Tumor Microenvironment-Triggered Self-Adaptive Polymeric Photosensitizers for Enhanced Photodynamic Therapy.

Photodynamic therapy (PDT) employs photosensitizers to convert nearby oxygen into toxic singlet oxygen (1O2) upon laser light irradiation, showing great potential as a noninvasive approach for tumor ablation. However, the therapeutic efficacy of PDT is essentially impeded by π-π stacking and the aggregation of photosensitizers. Herein, we propose a tumor microenvironment-triggered self-adaptive nanoplatform to weaken the aggregation of photosensitizers by selenium-based oxidation at the tumor site. The selenide units in a selenium-based porphyrin-containing amphiphilic copolymer (PSe) could be oxidized into hydrophilic selenoxide units, leading to the nanoplatform self-expansion and stretching of the distance between intramolecular porphyrin units. This process could provide a better switch to greatly reduce the aggregation of photosensitive porphyrin units, generating more 1O2 upon laser irradiation. As verified in a series of in vitro and in vivo studies, PSe could be efficiently self-adapted at tumor sites, thus significantly enhancing the PDT therapeutic effect against solid tumors and minimizing side effects.

A supramolecular nanoplatform for imaging-guided phototherapies via hypoxia tumour microenvironment remodeling.

Photodynamic therapy (PDT) has emerged as an invasive and promising antitumour treatment, however, the hypoxia in deep tumour tissues and the poor water-solubility of photosensitizers as bottlenecks greatly hinder PDT efficiency. Herein, a tumour microenvironment (TME) activated supramolecular nanoplatform consisting of the pillar[5]arene-based amphiphilic polymer POPD, the phototherapeutic agent Cy7-CN, respiratory medication atovaquone (ATO) and chemotherapeutic drug pyridinyl camptothecin (CPT-Py) was constructed for imaging-guided hypoxia-ameliorated phototherapies. Owing to host-guest interaction, the photochemical and photophysical properties of cyanine were improved exceedingly due to the suppression of π-π stacking. Triggered by the acidic microenvironment in tumour sites, the supramolecular nanoplatform would dissociate and release CPT-Py and ATO which inhibits mitochondria-associated oxidative phosphorylation (OXPHOS) and encourages more oxygen to be used in enhanced PDT. In vitro and in vivo studies verified that the rational combination of ATO-enhanced PDT and PTT overcame the disadvantages of single phototherapy and formed mutual promotion, and simultaneously sensitized chemotherapeutic drugs, which resulted in high tumour inhibition. It is hoped that the supramolecular nanoplatform could shed light on the development of phototherapeutic agents.

Inhibiting Radiative Transition-Mediated Multifunctional Polymeric Nanoplatforms for Highly Efficient Tumor Phototherapeutics.

It is highly desired to explore ideal phototherapeutic nanoplatforms, especially containing satisfactory phototherapeutic agents (PTAs), for potential cancer therapies. Herein, we proposed an effective strategy for designing a highly efficient PTA through inhibiting radiative transition (IRT). Specifically, we developed an ultralow radiative BODIPY derivative (TPA-IBDP) by simply conjugating two triphenylamine units to iodine-substituted BODIPY, which could simultaneously facilitate the nonradiative decay channels of singlet-to-triplet intersystem crossing and intramolecular charge transfer. In comparison to the normal BODIPY compound, TPA-IBDP exhibited an outstanding singlet oxygen yield (31.8-fold) and a higher photothermal conversion efficiency (PCE; over 3-fold), respectively, benefiting from the extended π-conjugated donor-to-accepter (D-A) structure and the heavy atom effect. For tumor phototherapy using TPA-IBDP, TPA-IBDP was conjugated with a H2O2-responsive amphiphilic copolymer POEGMA10-b-[PBMA5-co-(PS-N3)2] to construct a multifunctional phototherapeutic BODIPY-based nanoplatform (PB). PB produced abundant singlet oxygen (1O2) and heat along with negligible fluorescence emission under near-infrared laser irradiation. Additionally, PB could generate a GSH-depletion scavenger (quinone methide, QM) after reacting with the abundant intracellular H2O2 in tumor for the cooperative enhancement of IRT-mediated phototherapy. We envision that this highly efficient multifunctional phototherapeutic nanoplatform cooperated by GSH-depletion could be a valuable paradigm for tumor treatments.

Pillar[5]arene-Based Switched Supramolecular Photosensitizer for Self-Amplified and pH-Activated Photodynamic Therapy.

Photodynamic therapy (PDT) has emerged as a promising and spatiotemporally controllable cancer treatment modality. However, serious skin photosensitization during the PDT process limits the clinical application of PDT. Thus, the construction of "smart" and multifunctional photosensitizers has attracted substantial interest. Herein, we develop a mitochondria-targeting and pH-switched hybrid supramolecular photosensitizer by the host-guest interaction. The PDT efficacy of supramolecular photosensitizers can be quenched by the Förster resonance energy transfer (FRET) effect during long circulation and activated by the dissociation of supramolecular photosensitizers in an acidic tumor microenvironment, benefitting from the dynamic feature of the host-guest interaction and pH responsiveness of the water-soluble pillar[5]arene on gold nanoparticles. The rational integration of mitochondria-targeting and reductive glutathione (GSH) elimination in the hybrid switchable supramolecular photosensitizer prolongs the lifetime of reactive oxygen species generated in the PDT near mitochondria and further amplifies the PDT efficacy. Thus, the facile and versatile construction of switchable supramolecular photosensitizer offers not only the targeted and precise phototherapy but also high therapeutic efficacy, which would provide a new path for the clinic application of PDT.

Single-wavelength phototheranostics for colon cancer via the thiolytic reaction.

It's a huge challenge to develop effective nanosystems that combine the capabilities of diagnoses and therapies together for colon cancer in the clinic. Herein, we constructed a far-red absorbing phototheranostic nanosystem (FR-H2S) based on the thiolytic reaction of a dinitrophenyl modified phototheranostic prodrug and over-expressed H2S in colon cancer sites for precise imaging-guided phototherapy. FR-H2S with a BODIPY core not only could work as an imaging probe for diagnosis but also act as a phototherapeutic agent for cancer treatment under a single FR laser source (650 nm). FR-H2S exhibited a gradually enhanced fluorescence emission for precise diagnosis of H2S-rich colon tumor sites. After entering tumor cells, FR-H2S could generate abundant 1O2 and heat for phototherapies timely by using the same laser source (650 nm). We believe that this precise imaging-guided phototheranostic nanosystem could provide a promising approach to colon cancer with minimal damage.

NIR-Triggered Multifunctional and Degradable Nanoplatform Based on an ROS-Sensitive Block Copolymer for Imaging-Guided Chemo-Phototherapy.

Imaging-guided chemo-phototherapy based on multifunctional nanocarriers has emerged as a promising and high-efficient cancer treatment because of the inevitable limitations of single therapy. Herein, a near-infrared (NIR) light-activated degradable polymeric nanoplatform was fabricated for chemo-phototherapy. An NIR photosensitizer, IR780, and a chemotherapeutic drug, doxorubicin (DOX), were efficiently coloaded within a reactive oxygen species (ROS)-sensitive polymeric micelle based on an amphiphilic copolymer with degradable thioketal (TK) linkages. The obtained spherical nanoparticles (denoted as (IR780/DOX)@PTK) exhibited a notable photodynamic and photothermal effect upon NIR light exposure. Furthermore, due to the rapid cleavage of TK linkers induced by ROS generated from NIR-activated IR780, (IR780/DOX)@PTK also showed an NIR light-induced degradable feature, which can be used for light-triggered tumor-specific drug release and lead to ignorable systematic toxicity after biodegradation and drug delivery. Under the guidance of NIR fluorescence and photothermal dual modal imaging, (IR780/DOX)@PTK exhibited excellent tumor accumulation after intravenously injection into 4T1-tumor-bearing mice. As verified in both in vitro and in vivo study, (IR780/DOX)@PTK presented a significant tumor suppression effect by synergistic chemo-phototherapy.

NIR-Activated "OFF/ON" Photodynamic Therapy by a Hybrid Nanoplatform with Upper Critical Solution Temperature Block Copolymers and Gold Nanorods.

Photodynamic therapy (PDT) is a promising treatment modality for cancer treatment owing to its minimally invasive nature and negligible drug resistance. However, the disadvantages of conventional photosensitizers including universal aggregation-caused quenching (ACQ) effect or nonselective activation are still major hurdles for PDT clinical application. Herein, a new strategy for flexible manipulating photosensitizers in effective quenching and quick recovery of photoactivation is presented by introducing porphyrin units into upper critical solution temperature (UCST) block copolymer decorated gold nanorods (AuNR-P(AAm-co-AN-co-TPP)-b-PEG). The UCST block copolymer can achieve a self-quenching effect to make the porphyrin photosensitizers in the "Off" state by π-π stacking and hydrogen bonding interactions at physiological temperature, which greatly minimizes the nonselective phototoxicity of the photosensitizers to meet the requirement of phototherapy protected from sunlight. After the immigration of AuNR-P(AAm-co-AN-co-TPP)-b-PEG nanoparticles into the tumor tissue and the internalization by cancer cells, the UCST polymer chains can be extended under the local heating of AuNRs by NIR light irradiation, and then porphyrin photosensitizers are turned "On" to dramatically boost the PDT efficiency. Therefore, the process of PDT could be well manipulated in the "Off/On" state by the hybrid nanoplatform with UCST block copolymers and AuNRs, which will open new horizons for clinical treatments of PDT.

Multistep Consolidated Phototherapy Mediated by a NIR-Activated Photosensitizer.

The multifunctional effect of a single molecule for therapeutic functionalities on a single theranostic nanosystem has a great significance to enhance the accuracy of diagnosis and improve the efficacy of therapy. Herein, a biocompatible multistep phototherapeutic system (Ppa-Cy7-PEG-biotin) that contains a photosensitizer pyropheophorbide A (Ppa) with the covalent conjunction of a near-infrared (NIR) cyanine dye (Cy7) was successfully fabricated and functionalized with biotin for flexible specific tumor-targeting phototherapy. These theranostic micelles will disaggregate after NIR irradiation via the photodegradation of cyanine accompanied by the photothermal conversion and the optically controlled release for the restoration of photodynamic function of quenched Ppa. Consecutively, promoted treatments of photosensitive molecules greatly prolonged the tumor retention time and treatment efficiency, having a multistep antitumor effect both in vitro and in vivo. Different from the simple phototherapeutic configurations that only act on the superficial areas of tumors at mild doses, the multistep therapy can be competent for broadly damaging the superficial and deeper regions of tumors at the same dose. Therefore, as opposed to the general combination phototherapeutic approach, this strategy presents a photoactivation-based multistep phototheranostic platform with an enormous potential in enhanced combined phototherapy for cancer.

Hyaluronic acid conjugated polydopamine functionalized mesoporous silica nanoparticles for synergistic targeted chemo-photothermal therapy.

The integration of chemotherapy and photothermal therapy into one nanoplatform has attracted much attention for synergistic tumor treatment, but the practical clinical applications were usually limited by their synergistic effects and low selectivity for disease sites. To overcome these limitations, a tumor-specific and pH/NIR dual-responsive multifunctional nanocarrier coated with mussel inspired polydopamine and further conjugated with targeting molecular hyaluronic acid (HA) was designed and fabricated for synergistic targeted chemo-photothermal therapy. The synthesized versatile nanoplatform displayed strong near-infrared absorption because of the successful formation of polydopamine coating. Furthermore, the nanosystem revealed high storage capacity for drugs and pH/NIR dual-responsive release performance, which could effectively enhance the chemo-photothermal therapy effect. With this smart design, in vitro experimental results confirmed that the drug loaded multifunctional nanoparticles could be efficiently taken up by cancer cells, and exhibited remarkable tumor cell killing efficiency and excellent photothermal properties. Meanwhile, significant tumor regression in the tumor-bearing mice model was also observed due to the combination of chemotherapy and photothermal therapy. Thus, this work indicated that the simple multifunctional nanoplatform can be applied as an efficient therapeutic agent for site-specific synergistic chemo-photothermal therapy.

NIR-Activated Polymeric Nanoplatform with Upper Critical Solution Temperature for Image-Guided Synergistic Photothermal Therapy and Chemotherapy.

Premature and incomplete drug release is the typical bottleneck of drug release in traditional chemotherapy. Synergistic therapies are highly desirable in medicine and biology because they can compensate for the drawbacks of single therapy and significantly enhance the therapeutic efficacy. Herein, a novel near infrared (NIR)-activated polymeric nanoplatform with upper critical solution temperature (UCST) was constructed for image-guided synergistic photothermal therapy (PTT) and chemotherapy. UCST-responsive amphiphilic block copolymers were synthesized by reversible addition-fragmentation chain-transfer (RAFT) polymerization and then co-assembled with IR780 and cabazitaxel (Cab) to form spherical nanoparticles (NPs). IR780/Cab dual-loaded UCST polymeric NPs can produce local heating upon NIR laser irradiation and further lead to the dissociation of cargo-loaded NPs and controlled release of Cab. IR780 plays the role of both a heating generator and an activator for "on-demand" drug release. The investigation of in vivo fluorescence and photothermal imaging clearly demonstrated tumor targeting. Notably, both in vitro and in vivo studies illustrated that the synergistic PTT and chemotherapy presented better anticancer efficacy than that of PTT and chemotherapy simplely combined. Thus, the well-defined polymeric nanoplatform opens a versatile and effective path to develop image-guided synergistic therapies for tumor treatment.

Intracellular GSH-activated galactoside photosensitizers for targeted photodynamic therapy and chemotherapy.

Ligand-targeted cancer therapeutics has been developed to minimize non-specific cytotoxicity via ligand-drug conjugates during the past few decades. We present here the design and synthesis of a GSH-activated amphiphilic photosensitizer conjugated with galactose (TPP-S-S-Gal) for targeted photodynamic therapy. Furthermore, the galactoside photosensitizer as supramolecular amphiphiles can self-assemble into micelles, which can be applied in integrative cancer treatment with chemotherapy drugs such as camptothecin (CPT) encapsulated in the hydrophobic core of micelles. Upon reaction with free thiol GSH that is relatively abundant in tumor cells, disulfide bond cleavage occurs as well as the active photosensitizer TPP and chemotherapy drug CPT release, which can cause cell apoptosis. The in vitro biological assessment of TPP-S-S-Gal micelles against the A549 cell line was evaluated by MTT assay, flow cytometry and confocal scanning laser microscopy, respectively. According to the MTT assay, TPP-S-S-Gal micelles exhibited low dark toxicity and efficient integrative efficacy of PDT and chemotherapy towards A549 cells after light irradiation.