptide‐based multifunctional nanomaterials are discussed.
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.
Membrane‐anchoring photodynamic therapy: A pH‐driven membrane‐anchoring photodynamic therapy is developed to inhibit tumor growth and metastasis. With the formation of α‐helix structure in tumor acidic microenvironment, pH‐driven membrane anchoring photosensitizer can rapidly insert into tumor cell membrane and the membrane localized photodynamic therapy (PDT) directly induces significant membrane damage, giving rise to superior cell killing effect and enhanced PDT.
Modulating tumor microenvironment to amplify the therapeutic efficiency would be a novel strategy for effective cancer treatment. In this work, based on the TPZ-loaded porphyrinic metal organic ...framework PCN-224 (PCN stands for porous coordination network), a cancer cell membrane-coated nanoplatform (TPZ@PCN@Mem) was fabricated for tumor targeted PDT and the successively resulting hypoxia-amplified bioreductive therapy. After administration, TPZ@PCN@Mem exhibited the selective accumulation and long-term retention at tumor tissue due to the immune escape and homologous targeting endowed by the cancer membrane coating. Upon light irradiation, PCN-224-mediated toxic reactive oxygen species (ROS) were generated for PDT, and the resulting local hypoxia microenvironment would further accelerate the activation of TPZ for enhanced chemotherapy in 4T1 orthotopic tumor. The cascade synergistic therapeutic effects of TPZ@PCN@Mem could significantly suppress the primary tumor growth, and also inhibit its distal metastasis with minimal side effects. The study indicated an overwhelming superiority of utilizing this bioinspired strategy for tumor targeted PDT and hypoxia-activated bioreductive therapy, which provided a new insight for precise and effective tumor treatment.
In this paper, a self‐delivery system PpIX‐PEG‐(KLAKLAK)2 (designated as PPK) is fabricated to realize mitochondria‐targeted photodynamic tumor therapy. It is found that the PPK self‐delivery system ...exhibited high drug loading efficacy as well as novel capacity in generation of intracellular reactive oxygen species (ROS). This study also indicated that the photochemical internalization effect of the photosensitizer protoporphyrin IX (PpIX) under a short time light irradiation improved the cellular internalization of PPK. On the contrary, PPK could target to the subcellular organelle mitochondria due to the presence of proapoptosis (KLAKLAK)2 peptide. Importantly, the in situ generation of ROS in mitochondria enhanced the photodynamic therapy efficacy under another long time irradiation, leading to significant cell death with decreased mitochondrial membrane potential. Besides, relative high tumor accumulation, minimal systemic cytotoxicity and efficacious long‐term tumor inhibition in vivo are also confirmed by using a murine model. All these results demonstrated the self‐delivery system PPK with a dual‐stage light irradiation strategy is a promising nanoplatform for tumor treatment.
A mitochondria‐targeted self‐delivery system is developed for optical‐imaging‐guided photodynamic tumor therapy. A dual‐stage light irradiation strategy is used to optimize the synergistic effect between photosensitizer and (KLAKLAK)2, and significant efficacious tumor inhibition is observed both in vitro and in vivo.
Abstract Supramolecular photosensitizers (supraPSs) have emerged as effective photodynamic therapy (PDT) agents. Here, we propose the assembling capacity of supraPSs as a new strategy to construct ...theranostic nanoplatform with versatile functions aming at high-performance tumor therapy. By coating tirapazamine (TPZ)-loaded mesoporous silica nanoparticles (MSNs) with layer-by-layer (LbL) assembled multilayer, the versatile nanoplatform (TPZ@MCMSN-Gd3+ ) was obtained with the formation of supraPSs via host-guest interaction and the chelation with paramagnetic Gd3+ . The TPZ@MCMSN-Gd3+ could be specifically uptaken by CD44 receptor overexpressed tumor cells and respond to hyaluronidase (HAase) to trigger the release of therapeutics. As confirmed by in vivo studies, TPZ@MCMSN-Gd3+ showed preferential accumulation in tumor site and significantly inhibited the tumor progression by the collaboration of PDT and bioreductive chemotherapy under NIR fluorescence/MR imaging guidance. Taken together, this supraPSs based strategy paves a new paradigm of the way for the construction of theranostic nanoplatform.
Chemotherapy is well recognized to induce immune responses during some chemotherapeutic drugs‐mediated tumor eradication. Here, a strategy involving blocking programmed cell death protein 1 (PD‐1) to ...enhance the chemotherapeutic effect of a doxorubicin nanoprodrug HA‐Psi‐DOX is proposed and the synergetic mechanism between them is further studied. The nanoprodrugs are fabricated by conjugating doxorubicin (DOX) to an anionic polymer hyaluronic acid (HA) via a tumor overexpressed matrix metalloproteinase sensitive peptide (CPLGLAGG) for tumor targeting and enzyme‐activated drug release. Once accumulated at the tumor site, the nanoprodrug can be activated to release antitumor drug by tumor overexpressed MMP‐2. It is found that HA‐Psi‐DOX nanoparticles can kill tumor cells effectively and initiate an antitumor immune response, leading to the upregulation of interferon‐γ. This cytokine promotes the expression of programmed cell death protein‐ligand 1 (PD‐L1) on tumor cells, which will cause immunosuppression after interacting with PD‐1 on the surface of lymphocytes. The results suggest that the therapeutic efficiency of HA‐Psi‐DOX nanoparticles is significantly improved when combined with checkpoint inhibitors anti‐PD‐1 antibody (α‐PD1) due to the neutralization of immunosuppression by blocking the interaction between PD‐L1 and PD‐1. This therapeutic system by combining chemotherapy and immunotherapy further increases the link between conventional tumor therapies and immunotherapy.
A hyaluronic acid‐PLGLAGG‐doxorubicin (HA‐Psi‐DOX) nanoprodrug with matrix metalloproteinase‐2 responsive ability is designed for efficient chemotherapy and immunotherapy against tumors. During the treatment, the programmed cell death protein‐ligand 1 (PD‐L1) on tumor cells is upregulated due to secreted interferon‐γ by activated immune cells. Blocking the interaction between PD‐L1 and PD‐1 significantly improves the antitumor efficiency of HA‐Psi‐DOX.
Multidrug resistance (MDR) remains one of the biggest obstacles in chemotherapy of tumor mainly due to P‐glycoprotein (P‐gp)‐mediated drug efflux. Here, a transformable chimeric peptide is designed ...to target and self‐assemble on cell membrane for encapsulating cells and overcoming tumor MDR. This chimeric peptide (C16‐K(TPE)‐GGGH‐GFLGK‐PEG8, denoted as CTGP) with cathepsin B‐responsive and cell membrane‐targeting abilities can self‐assemble into nanomicelles and further encapsulate the therapeutic agent doxorubicin (termed as CTGP@DOX). After the cleavage of the Gly‐Phe‐Leu‐Gly (GFLG) sequence by pericellular overexpressed cathepsin B, CTGP@DOX is dissociated and transformed from spherical nanoparticles to nanofibers due to the hydrophilic–hydrophobic conversion and hydrogen bonding interactions. Thus obtained nanofibers with cell membrane‐targeting 16‐carbon alkyl chains can adhere firmly to the cell membrane for cell encapsulation and restricting DOX efflux. In comparison to free DOX, 45‐time higher drug retention and 49‐fold greater anti‐MDR ability of CTGP@DOX to drug‐resistant MCF‐7R cells are achieved. This novel strategy to encapsulate cells and reverse tumor MDR via morphology transformation would open a new avenue towards chemotherapy of tumor.
A transformable chimeric peptide (C16‐K(TPE)‐GGGH‐GFLGK‐PEG8, denoted as CTGP) with cell‐encapsulation properties is designed to deliver doxorubicin (DOX) into tumor regions, for restricting DOX efflux, and overcoming multidrug resistance. After cleaving by tumor pericellular hypersecreted cathepsin B, CTGP@DOX can transform into dense nanofibers, which adhere firmly to cell membrane to encapsulate cells, restrict DOX efflux, and reverse tumor multidrug resistance.
A multifunctional prodrug, designated as TPP‐L‐GEM, is fabricated to realize image‐guided in situ tumor photodynamic therapy (PDT) with red light activatable chemotherapy. Gemcitabine is conjugated ...with a fluorescent photosensitizer, meso‐tetraphenylporphyrin (TPP), by a reactive oxygen species cleavable thioketal linker. Under the irradiation of low‐energy red light, TPP can generate singlet oxygen and damage tumor cells by photodynamic therapy. Simultaneously, the thioketal linkage can be cleaved by singlet oxygen and result in a cascaded gemcitabine release, causing sustained cell damage by chemotherapy. With the combination of PDT and cascaded chemotherapy, TPP‐L‐GEM shows significant tumor therapeutic efficacy in vitro and in vivo. Furthermore, the inherent fluorescent property of TPP endows the TPP‐L‐GEM prodrug with noninvasive drug tracking capability, which is favorable for image‐guided tumor therapy.
A red light activatable multifunctional prodrug is fabricated to realize in situ tumor photodynamic therapy (PDT) with cascaded chemotherapy. This multifunctional prodrug demonstrates a new strategy for image‐guided combination therapy of PDT with cascaded chemotherapy.
To integrate treatments of photothermal therapy, photodynamic therapy (PDT), and chemotherapy, this study reports on a multifunctional nanocomposite based on mesoporous silica‐coated gold nanorod for ...high‐performance oncotherapy. Gold nanorod core is used as the hyperthermal agent and mesoporous silica shell is used as the reservoir of photosensitizer (Al(III) phthalocyanine chloride tetrasulfonic acid, AlPcS4). The mesoporous silica shell is modified with β‐cyclodextrin (β‐CD) gatekeeper via redox‐cleavable Pt(IV) complex for controlled drug release. Furthermore, tumor targeting ligand (lactobionic acid, LA) and long‐circulating poly(ethylene glycol) chain are introduced via host–guest interaction. It is found that the nanocomposite can specifically target to hepatoma cells by virtue of the LA targeting moiety. Due to the abundant existence of reducing agents within tumor cells, β‐CD can be removed by reducing the Pt(IV) complex to active cisplatin drug for chemotherapy, along with the releasing of entrapped AlPcS4 for effective PDT. As confirmed by in vitro and in vivo studies, the nanocomposite exhibits an obvious near‐infrared induced thermal effect, which significantly improves the PDT and chemotherapy efficiency, resulting in a superadditive therapeutic effect. This collaborative strategy paves the way toward high‐performance nanotherapeutics with a superior antitumor efficacy and much reduced side effects.
Collaborative tumor‐targeted therapy: A highly integrated nanocomposite is constructed based on mesoporous silica‐coated gold nanorods for tumor‐targeted therapy by virtue of the GNR‐mediated PTT, PS‐mediated PDT, and platinum‐based chemotherapy. In vitro and in vivo results confirm that this multifunctional nanocomposite can serve as an ideal platform for tri‐model high‐performance tumor therapy.
