Photodynamic therapy synergizes with PD-L1 checkpoint blockade for immunotherapy of CRC by multifunctional nanoparticles.

Checkpoint inhibitors, such as anti-PD-1/PD-L1 antibodies, have been shown to be extraordinarily effective, but their durable response rate remains low, especially in colorectal cancer (CRC). Recent studies have shown that photodynamic therapy (PDT) could effectively enhance PD-L1 blockade therapeutic effects, although the reason is still unclear. Here, we report the use of multifunctional nanoparticles (NPs) loaded with photosensitized mTHPC (mTHPC@VeC/T-RGD NPs)-mediated PDT treatment to potentiate the anti-tumor efficacy of PD-L1 blockade for CRC treatment and investigate the underlying mechanisms of PDT enhancing PD-L1 blockade therapeutic effect in this combination therapy. In this study, the mTHPC@VeC/T-RGD NPs under the 660-nm near infrared (NIR) laser could kill tumor cells by inducing apoptosis and/or necrosis and stimulating systemic immune response, which could be further promoted by the PD-L1 blockade to inhibit primary and distant tumor growth, as well as building long-term host immunological memory to prevent tumor recurrence. Furthermore, we detected that mTHPC@VeC/T-RGD NP-mediated PDT sensitizes tumors to PD-L1 blockade therapy mainly because PDT-mediated hypoxia could induce the hypoxia-inducible factor 1α (HIF-1α) signaling pathway that upregulates PD-L1 expression in CRC. Taken together, our work demonstrates that mTHPC@VeC/T-RGD NP-mediated PDT is a promising strategy that may potentiate the response rate of anti-PD-L1 checkpoint blockade immunotherapies in CRC.

Enhancement of target toxin neutralization effect in vivo by PEGylation of multifunctionalized lipid nanoparticles.

Protein-protein (e.g., antibody-antigen) interactions comprise multiple weak interactions. We have previously reported that lipid nanoparticles (LNPs) bind to and neutralize target toxic peptides after multifunctionalization of the LNP surface (MF-LNPs) with amino acid derivatives that induce weak interactions; however, the MF-LNPs aggregated after target capture and showed short blood circulation times. Here we optimized polyethylene glycol (PEG)-modified MF-LNPs (PEG-MF-LNPs) to inhibit the aggregation and increase the blood circulation time. Melittin was used as a target toxin, and MF-LNPs were prepared with negatively charged, hydrophobic, and neutral amino-acid-derivative-conjugated functional lipids. In this study, MF-LNPs modified with only PEG5k (PEG5k-MF-LNPs) and with both PEG5k and PEG2k (PEGmix-MF-LNPs) were prepared, where PEG5k and PEG2k represent PEG with a molecular weight of 5000 and 2000, respectively. PEGylation of the MF-LNPs did not decrease the melittin neutralization ability of nonPEGylated MF-LNPs, as tested by hemolysis assay. The PEGmix-MF-LNPs showed better blood circulation characteristics than the PEG5k-MF-LNPs. Although the nonPEGylated MF-LNPs immediately aggregated when mixed with melittin, the PEGmix-MF-LNPs did not aggregate. The PEGmix-MF-LNPs dramatically increased the survival rate of melittin-treated mice, whereas the nonPEGylated MF-LNPs increased slightly. These results provide a fundamental strategy to improve the in vivo toxin neutralization ability of MF-LNPs.

pH-sensitive dual drug loaded janus nanoparticles by oral delivery for multimodal analgesia.

BACKGROUND: Based on the concept of "multimodal analgesia", a novel dual drug delivery system was designed to achieve synergistic analgesia between najanajaatra venom protein (αCT) and resveratrol (Res). In order to meet the joint loading of two drugs with different physicochemical properties without affecting each other, an oral Janus nanoparticle (JNP) with a unique cavity structure and synergistic drug delivery was constructed using an improved double emulsion solvent evaporation method, and combined with low-molecular-weight chitosan/sodium alginate and PLGA to achieve its pH-responsive. RESULTS: The synthesized αCT/Res-JNPs are homogeneous in shape, with a two-compartment structure, approximately 230 nm in size, and zeta potential of 23.6 mV. Drug release assayed in vitro show that JNP was stable in simulated gastric juice (pH = 1.2) but was released in phosphate buffer saline (pH = 7.4). After intragastric administration in rats, PK evaluation showed that αCT/Res-JNPs could significantly improve the oral bioavailability, and the simultaneous encapsulation of the two drugs had no significant interaction on PK parameters. An obvious synergistic analgesic effects of αCT/Res-JNPs was confirmed in a spinal cord injury and acute pain model. Confocal laser scanning microscopy and single-pass intestinal perfusion model provided strong evidence that αCT/Res-JNPs could pass through intestinal epithelial cells, and the endocytosis pathway was mainly involved in the mediation and pinocytosis of reticulin. The concentrations of αCT and Res from αCT/Res-JNP in lymphatic transport were only about 8.72% and 6.08% of their blood concentrations at 1 h, respectively, which indicated that lymphatic transport in the form of JNP has limited advantages in improving the oral bioavailability of Res and αCT. Cellular uptake efficiency at 4 h was about 10-15% in Caco-2 cell lines for αCT/Res-JNP, but was reduced to 7% in Caco-2/HT29-MTX co-culture models due to the hindrance by the mucus layers. Approximately 12-17% of αCT/Res-JNP were transported across Caco-2/HT29-MTX/Raji monolayers. The cumulative absorption of JNP in three cell models was higher than that of free drug. CONCLUSIONS: This study investigated the contribution of Janus nanoparticles in oral absorption, and provide a new perspective for oral administration and analgesic treatment of dual drug delivery system containing peptide drugs.

Biocompatible AIEgen/p-glycoprotein siRNA@reduction-sensitive paclitaxel polymeric prodrug nanoparticles for overcoming chemotherapy resistance in ovarian cancer.

Nanoparticle drug delivery system (NDDS) is quite different from the widely studied traditional chemotherapy which suffers from drug resistance and side effect. NDDS offers the straightforward solution to the chemotherapy problem and provides an opportunity to monitor the drug delivery process in real time. In this vein, we developed one NDDS, namely Py-TPE/siRNA@PMP, to relieve resistance and side effects during chemotherapy against ovarian cancer. The Py-TPE/siRNA@PMP is a multifunctional polymeric nanoparticle contained several parts as follows: (1) a nanoparticle (NP) self-assembled by reduction-sensitive paclitaxel polymeric prodrug (PMP); (2) the glutathione (GSH)-responsive release of paclitaxel (PTX) for the suppression of ovarian cancer cells; (3) the P-glycoprotein (P-gp) siRNA for restoring the sensitivity of chemo-resistant tumor cells to chemotherapy; (4) the positively charged aggregation-induced emission fluorogen (AIEgen) Py-TPE for tumor imaging and promoting encapsulation of siRNA into the nanoparticle. Methods: The Py-TPE/siRNA@PMP nanoparticles were prepared by self-assembly method and characterized by the UV-Vis absorption spectra, zeta potentials, TEM image, stability assay and hydrodynamic size distributions. The combinational therapeutic effects of Py-TPE/siRNA@PMP on overcoming chemotherapy resistance were explored both in vitro and in vivo.Result: The Py-TPE/siRNA@PMP exhibited an average hydrodynamic size with a good stability. Meanwhile they gave rise to the remarkable chemotoxicity performances in vitro and suppressed the tumors growth in both SKOV-3/PTX (PTX resistance) subcutaneous and intraperitoneal metastasis tumor models. The investigations on ovarian cancer patient-derived xenografts (PDX) model revealed that Py-TPE/siRNA@PMP was able to effectively overcome their chemo-resistance with minimal side effects. Conclusion: Our findings demonstrated the Py-TPE/siRNA@PMP as a promising agent for the highly efficient treatment of PTX-resistant cells and overcoming the shortage of chemotherapy in ovarian cancer.

Dual-ligand supramolecular nanofibers inspired by the renin-angiotensin system for the targeting and synergistic therapy of myocardial infarction.

Rationale: The compensatory activation of the renin-angiotensin system (RAS) after myocardial infarction (MI) plays a crucial role in the pathogenesis of heart failure. Most existing studies on this subject focus on mono- or dual-therapy of blocking the RAS, which exhibit limited efficacy and often causes serious adverse reactions. Few studies have been conducted on targeted therapy based on the activated RAS post-MI. Thus, the development of multiple-functional nanomedicine with concurrent targeting ability and synergistic therapeutic effect against RAS may show great promise in improving cardiac function post-MI. Methods: We utilized a cooperative self-assembly strategy constructing supramolecular nanofibers- telmisartan-doped co-assembly nanofibers ( TDCNfs ) to counter-regulate RAS through targeted delivery and combined therapy. TDCNfs were prepared through serial steps of solvent exchange, heating incubation, gelation, centrifugation, and lyophilization, in which the telmisartan was doped in the self-assembly process of Ang1-7 to obtain the co-assembly nanofibers wherein they act as both therapeutic agents and target-guide agents. Results: TDCNfs exhibited the desired binding affinity to the two different receptors, AT1R and MasR. Through the dual ligand-receptor interactions to mediate the coincident downstream pathways, TDCNfs not only displayed favorably targeted properties to hypoxic cardiomyocytes, but also exerted synergistic therapeutic effects in apoptosis reduction, inflammatory response alleviation, and fibrosis inhibition in vitro and in vivo, significantly protecting cardiac function and mitigating post-MI adverse outcomes. Conclusion: A dual-ligand nanoplatform was successfully developed to achieve targeted and synergistic therapy against cardiac deterioration post-MI. We envision that the integration of multiple therapeutic agents through supramolecular self-assembly would offer new insight for the systematic and targeted treatment of cardiovascular diseases.

Multifunctional nanoparticle PEG­Ce6­Gd for MRI­guided photodynamic therapy.

Gliomas are one of the most common types of primary brain tumors. Despite recent advances in the combination of surgery, radiotherapy, systemic therapy (chemotherapy, targeted therapy) and supportive therapy in the multimodal treatment of gliomas, the overall prognosis remains poor and the long­term survival rate is low. Thus, it is crucial to develop a novel glioma management method. Due to its relatively non­invasive, selective and repeatable characteristics, photodynamic therapy (PDT) has been investigated for glioma therapy in the past decade, exhibiting higher selectivity and lower side effects compared with those of conventional therapy. However, most of the photosensitizers (PSs) are highly hydrophobic, leading to poor water solubility, rapid degradation with clearance in blood circulation and ultimately, low bioavailability. In the present study, hydrophilic polyethylene glycol (PEG)­chlorin e6 (Ce6) chelated gadolinium ion (Gd3+) nanoparticles (PEG­Ce6­Gd NPs) were synthesized via a chelation and self­assembly process. Initially, the cell cytotoxicity of PEG­Ce6­Gd NPs was evaluated with or without laser irradiation. The in vitro study demonstrated the lack of toxicity of PEG­Ce6­Gd NPs to tumor cells in the absence of laser irradiation. However, its toxicity was enhanced under laser irradiation. Moreover, the size and weight of brain tumors were significantly decreased in mice with glioma xenografts, which was further confirmed via histological analysis. Subsequently, the results indicated that the PEG­Ce6­Gd NPs had a favorable T1­weighted contrast performance (0.43 mg ml­1 s­1) and were observed to have significant contrast enhancement at the tumor site from 0.25 to 1 h post­injection in vivo. The favorable MRI, as well as the synergetic photodynamic antitumor effect and antineoplastic ability of PEG­Ce6­Gd NPs was identified. It was suggested that PEG­Ce6­Gd NPs had great potential in the diagnosis and PDT treatment of gliomas, and possibly other cancer types, with prospects of clinical application in the near future.

Oral Administration of Resveratrol-Selenium-Peptide Nanocomposites Alleviates Alzheimer's Disease-like Pathogenesis by Inhibiting Aß Aggregation and Regulating Gut Microbiota.

Alzheimer's disease (AD) is a neurodegenerative disease associated with amyloid-ß (Aß) deposition, leading to neurotoxicity (oxidative stress and neuroinflammation) and gut microbiota imbalance. Resveratrol (Res) has neuroprotective properties, but its bioavailability in vivo is very low. Herein, we developed a small Res-selenium-peptide nanocomposite to enable the application of Res for eliminating Aß aggregate-induced neurotoxicity and mitigating gut microbiota disorder in aluminum chloride (AlCl3) and d-galactose(d-gal)-induced AD model mice. Res functional selenium nanoparticles (Res@SeNPs) (8 ± 0.34 nm) were prepared first, after which the surface of Res@SeNPs was decorated with a blood-brain barrier transport peptide (TGN peptide) to generate Res-selenium-peptide nanocomposites (TGN-Res@SeNPs) (14 ± 0.12 nm). Oral administration of TGN-Res@SeNPs improves cognitive disorder through (1) interacting with Aß and decreasing Aß aggregation, effectively inhibiting Aß deposition in the hippocampus; (2) decreasing Aß-induced reactive oxygen species (ROS) and increasing activity of antioxidation enzymes in PC12 cells and in vivo; (3) down-regulating Aß-induced neuroinflammation via the nuclear factor kappa B/mitogen-activated protein kinase/Akt signal pathway in BV-2 cells and in vivo; and (4) alleviating gut microbiota disorder, particularly with respect to oxidative stress and inflammatory-related bacteria such as Alistipes, Helicobacter, Rikenella, Desulfovibrio, and Faecalibaculum. Thus, we anticipate that Res-selenium-peptide nanocomposites will offer a new potential strategy for the treatment of AD.

Nanoscale investigation of human skin and study of skin penetration of Janus nanoparticles.

Janus nanoparticles (JNP) are innovative nanocarriers with an interesting pharmaceutical and cosmetic potential. They are characterized by the presence of a lipid compartment associated with an aqueous compartment delimited by a phospholipid bilayer containing phospholipids and non-ionic surfactants. The hydrodynamic diameter of JNP varies between 150 and 300 nm. The purpose of this study was to answer the following questions: after cutaneous application, are JNP penetrating? If so, how deep? And in which state, intact or degraded? It was essential to understand these phenomena in order to control the rate and kinetics of diffusion of active ingredients, which can be encapsulated in this vehicle for pharmaceutical or cosmetic purposes. An innovative technique called AFM-IR, was used to elucidate the behavior of JNP after cutaneous application. This instrument, coupling atomic force microscopy and IR spectroscopy, allowing to perform chemical analysis at the nanometer scale thanks to local absorption measurements. The identification of organic molecules at the nanoscale is possible without any labelling. Before cutaneous application of JNP, the nano-structure of untreated human skin was investigated with AFM-IR. Then, in vitro human skin penetration of JNP was studied using Franz cells, and AFM-IR allowed us to perform ultra-local information investigations.

Cascade-Targeting of Charge-Reversal and Disulfide Bonds Shielding for Efficient DOX Delivery of Multistage Sensitive MSNs-COS-SS-CMC.

BACKGROUND: Although pH and redox sensitiveness have been extensively investigated to improve therapeutic efficiency, the effect of disulfide bonds location and pH-triggered charge-reversal on cascade-targeting still need to be further evaluated in cancer treatment with multi-responsive nanoparticles. PURPOSE: The aim of this study was to design multi-responsive DOX@MSNs-COS-NN-CMC, DOX@MSNs-COS-SS-CMC and DOX@MSNs-COS-CMC-SS and systematically investigate the effects of disulfide bonds location and charge-reversal on the cancer cell specificity, endocytosis mechanisms and antitumor efficiency. RESULTS: In vitro drug release rate of DOX@MSNs-COS-SS-CMC in tumor environments was 7-fold higher than that under normal physiological conditions after 200 h. Furthermore, the fluorescence intensity of DOX@MSNs-COS-SS-CMC and DOX@MSNs-COS-CMC-SS was 1.9-fold and 1.3-fold higher than free DOX at pH 6.5 and 10 mM GSH. In addition, vesicular transport might be a factor that affects the uptake efficiency of DOX@MSNs-COS-SS-CMC and DOX@MSNs-COS-CMC-SS. The clathrin-mediated endocytosis and endosomal escape of DOX@MSNs-COS-SS-CMC enhanced cellular internalization and preserved highly controllable drug release into the perinuclear of HeLa cells. DOX@MSNs-COS-SS-CMC exhibited a synergistic chemotherapy in preeminent tumor inhibition and less side effects of cardiotoxicity. CONCLUSION: The cascade-targeting of charge-reversal and disulfide bonds shielding would be a highly personalized strategy for cervical cancer treatment.

CXCL12/CXCR4 Axis-Targeted Dual-Functional Nano-Drug Delivery System Against Ovarian Cancer.

INTRODUCTION: Traditional chemotherapy for ovarian cancer is limited due to drug resistance and systemic side effects. Although various targeted drug delivery strategies have been designed to enhance drug accumulation at the tumor site, simply improvement of targeting capability has not consistently led to satisfactory outcomes. Herein, AMD3100 was selected as the targeting ligand because of its high affinity to chemokine receptor 4 (CXCR4), which was highly expressed on ovarian cancer cells. Moreover, the AMD3100 has been proved having blockage capability of stromal cell-derived factor 1 (SDF-1 or CXCL12)/CXCR4 axis and to be a sensitizer of chemotherapeutic therapy. We designed a dual-functional targeting delivery system by modifying paclitaxel (PTX)-loaded PEGylation bovine serum albumin (BSA) nanoparticles (NPs) with AMD3100 (AMD-NP-PTX), which can not only achieve specific tumor-targeting efficiency but also enhance the therapeutic outcomes. METHODS: AMD3100 was chemically modified to Mal-PEG-NHS followed by reacting with BSA, then AMD-NP-PTX was synthesized and characterized. The targeting efficiency of AMD-NP was evaluated both in vitro and in vivo. The anticancer effect of AMD-NP-PTX was determined on Caov3 cells and ovarian cancer-bearing nude mice. Finally, the potential therapeutic mechanism was studied. RESULTS: AMD-NP-PTX was synthesized successfully and well characterized. Cellular uptake assay and in vivo imaging experiments demonstrated that NPs could be internalized by Caov3 cells more efficiently after modification of AMD3100. Furthermore, the AMD-NP-PTX exhibited significantly enhanced inhibition effect on tumor growth and metastasis compared with PTX, NP-PTX and free AMD3100 plus NP-PTX both in vitro and in vivo, and demonstrated improved safety profile. We also confirmed that AMD-NP-PTX worked through targeting CXCL12/CXCR4 axis, thereby disturbing its downstream signaling pathways including epithelial-mesenchymal transition (EMT) processes and nuclear factor κB (NF-κB) pathway. CONCLUSION: The AMD-NP-PTX we designed would open a new avenue for dual-functional NPs in ovarian cancer therapy.

Iron(II) phthalocyanine Loaded and AS1411 Aptamer Targeting Nanoparticles: A Nanocomplex for Dual Modal Imaging and Photothermal Therapy of Breast Cancer.

PURPOSE: A multi-functional nanoplatform with diagnostic imaging and targeted treatment functions has aroused much interest in the nanomedical research field and has been paid more attention in the field of tumor diagnosis and treatment. However, some existing nano-contrast agents have encountered difficulties in different aspects during clinical promotion, such as complicated preparation process and low specificity. Therefore, it is urgent to find a nanocomplex with good targeting effect, high biocompatibility and significant therapeutic effect for the integration of diagnosis and treatment and clinical transformation. MATERIALS AND METHODS: Nanoparticles (NPs) targeting breast cancer were synthesized by phacoemulsification which had liquid fluorocarbon perfluoropentane(PFP) in the core and were loaded with Iron(II) phthalocyanine (FePc) on the shell. The aptamer (APT) AS1411 was outside the shell used as a molecular probe. Basic characterization and targeting abilities of the NPs were tested, and their cytotoxicity and biological safety in vivo were evaluated through CCK-8 assay and blood bio-chemical analysis. The photoacoustic (PA) and ultrasound (US) imaging system were used to assess the effects of AS1411-PLGA@FePc@PFP (A-FP NPs) as dual modal contrast agent in vitro and in vivo. The effects of photothermal therapy (PTT) in vitro and in vivo were evaluated through MCF-7 cells and tumor-bearing nude mouse models. RESULTS: A-FP NPs, with good stability, great biocompatibility and low toxicity, were of 201.87 ± 1.60 nm in diameter, and have an active targeting effect on breast cancer cells and tissues. With the help of PA/US imaging, it was proved to be an excellent dual modal contrast agent for diagnosis and guidance of targeted therapy. Meanwhile, it can heat up under near-infrared (NIR) laser irradiation and has achieved obvious antitumor effect both in vitro and in vivo experiments. CONCLUSION: As a kind of nanomedicine, A-FP NPs can be used in the integration of diagnosis and treatment. The treatment effects and biocompatibility in vivo may provide new thoughts in the clinical transformation of nanomedicine and early diagnosis and treatment of breast cancer.

Indocyanine Green and Curcumin Co-Loaded Nano-Fireball-Like Albumin Nanoparticles Based on Near-Infrared-Induced Hyperthermia for Tumor Ablation.

BACKGROUND: Indocyanine green (ICG) has received considerable interest as a biocompatible organic photothermal agent, and curcumin (Cur) is considered an attractive natural chemopreventive and chemotherapeutic compound. However, the in vivo applicability of ICG and Cur is significantly restricted by their poor ability to target tumors and their extremely low solubility. MATERIALS AND METHODS: To address these problems, ICG/Cur-loaded albumin nanoparticles (ICG-BSA-Cur-NPs) based on the nabTM (nanoparticle albumin-bound) technology were applied to neuroblastomas in vivo. RESULTS: The fabricated ICG-BSA-Cur-NPs were found to be spherical, ~150 nm in size and highly dispersible and stable in aqueous solution. Approximately 80% of the incorporated ICG and Cur were gradually released from the NPs over 48 h. All formulations of ICG-BSA-Cur-NPs (5~20 µg/mL) showed efficient hyperthermia profiles (up to 50-60°C within 5 min) in response to 808-nm NIR laser irradiation in vitro and in vivo. Notably, ICG-BSA-Cur-NPs illuminated with 808-nm laser irradiation (1.5 W/cm2) showed excellent cytotoxicity toward N2a cells in vitro and undisputable antitumor efficacy in N2a-xenografted mice in vivo, compared to other tested sample groups (tumor volumes for PBS, BSA-Cur-NPs, free ICG, and ICG-BSA-Cur-NPs groups were 1408.6 ± 551.9, 1190.6 ± 343.6, 888.6 ± 566.2, and 103.0 ± 111.3 mm3, respectively). CONCLUSION: We demonstrate that these hyperthermal chemotherapeutic ICG-BSA-Cur-NPs have potential as a future brain tumor treatment.

Light-activated gold nanorod vesicles with NIR-II fluorescence and photoacoustic imaging performances for cancer theranostics.

Fluorescence (FL) and photoacoustic (PA) imaging in the second near infrared window (NIR-II FL and NIR-II PA) hold great promise for biomedical applications because of their non-invasive nature and excellent spatial resolution properties. Methods: We develop a NIR-II PA and NIR-II FL dual-mode imaging gold nanorod vesicles (AuNR Ves) by self-assembly of amphiphilic AuNR coated with light responsive polyprodrug of Ru-complex and PEG, and NIR-II cyanine dye (IR 1061). The AuNR Ves showed strong ligh absorption property and PA imaging performance in the NIR-II windows. Moreover, the NIR-II fluorescence signal of IR 1061 loaded in the AuNR Ve is quenched. Results: The AuNR Ves can release photosensitizer Ru-complex and IR 1061 sequentially triggered by NIR light irradiation, leading to a corresponding NIR-II PA signal decrease and NIR-II FL signal recovery. Meanwhile, Ru-complex can not only serve as a chemotherapeutic drug but also generate singlet oxygen (1O2) under NIR light irradiation. The release of Ru-complex and photodynamic therapy are guided by the responsive variation of NIR-II PA and NIR-II FL signals. Conclusions: The AuNR Ve possessing not only precisely control 1O2/drug release but also the intrinsic ability to monitor therapy process offers a new strategy for the development of smart theranostic nanoplatform.

Hypoxia-Targeting Multifunctional Nanoparticles for Sensitized Chemotherapy and Phototherapy in Head and Neck Squamous Cell Carcinoma.

PURPOSE: Chemotherapy in head and neck squamous cell carcinoma (HNSCC) has many systemic side effects, as well as hypoxia-induced chemoresistance. To reduce side effects and enhance chemosensitivity are urgently needed. METHODS: We synthesized a drug delivery system (named CECMa NPs) based on cisplatin (CDDP) and metformin (chemotherapeutic sensitizer), of which chlorin e6 (Ce6) and polyethylene glycol diamine (PEG) were synthesized as the shell, an anti-LDLR antibody (which can target to hypoxic tumor cells) was modified on the surface to achieve tumor targeting. RESULTS: The NPs possessed a great synergistic effect of chemotherapy and phototherapy. After laser stimulation, both CDDP and metformin can be released in situ to achieve anti-tumor effects. Meanwhile, PDT and PTT triggered by a laser have anticancer effects. Furthermore, compared with free cisplatin, CECMa exhibits less systemic toxicity with laser irradiation in the xenograft mouse tumor model. CONCLUSION: CECMa effectively destroyed the tumors via hypoxia targeting multimodal therapy both in vitro and in vivo, thereby providing a novel strategy for targeting head and neck squamous cell carcinoma.

Metal-Organic Framework Nanoparticle-Based Biomineralization: A New Strategy toward Cancer Treatment.

Cancer treatment using functional proteins, DNA/RNA, or complex bio-entities is important in both preclinical and clinical studies. With the help of nano-delivery systems, these biomacromolecules can enrich cancer tissues to match the clinical requirements. Biomineralization via a self-assembly process has been widely applied to provide biomacromolecules exoskeletal-like protection for immune shielding and preservation of bioactivity. Advanced metal-organic framework nanoparticles (MOFs) are excellent supporting matrices due to the low toxicity of polycarboxylic acids and metals, high encapsulation efficiency, and moderate synthetic conditions. In this review, we study MOFs-based biomineralization for cancer treatment and summarize the unique properties of MOF hybrids. We also evaluate the outlook of potential cancer treatment applications for MOFs-based biomineralization. This strategy likely opens new research orientations for cancer theranostics.

Polyphenol-Based Particles for Theranostics.

Polyphenols, due to their high biocompatibility and wide occurrence in nature, have attracted increasing attention in the engineering of functional materials ranging from films, particles, to bulk hydrogels. Colloidal particles, such as nanogels, hollow capsules, mesoporous particles and core-shell structures, have been fabricated from polyphenols or their derivatives with a series of polymeric or biomolecular compounds through various covalent and non-covalent interactions. These particles can be designed with specific properties or functionalities, including multi-responsiveness, radical scavenging capabilities, and targeting abilities. Moreover, a range of cargos (e.g., imaging agents, anticancer drugs, therapeutic peptides or proteins, and nucleic acid fragments) can be incorporated into these particles. These cargo-loaded carriers have shown their advantages in the diagnosis and treatment of diseases, especially of cancer. In this review, we summarize the assembly of polyphenol-based particles, including polydopamine (PDA) particles, metal-phenolic network (MPN)-based particles, and polymer-phenol particles, and their potential biomedical applications in various diagnostic and therapeutic applications.

Multifunctional nanoparticles for intracellular drug delivery and photoacoustic imaging of mesenchymal stem cells.

Strategies that control the differentiation of mesenchymal stem cells (MSC) and enable image-guided cell implantation and longitudinal monitoring could advance MSC-based therapies for bone defects and injuries. Here we demonstrate a multifunctional nanoparticle system that delivers resveratrol (RESV) intracellularly to improve osteogenesis and enables photoacoustic imaging of MSCs. RESV-loaded nanoparticles (RESV-NPs), formulated from poly (lactic-co-glycolic) acid and iron oxide, enhanced the stability of RESV by 18-fold and served as photoacoustic tomography (PAT) contrast for MSCs. Pre-loading MSCs with RESV-NP upregulated RUNX2 expression with a resultant increase in mineralization by 27% and 45% compared to supplementation with RESV-NP and free RESV, respectively, in 2-dimensional cultures. When grown in polyethylene glycol-based hydrogels, MSCs pre-loaded with RESV-NPs increased the overall level and homogeneity of mineralization compared to those supplemented with free RESV or RESV-NP. The PAT detected RESV-NP-loaded MSCs with a resolution of 1500 cells/µL, which ensured imaging of MSCs upon encapsulation in a PEG-based hydrogel and implantation within the rodent cranium. Significantly, RESV-NP-loaded MSCs in hydrogels did not show PAT signal dilution over time or a reduction in signal upon osteogenic differentiation. This multifunctional NP platform has the potential to advance translation of stem cell-based therapies, by improving stem cell function and consistency via intracellular drug delivery, and enabling the use of a promising emerging technology to monitor cells in a clinically relevant manner.

Recent Developments of Supramolecular Metal-based Structures for Applications in Cancer Therapy and Imaging.

The biomedical application of discrete supramolecular metal-based structures, including supramolecular coordination complexes (SCCs), is still an emergent field of study. However, pioneering studies over the last 10 years demonstrated the potential of these supramolecular compounds as novel anticancer drugs, endowed with different mechanisms of action compared to classical small-molecules, often related to their peculiar molecular recognition properties. In addition, the robustness and modular composition of supramolecular metal-based structures allows for an incorporation of different functionalities in the same system to enable imaging in cells via different modalities, but also active tumor targeting and stimuli-responsiveness. Although most of the studies reported so far exploit these systems for therapy, supramolecular metal-based structures may also constitute ideal scaffolds to develop multimodal theranostic agents. Of note, the host-guest chemistry of 3D self-assembled supramolecular structures - within the metallacages family - can also be exploited to design novel drug delivery systems for anticancer chemotherapeutics. In this review, we aim at summarizing the pivotal concepts in this fascinating research area, starting with the main design principles and illustrating representative examples while providing a critical discussion of the state-of-the-art. A section is also included on supramolecular organometallic complexes (SOCs) whereby the (organic) linker is forming the organometallic bond to the metal node, whose biological applications are still to be explored. Certainly, the myriad of possible supramolecular metal-based structures and their almost limitless modularity and tunability suggests that the biomedical applications of such complex chemical entities will continue along this already promising path.

AIE-based theranostic systems for detection and killing of pathogens.

Pathogenic bacteria, fungi and viruses pose serious threats to the human health under appropriate conditions. There are many rapid and sensitive approaches have been developed for identification and quantification of specific pathogens, but many challenges still exist. Culture/colony counting and polymerase chain reaction are the classical methods used for pathogen detection, but their operations are time-consuming and laborious. On the other hand, the emergence and rapid spread of multidrug-resistant pathogens is another global threat. It is thus of utmost urgency to develop new therapeutic agents or strategies. Luminogens with aggregation-induced emission (AIEgens) and their derived supramolecular systems with unique optical properties have been developed as fluorescent probes for turn-on sensing of pathogens with high sensitivity and specificity. In addition, AIE-based supramolecular nanostructures exhibit excellent photodynamic inactivation (PDI) activity in aggregate, offering great potential for not only light-up diagnosis of pathogen, but also image-guided PDI therapy for pathogenic infection.