Photosensitizer‐Conjugated Albumin−Polypyrrole Nanoparticles for Imaging‐Guided In Vivo Photodynamic/Photothermal Therapy

Conjugated polymers with strong absorbance in the near‐infrared (NIR) region have been widely explored as photothermal therapy agents due to their excellent photostability and high photothermal conversion efficiency. Herein, polypyrrole (PPy) nanoparticles are fabricated by using bovine serum albumin (BSA) as the stabilizing agent, which if preconjugated with photosensitizer chlorin e6 (Ce6) could offer additional functionalities in both imaging and therapy. The obtained PPy@BSA‐Ce6 nanoparticles exhibit little dark toxicity to cells, and are able to trigger both photodynamic therapy (PDT) and photothermal therapy (PTT). As a fluorescent molecule that in the meantime could form chelate complex with Gd³⁺, Ce6 in PPy@BSA‐Ce6 nanoparticles after being labeled with Gd³⁺ enables dual‐modal fluorescence and magnetic resonance (MR) imaging, which illustrate strong tumor uptake of those nanoparticles after intravenous injection into tumor‐bearing mice. In vivo combined PDT and PTT treatment is then carried out after systemic administration of PPy@BSA‐Ce6, achieving a remarkably improved synergistic therapeutic effect compared to PDT or PTT alone. Hence, a rather simple one‐step approach to fabricate multifunctional nanoparticles based on conjugated polymers, which appear to be promising in cancer imaging and combination therapy, is presented.     

Multifunctional Conjugated Polymer Nanoparticles for Image‐Guided Photodynamic and Photothermal Therapy

A multifunctional theranostic platform based on conjugated polymer nanoparticles (CPNs) with tumor targeting, fluorescence detection, photodynamic therapy (PDT), and photothermal therapy (PTT) is developed for effective cancer imaging and therapy. Two conjugated polymers, poly[9,9‐bis(2‐(2‐(2‐methoxyethoxy)ethoxy)‐ethyl)fluorenyldivinylene]‐alt‐4,7‐(2,1,3‐benzothiadiazole) with bright red emission and photosensitizing ability and poly[(4,4,9,9‐tetrakis(4‐(octyloxy)phenyl)‐4,9‐dihydro‐s‐indacenol‐dithiophene‐2,7‐diyl)‐alt‐co‐4,9‐bis(thiophen‐2‐yl)‐6,7‐bis(4‐(hexyloxy)phenyl)‐thiadiazolo‐quinoxaline] with strong near‐infrared absorption and excellent photothermal conversion ability are co‐loaded into one single CPN via encapsulation approach using lipid‐polyethylene glycol as the matrix. The obtained co‐loaded CPNs show sizes of around 30 nm with a high singlet oxygen quantum yield of 60.4% and an effective photothermal conversion efficiency of 47.6%. The CPN surface is further decorated with anti‐HER2 affibody, which bestows the resultant anti‐HER2‐CPNs superior selectivity toward tumor cells with HER2 overexpression both in vitro and in vivo. Under light irradiation, the PDT and PTT show synergistic therapeutic efficacy, which provides new opportunities for the development of multifunctional biocompatible organic materials in cancer therapy.     

A Porphyrin‐Based Conjugated Polymer for Highly Efficient In Vitro and In Vivo Photothermal Therapy

Conjugated polymers have been increasingly studied for photothermal therapy (PTT) because of their merits including large absorption coefficient, facile tuning of exciton energy dissipation through nonradiative decay, and good therapeutic efficacy. The high photothermal conversion efficiency (PCE) is the key to realize efficient PTT. Herein, a donor–acceptor (D–A) structured porphyrin‐containing conjugated polymer (PorCP) is reported for efficient PTT in vitro and in vivo. The D–A structure introduces intramolecular charge transfer along the backbone, resulting in redshifted Q band, broadened absorption, and increased extinction coefficient as compared to the state‐of‐art porphyrin‐based photothermal reagent. Through nanoencapsulation, the dense packing of a large number of PorCP molecules in a single nanoparticle (NP) leads to favorable nonradiative decay, good photostability, and high extinction coefficient of 4.23 × 10⁴m ^?1 cm^?1 at 800 nm based on porphyrin molar concentration and the highest PCE of 63.8% among conjugated polymer NPs. With the aid of coloaded fluorescent conjugated polymer, the cellular uptake and distribution of the PorCP in vitro can be clearly visualized, which also shows effective photothermal tumor ablation in vitro and in vivo. This research indicates a new design route of conjugated polymer‐based photothermal therapeutic materials for potential personalized theranostic nanomedicine.     

Self‐Assembled Peptide‐ and Protein‐Based Nanomaterials for Antitumor Photodynamic and Photothermal Therapy

Tremendous interest in self‐assembly of peptides and proteins towards functional nanomaterials has been inspired by naturally evolving self‐assembly in biological construction of multiple and sophisticated protein architectures in organisms. Self‐assembled peptide and protein nanoarchitectures are excellent promising candidates for facilitating biomedical applications due to their advantages of structural, mechanical, and functional diversity and high biocompability and biodegradability. Here, this review focuses on the self‐assembly of peptides and proteins for fabrication of phototherapeutic nanomaterials for antitumor photodynamic and photothermal therapy, with emphasis on building blocks, non‐covalent interactions, strategies, and the nanoarchitectures of self‐assembly. The exciting antitumor activities achieved by these phototherapeutic nanomaterials are also discussed in‐depth, along with the relationships between their specific nanoarchitectures and their unique properties, providing an increased understanding of the role of peptide and protein self‐assembly in improving the efficiency of photodynamic and photothermal therapy.     

Mitochondria‐Targeted Polydopamine Nanocomposite with AIE Photosensitizer for Image‐Guided Photodynamic and Photothermal Tumor Ablation

Photodynamic therapy (PDT) and photothermal therapy (PTT) are two kinds of treatment for tumors. Herein, a new aggregation‐induced emission (AIE)gen (MeO‐TPE‐indo, MTi) is synthesized with a D–π–A conjugated structure. MTi, which has an electron donor and an acceptor on a tetraphenylethene (TPE) conjugated skeleton, can induce the effective generation of reactive oxygen species (ROS) for PDT. With the guide of the indolium group, MTi can target and image mitochondrion selectively. In order to get good dispersion in water and long‐time retention in tumors, MTi is modified on the surface of polydopamine nanoparticles (PDA NPs) to form the nanocomposite (PDA‐MeO‐TPE‐indo, PMTi ) by π–π and hydrogen interactions. PMTi is a nanoscale composite for imaging‐guided PDT and PTT in tumor treatment, which is constructed with AIEgens and PDA for the first time. The organic functional molecules are combined with nanomaterials for building a multifunctional diagnosis and treatment platform by utilizing the advantages of both sides.     

A Tumor‐Microenvironment‐Activated Nanozyme‐Mediated Theranostic Nanoreactor for Imaging‐Guided Combined Tumor Therapy

Activatable theranostic agents that can be activated by tumor microenvironment possess higher specificity and sensitivity. Here, activatable nanozyme‐mediated 2,2′‐azino‐bis (3‐ethylbenzothiazoline‐6‐sulfonic acid) (ABTS) loaded ABTS@MIL‐100/poly(vinylpyrrolidine) (AMP) nanoreactors (NRs) are developed for imaging‐guided combined tumor therapy. The as‐constructed AMP NRs can be specifically activated by the tumor microenvironment through a nanozyme‐mediated “two‐step rocket‐launching‐like” process to turn on its photoacoustic imaging signal and photothermal therapy (PTT) function. In addition, simultaneously producing hydroxyl radicals in response to the high H₂O₂ level of the tumor microenvironment and disrupting intracellular glutathione (GSH) endows the AMP NRs with the ability of enhanced chemodynamic therapy (ECDT), thereby leading to more efficient therapeutic outcome in combination with tumor‐triggered PTT. More importantly, the H₂O₂‐activated and acid‐enhanced properties enable the AMP NRs to be specific to tumors, leaving the normal tissues unharmed. These remarkable features of AMP NRs may open a new avenue to explore nanozyme‐involved nanoreactors for intelligent, accurate, and noninvasive cancer theranostics.     

An Activatable Phototheranostic Nanoplatform for Tumor Specific NIR-II Fluorescence Imaging and Synergistic NIR-II Photothermal-Chemodynamic Therapy

The phototheranostics in the second near-infrared window (NIR-II) have proven to be promising for the precise cancer theranostics. However, the non-responsive and “always on” imaging mode lacks the selectivity, leading to the poor diagnosis specificity. Herein, a tumor microenvironment (TME) activated NIR-II phototheranostic nanoplatform (Ag₂S-Fe(III)-DBZ Pdots, AFD NPs) is designed based on the principle of Förster resonance energy transfer (FRET). The AFD NPs are fabricated through self-assembly of Ag₂S QDs (NIR-II fluorescence probe) and ultra-small semiconductor polymer dots (DBZ Pdots, NIR-II fluorescence quencher) utilizing Fe(III) as coordination nodes. In normal tissues, the AFD NPs maintain in “off” state, due to the FRET between Ag₂S QDs and DBZ Pdots. However, the NIR-II fluorescence signal of AFD NPs can be rapidly “turn on” by the overexpressed GSH in tumor tissues, achieving a superior tumor-to-normal tissue (T/NT) signal ratio. Moreover, the released Pdots and reduced Fe(II) ions provide NIR-II photothermal therapy (PTT) and chemodynamic therapy (CDT), respectively. The GSH depletion and NIR-II PTT effect further aggravate CDT mediated oxidative damage toward tumors, achieving the synergistic anti-tumor therapeutic effect. The work provides a promising strategy for the development of TME activated NIR-II phototheranostic nanoprobes.     

Biocompatible Conjugated Polymer Nanoparticles for Efficient Photothermal Tumor Therapy

Conjugated polymers (CPs) with strong near‐infrared (NIR) absorption and high heat conversion efficiency have emerged as a new generation of photothermal therapy (PTT) agents for cancer therapy. An efficient strategy to design NIR absorbing CPs with good water dispersibility is essential to achieve excellent therapeutic effect. In this work, poly[9,9‐bis(4‐(2‐ethylhexyl)phenyl)fluorene‐alt‐co‐6,7‐bis(4‐(hexyloxy)phenyl)‐4,9‐di(thiophen‐2‐yl)‐thiadiazoloquinoxaline] (PFTTQ) is synthesized through the combination of donor–acceptor moieties by Suzuki polymerization. PFTTQ nanoparticles (NPs) are fabricated through a precipitation approach using 1,2‐distearoyl‐ sn ‐glycero‐3‐phosphoethanolamine‐N‐[methoxy(polyethylene glycol)‐2000] (DSPE‐PEG₂₀₀₀) as the encapsulation matrix. Due to the large NIR absorption coefficient (3.6 L g^‐1 cm^‐1), the temperature of PFTTQ NP suspension (0.5 mg/mL) could be rapidly increased to more than 50 °C upon continuous 808 nm laser irradiation (0.75 W/cm²) for 5 min. The PFTTQ NPs show good biocompatibility to both MDA‐MB‐231 cells and Hela cells at 400 μg/mL of NPs, while upon laser irradiation, effective cancer cell killing is observed at a NP concentration of 50 μg/mL. Moreover, PFTTQ NPs could efficiently ablate tumor in in vivo study using a Hela tumor mouse model. Considering the large amount of NIR absorbing CPs available, the general encapsulation strategy will enable the development of more efficient PTT agents for cancer or tumor therapy.     

Flexible Photothermal Assemblies with Tunable Gold Patterns for Improved Imaging‐Guided Synergistic Therapy

Self‐assembly of gold nanoparticles demonstrates a promising approach to realize enhanced photoacoustic imaging (PAI) and photothermal therapy (PTT) for accurate diagnosis and efficient cancer therapy. Herein, unique photothermal assemblies with tunable patterns of gold nanoparticles (including arcs, rings, ribbons, and vesicles) on poly(lactic‐co‐glycolic acid) (PLGA) spheres are constructed taking advantage of emulsion‐confined and polymer‐directed self‐assembly strategies. The influencing factors and formation mechanism to produce the assemblies are investigated in details. Both the emulsion structure and migration behaviors of amphiphilic block copolymer tethered gold nanoparticles are found to contribute to the formation of versatile photothermal assemblies. Hyaluronic acid‐modified R‐PLGA‐Au (RPA) exhibits outstanding photothermal performances under NIR laser irradiation, which is induced by strong plasmonic coupling between adjacent gold nanoparticles. It is interesting that secondary assembly of RPA can be triggered by NIR laser irradiation. Prolonged residence time in tumors is achieved after RPA assemblies are fused into superstructures with larger sizes, realizing real‐time monitoring of the therapeutic processes via PAI with enhanced photoacoustic signals. Notably, synergistic effect resulting from PTT‐enhanced chemotherapy is realized to demonstrate high antitumor performance. This work provides a facile strategy to construct flexible photothermal assemblies with favorable properties for imaging‐guided synergistic therapy.     

Intracellular Dual Fluorescent Lightup Bioprobes for Image‐Guided Photodynamic Cancer Therapy

An intracellular dual fluorescent light‐up bioprobe with aggregation‐induced emission features and endogenously producing photosensitizer protoporphyrin IX (PpIX) abilities is designed and synthesized. The bioprobe is nonemissive in physiological environment. However, the bioprobe can selectively light up cancer cells with blue fluorescence of tetraphenylene (TPE) and red fluorescence of PpIX, owing to the release of TPE and methyl aminolevulinate after targeted internalization by cancer cells. Moreover, upon endogenous generation and accumulation of PpIX in cancer cells, efficient photodynamic ablation of cancer cells after light irradiation is demonstrated with easy regulation for optimal therapeutic efficacy. The design of such dual fluorescent light‐up bioprobes might provide a new opportunity for targeted and image‐guided photodynamic cancer therapy.