Nuclear and Fluorescent Labeled PD-1-Liposome-DOX-64Cu/IRDye800CW Allows Improved Breast Tumor Targeted Imaging and Therapy.

The overexpression of programmed cell death-1 (PD-1) in tumors as breast cancer makes it a possible target for cancer imaging and therapy. Advances in molecular imaging, including radionuclide imaging and near-infrared fluorescence (NIRF) imaging, enable the detection of tumors with high sensitivity. In this study, we aim to develop a novel PD-1 antibody targeted positron emission tomography (PET) and NIRF labeled liposome loaded with doxorubicin (DOX) and evaluate its application for in vivo cancer imaging and therapy. IRDye800CW and 64Cu were conjugated to liposomes with PD-1 antibody labeling, and DOX was inside the liposomes to form theranostic nanoparticles. The 4T1 tumors were successfully visualized with PD-1-Liposome-DOX-64Cu/IRDye800CW using NIRF/PET imaging. The bioluminescent imaging (BLI) results showed that tumor growth was significantly inhibited in the PD-1-Liposome-DOX-treated group than the IgG control. Our results highlight the potential of using dual-labeled theranostic PD-1 mAb-targeted Liposome-DOX-64Cu/IRDye800CW for the management of breast tumor.

Microwave-Triggered Smart Drug Release from Liposomes Co-encapsulating Doxorubicin and Salt for Local Combined Hyperthermia and Chemotherapy of Cancer.

The microwave and temperature sensitive liposomes were fabricated successfully from 1,2-dipalmityol-sn-glycero-3-phosphocholine (DPPC), cholesterol, and 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)-2000 (DSPE-PEG2000) with a molar ratio of 4:1:0.26 by co-encapsulating NaCl and doxorubicin (DOX) through the thin-film hydration method to externally manipulate drug release at a predetermined location in the body at a desired time in the right dosage for combination microwave hyperthermia and chemotherapy of cancer to afford a synergistic therapeutic effect. It was found that the confinement of the high concentration of NaCl ions inside the small size of the liposomes led to a more-rapid temperature elevation than the dissociative ions upon microwave treatment. More than 67.6% doxorubicin was released from the DOX and NaCl co-loaded liposomes (DOX&NaCl@liposomes) upon microwave irradiation for 2 min. After incubation with 2 mg/mL DOX&NaCl@liposomes for 4 h followed by treatment with microwave for 2 min, the inhibition rate of human breast cancer cell MDA-MB-231 was evaluated as 76.1%, much higher than that for NaCl@liposomes (29.8%) and DOX@liposomes (40.2%). The tumor growth inhibition was evaluated to be 73.4% after intravenous injection of DOX&NaCl@liposomes followed by microwave irradiation, much higher than that with only NaCl@liposomes (41.5%) or DOX@liposomes (45.5%) combined with microwave irradiation. Therefore, DOX&NaCl@liposomes could serve as a promising thermochemotherapy nanomedicine for cancer treatment because of its excellent microwave susceptible property and good biocompatibility.

Prussian Blue Modified PLA Microcapsules Containing R6G for Ultrasonic/Fluorescent Bimodal Imaging Guided Photothermal Tumor Therapy.

A theranostic agent has been successfully constructed for fluorescence/ultrasound dual-modal imaging guided photothermal therapy by loading the fluorescent dye R6G into polylactide microcapsules (PLA MCs) followed by deposition of Prussian blue nanoparticles (PB NPs) into the surface of PLA MCs. It was proved that the obtained microcapsules of R6G@PLA/PB MCs could serve as an efficient probe to simultaneously enhance fluorescence imaging and ultrasound imaging greatly in vivo. R6G@PLA/PB MCs exhibited significant photothermal cytotoxicity. Cancer cells could be killed efficiently through photothermal effects of R6G@PLA/PB MCs due to the strong absorption of PB NPs in the near infrared region under laser irradiation. In a word, R6G@PLA/PB MCs integrate multiple capabilities for effective tumor imaging and therapy. Such a single agent provides us a possibility to interpret accurately the obtained images, identify the size and location of the tumor, as well as guide and monitor the photothermal therapy.

Monitoring Tumor Targeting and Treatment Effects of IRDye 800CW and GX1-Conjugated Polylactic Acid Nanoparticles Encapsulating Endostar on Glioma by Optical Molecular Imaging.

Molecular imaging used in cancer diagnosis and therapeutic response monitoring is important for glioblastoma (GBM) research. Antiangiogenic therapy currently is one of the emerging approaches for GBM treatment. In this study, a multifunctional nanoparticle was fabricated that can facilitate the fluorescence imaging of tumor and deliver a therapeutic agent to the tumor region in vivo and therefore possesses broad application in cancer diagnosis and treatment. This particle was polylactic acid (PLA) nanoparticles encapsulating Endostar, which was further conjugated with GX1 peptide and the near-infrared (NIR) dye IRDye 800CW (IGPNE). We demonstrated noninvasive angiogenesis targeting and therapy of IGPNE on U87MG xenografts in vivo using dual-modality optical molecular imaging including NIR fluorescence molecular imaging (FMI) and bioluminescence imaging (BLI). The NIR FMI results demonstrated that IGPNE had more accumulation to the tumor site compared to free IRDye 800CW. To further evaluate the antitumor treatment efficacy of IGPNE, BLI and immunohistochemistry analysis were performed on tumor-bearing mice. With the aid of molecular imaging, the results confirmed that IGPNE enhanced antitumor treatment efficacy compared to free Endostar. In conclusion, IGPNE realizes real-time imaging of U87MG tumors and improves the antiangiogenic therapeutic efficacy in vivo.

Doping hydroxylated cationic lipid into PEGylated cerasome boosts in vivo siRNA transfection efficacy.

The therapeutic application of small interfering RNA (siRNA) requires safe nanocarriers for specific and efficient delivery in vivo. Herein, PEGylated cationic cerasomes (PCCs) were fabricated by doping a cationic lipid with a hydroxyl group into nanohybrid cerasomes. Multiple properties of PCCs provide a solution to many of the limitations associated with current platforms for the delivery of siRNA. The polyorganosiloxane surface imparts PCCs with higher morphological stability than conventional liposomes. The PEGylation of the cationic cerasome could protect the cerasome nanoparticles from agglomeration and macrophage capture, reduce protein absorption, and consequently prolong the blood circulating time and enhance the siRNA delivery efficiency. In addition, incorporation of the lipid containing a hydroxyl group further facilitates endosome release. Moreover, PCCs were further used to transport siRNA into the cytosol primarily via endocytosis. When applied to systemic administration, PCCs have demonstrated effective delivery into the liver and preferential uptake by hepatocytes in mice, thereby leading to high siRNA gene-silencing activity. All these results show potential therapeutic applications of PCCs-mediated delivery of siRNA for liver diseases.

Regulation of CTLs/Tregs via Highly Stable and Ultrasound-Responsive Cerasomal Nano-Modulators for Enhanced Colorectal Cancer Immunotherapy.

Immunotherapy is showing good potential for colorectal cancer therapy, however, low responsive rates and severe immune-related drug side effects still hamper its therapeutic effectiveness. Herein, a highly stable cerasomal nano-modulator (DMC@P-Cs) with ultrasound (US)-controlled drug delivery capability for selective sonodynamic-immunotherapy is fabricated. DMC@P-Cs' lipid bilayer is self-assembled from cerasome-forming lipid (CFL), pyrophaeophorbid conjugated lipid (PL), and phospholipids containing unsaturated chemical bonds (DOPC), resulting in US-responsive lipid shell. Demethylcantharidin (DMC) as an immunotherapy adjuvant is loaded in the hydrophilic core of DMC@P-Cs. With US irradiation, reactive oxygen species (ROS) can be effectively generated from DMC@P-Cs, which can not only kill tumor cells for inducing immunogenic cell death (ICD), but also oxidize unsaturated phospholipids-DOPC to change the permeability of the lipid bilayers and facilitate controlled release of DMC, thus resulting in down-regulation of regulatory T cells (Tregs) and amplification of anti-tumor immune responses. After intravenous injection, DMC@P-Cs can efficiently accumulate at the tumor site, and local US treatment resulted in 94.73% tumor inhibition rate. In addition, there is no detectable systemic toxicity. Therefore, this study provides a highly stable and US-controllable smart delivery system to achieve synergistical sonodynamic-immunotherapy for enhanced colorectal cancer therapy.

Ultrasound-Controlled Delivery of Growth Factor-Loaded Cerasomes Combined with Polycaprolactone Scaffolds Seeded with Bone Marrow Mesenchymal Stem Cells for Biomimetic Tendon-to-Bone Interface Engineering.

Rotator cuff tear (RCT) is a prevalent shoulder injury that poses challenges for achieving continuous and functional regeneration of the tendon-to-bone interface (TBI). In this study, we controlled the delivery of growth factors (GFs) from liposomal nanohybrid cerasomes by ultrasound and implanted three-dimensional printed polycaprolactone (PCL) scaffolds modified with polydopamine loaded with bone marrow mesenchymal stem cells (BMSCs) to repair tears of the infraspinatus tendon in a lapine model. Direct suturing (control, CTL) was used as a control. The PCL/BMSC/cerasome (PBC) devices are sutured with the enthesis of the infraspinatus tendon. The cerasomes and PCL scaffolds are highly stable with excellent biocompatibility. The roles of GFs BMP2, TGFß1, and FGF2 in tissue-specific differentiation are validated. Compared with the CTL group, the PBC group had significantly greater proteoglycan deposition (P = 0.0218), collagen volume fraction (P = 0.0078), and proportions of collagen I (P = 0.0085) and collagen III (P = 0.0048). Biotin-labeled in situ hybridization revealed a high rate of survival for transplanted BMSCs. Collagen type co-staining at the TBI is consistent with multiple collagen regeneration. Our studies demonstrate the validity of biomimetic scaffolds of TBI with BMSC-seeded PCL scaffolds and GF-loaded cerasomes to enhance the treatment outcomes for RCTs.

Design and synthesis of lipidic organoalkoxysilanes for the self-assembly of liposomal nanohybrid cerasomes with controlled drug release properties.

This paper reports the facile design and synthesis of a series of lipidic organoalkoxysilanes with different numbers of triethoxysilane headgroups and hydrophobic alkyl chains linked by glycerol and pentaerythritol for the construction of cerasomes with regulated surface siloxane density and controlled release behavior. It was found that the number of triethoxysilane headgroups affected the properties of the cerasomes for encapsulation efficiency, drug loading capacity, and release behavior. For both water-soluble doxorubicin (DOX) and water-insoluble paclitaxel (PTX), the release rate from the cerasomes decreased as the number of triethoxysilane headgroups increased. The slower release rate from the cerasomes was attributed to the higher density of the siloxane network on the surface of the cerasomes, which blocks the drug release channels. In contrast to the release results with DOX, the introduction of one more hydrophobic alkyl chain into the cerasome-forming lipid resulted in a slower release rate of PTX from the cerasomes due to the formation of a more compact cerasome bilayer. An MTT viability assay showed that all of these drug-loaded cerasomes inhibited proliferation of the HepG2 cancer cell line. The fine tuning of the chemical structure of the cerasome-forming lipids would foster a new strategy to precisely regulate the release rate of drugs from cerasomes.

Charge Reversal Polypyrrole Nanocomplex-Mediated Gene Delivery and Photothermal Therapy for Effectively Treating Papillary Thyroid Cancer and Inhibiting Lymphatic Metastasis.

As a traditional treatment for papillary thyroid cancer (PTC), surgical resection of diseased tissues often brings lots of inconveniences to patients, and the tumor recurrence and metastasis are difficult to avoid. Herein, we developed a gene and photothermal combined therapy nanosystem based on a polypyrrole (Ppy)-poly(ethylene imine)-siILK nanocomplex (PPRILK) to achieve minimally invasive ablation and lymphatic metastasis inhibition in PTC simultaneously. In this system, gelatin-stabilized Ppy mainly acted as a photothermal- and photoacoustic (PA)-responsive nanomaterial and contributed to its well-behaved photosensitivity in the near-infrared region. Moreover, gelatin-stabilized Ppy possessed a charge reversal function, facilitating the tight conjunction of siILK gene at physiological pH (7.35-7.45) and its automatic release into acidic lysosomes (pH 4.0-5.5); the proton sponge effect generated during this process further facilitated the escape of siILK from lysosomes to the cytoplasm and played its role in inhibiting PTC proliferation and lymphatic metastasis. With the guidance of fluorescence and PA bimodal imaging, gene delivery and Ppy location in tumor regions could be clearly observed. As a result, tumors were completely eradicated by photothermal therapy, and the recurrences and metastases were obviously restrained by siILK.

Ultrasound Microbubbles Mediated Sonosensitizer and Antibody Co-delivery for Highly Efficient Synergistic Therapy on HER2-Positive Gastric Cancer.

Trastuzumab combined with chemotherapy is the first-line treatment for advanced HER2-positive gastric cancer, but it still suffers from limited therapeutic efficiency and serious side effects, which are usually due to the poor delivery efficiency and the drug resistance of tumor cells to the chemotherapeutic drugs. Herein, a type of ultrasound microbubble for simultaneous delivery of sonosensitizers and therapeutic antibodies to achieve targeting combination of sonodynamic therapy and antibody therapy of HER2-positive gastric cancer was constructed from pyropheophorbide-lipid followed by trastuzumab conjugation (TP MBs). In vitro and in vivo studies showed that TP MBs had good biological safety, and their in vivo delivery can be monitored by ultrasound/fluorescence bimodal imaging. With ultrasound (US) located at the tumor area, TP MBs can be converted into nanoparticles (TP NPs) in situ by US-targeted microbubble destruction; plus the enhanced permeability and retention effects and the targeting effects of trastuzumab, the enrichment of sonosensitizers and antibodies in the tumor tissue can be greatly enhanced (∼2.1 times). When combined with ultrasound, TP MBs can not only increase the uptake of sonosensitizers in HER2-positive gastric cancer NCI-N87 cells but also efficiently generate singlet oxygen to greatly increase the killing effect on cells, obviously inhibiting the tumor growth in HER2-positive gastric cancer NCI-N87 cell models with a tumor inhibition rate up to 79.3%. Overall, TP MBs combined with US provided an efficient way for co-delivery of sonosensitizers and antibodies, greatly enhancing the synergistic therapeutic effect on HER2-positive gastric cancer while effectively reducing the side effects.

Complementing Cancer Photodynamic Therapy with Ferroptosis through Iron Oxide Loaded Porphyrin-Grafted Lipid Nanoparticles.

Nanomaterials that combine multimodality imaging and therapeutic functions within a single nanoplatform have drawn extensive attention for molecular medicines and biological applications. Herein, we report a theranostic nanoplatform based on a relatively smaller (<20 nm) iron oxide loaded porphyrin-grafted lipid nanoparticles (Fe3O4@PGL NPs). The amphiphilic PGL easily self-assembled on the hydrophobic exterior surface of ultrasmall Fe3O4 NPs, resulting in a final ultrasmall Fe3O4@PGL NPs with diameter of ∼10 nm. The excellent self-assembling nature of the as-synthesized PGL NPs facilitated a higher loading of porphyrins, showed a negligible dark toxicity, and demonstrated an excellent photodynamic effect against HT-29 cancer cells in vitro. The in vivo experimental results further confirmed that Fe3O4@PGL NPs were ideally qualified for both the fluorescence and magnetic resonance (MR) imaging guided nanoplatforms to track the biodistribution and therapeutic responses of NPs as well as to simultaneously trigger the generation of highly cytotoxic reactive oxygen species (ROS) necessary for excellent photodynamic therapy (PDT). After recording convincing therapeutic responses, we further evaluated the ability of Fe3O4@PGL NPs/Fe3O4@Lipid NPs for ferroptosis therapy (FT) via tumor microenvironment (TME) modulation for improved anticancer activity. We hypothesized that tumor-associated macrophages (TAMs) could significantly improve the efficacy of FT by accelerating the Fenton reaction in vitro. In our results, the Fe ions released in vitro directly contributed to the Fenton reaction, whereas the presence of RAW 264.7 macrophages further accelerated the ROS generation as observed by the fluorescence imaging. The significant increase in the ROS during the coincubation of NPs, endocytosed by HT-29 cells and RAW264.7 cells, further induced increased cellular toxicity of cancer cells.

Facile and Versatile Surface Functional Polyetheretherketone with Enhanced Bacteriostasis and Osseointegrative Capability for Implant Application.

Implant-associated infections and inadequate osseointegration are two challenges of implant materials in orthopedics. In this study, a lithium-ion-loaded (Li+)/mussel-inspired antimicrobial peptide (AMP) designed to improve the osseointegration and inhibit bacterial infections effectively is prepared on a polyetheretherketone (PEEK) biomaterial surface through the combination of hydrothermal treatment and mussel-inspired chemistry. The results illustrate that the multifunctional PEEK material demonstrated a great inhibitory effect on Escherichia coli and Staphylococcus aureus, which was attributed to irreversible bacterial membrane damage. In addition, the multifunctional PEEK can simultaneously upregulate the expression of osteogenesis-associated genes/proteins via the Wnt/ß-catenin signaling pathway. Furthermore, an in vivo assay of an infection model revealed that the multifunctional PEEK implants killed bacteria with an efficiency of 95.03%. More importantly, the multifunctional PEEK implants accelerated the implant-bone interface osseointegration compared with pure PEEK implants in the noninfection model. Overall, this work provides a promising strategy for improving orthopedic implant materials with ideal osseointegration and infection prevention simultaneously, which may have broad application clinical prospects.

Highly stable near-infrared dye conjugated cerasomes for fluorescence imaging-guided synergistic chemo-photothermal therapy of colorectal cancer.

Colorectal cancer is a common malignant tumour with a low 5-year survival rate. A combination therapy with high selectivity and easy controllability is a pressing need for the effective treatment of such cancer. In this study, an indocyanine green derivative (Cy7)-conjugated lipid with a terminal carboxyl group was synthesized, which could self-assemble with a cerasome-forming lipid (CFL) into nanoparticles (NPs) by encapsulating doxorubicin (DOX) to achieve combined photothermal chemotherapy. The resulting Gly@Cy7-Si-DOX NPs with a surface covalent silicate framework showed excellent morphological stability and colloidal stability. Specifically, the conjugated Cy7 was covalently conjugated in the liposomal bilayer, resulting in high drug loading content, high photostability, and high photothermal conversion efficiency, which enabled the resulting nanoparticles to be an effective platform for photothermal therapy. Meanwhile, the encapsulated DOX leaked only slightly under physiological conditions due to the silicate surface of Gly@Cy7-Si-DOX NPs and exhibited controlled release in a weakly acidic environment or under near-infrared (NIR) light irradiation for chemotherapy. Gly@Cy7-Si-DOX NPs were efficiently taken up by tumour cells. Upon light irradiation, the released DOX entered the nuclei of tumour cells, as observed by confocal microscopy and flow cytometry. In vitro cell experiments indicated that both healthy cells and tumour cells were viable under treatment with only Gly@Cy7-Si-DOX NPs, indicating the encapsulated DOX was stably confined to the NPs, and cells were significantly killed when treated with both Gly@Cy7-Si-DOX NPs and NIR laser irradiation. After i.v. administration, Gly@Cy7-Si-DOX NPs accumulated at the tumour site, as monitored by near-infrared fluorescence imaging. A significant tumour inhibition rate (95.8%) was also achieved in a HT-29 colorectal cancer model when treated with Gly@Cy7-Si-DOX NPs plus irradiation. Therefore, the Gly@Cy7-Si-DOX NPs hold great promise for controllable combined colorectal cancer photothermal chemotherapy.

Synergistic triple-combination therapy with hyaluronic acid-shelled PPy/CPT nanoparticles results in tumor regression and prevents tumor recurrence and metastasis in 4T1 breast cancer.

Breast cancer is characterized by high aggression, poor prognosis, and high recurrence rate. Early detection and specific targeted treatment with less toxicity are the ultimate goals for breast cancer therapy. To improve antitumor therapeutic effects, we developed a novel polypyrrole nanoparticle using the near infrared dye IRDye800CW with camptothecin (CPT)-conjugated hyaluronic acid (HA) shell (PPy@CPT-HA-IRDye800CW) and performed a photothermal therapy (PTT), along with chemotherapy, guided by fluorescence and photoacoustic dual-modality imaging, in combination with immunotherapy. Irradiation with near infrared (NIR) light offered a strong PTT effect and promoted CPT drug release in tumors. Moreover, we found that chemo-photothermal therapy with PPy@CPT-HA-IRDye800CW NPs, in combination with immune checkpoint inhibitor anti-PD-L1 immunotherapy, synergistically enhanced the anti-tumor immune response, thereby eliminating primary breast cancer and preventing tumor metastases and recurrences in 4T1 tumor-bearing mice. This approach may provide important clues for the clinical management of breast cancer and other malignant tumors.

Bubble-Manipulated Local Drug Release from a Smart Thermosensitive Cerasome for Dual-Mode Imaging Guided Tumor Chemo-Photothermal Therapy.

Thermosensitive liposomes have demonstrated great potential for tumor-specific chemotherapy. Near infrared (NIR) dyes loaded liposomes have also shown improved photothermal effect in cancer theranostics. However, the instability of liposomes often causes premature release of drugs or dyes, impeding their antitumor efficacy. Herein, we fabricated a highly stable thermo-responsive bubble-generating liposomal nanohybrid cerasome with a silicate framework, combined with a NIR dye to achieve NIR light stimulated, tumor-specific, chemo-photothermal synergistic therapy. Methods: In this system, NIR dye of 1,1'-Dioctadecyl-3,3,3',3'- Tetramethylindotricarbocyanine iodide (DiR) with long carbon chains was self-assembled with a cerasome-forming lipid (CFL) to encapsulate ammonium bicarbonate (ABC), which was further used for actively loading doxorubicin (DOX), affording a thermosensitive and photosensitive DOX-DiR@cerasome (ABC). Results: The resulting cerasome could disperse well in different media. Upon NIR light mediated thermal effect, ABC was decomposed to generate CO2 bubbles, resulting in a permeable channel in the cerasome bilayer that significantly enhanced DOX release. After intravenous injection into tumor-bearing mice, DOX-DiR@cerasome (ABC) could be efficiently accumulated at the tumor tissue, as monitored by DiR fluorescence, lasting for more than 5 days. NIR light irradiation was then performed at 36h to locally heat the tumors, resulting in immediate CO2 bubble generation, which could be clearly detected by ultrasound imaging, facilitating the monitoring process of controlled release of the drug. Significant antitumor efficacy could be obtained for the DOX-DiR@cerasome (ABC) + laser group, which was further confirmed by tumor tissue histological analysis.

Host-Guest Polypyrrole Nanocomplex for Three-Stimuli-Responsive Drug Delivery and Imaging-Guided Chemo-Photothermal Synergetic Therapy of Refractory Thyroid Cancer.

Despite the good prognosis of the low-risk thyroid cancer, there are no truly effective treatments for radioactive iodine-refractory thyroid cancer. Herein, a novel theranostic nanoplatform, as well as a smart doxorubucin (DOX) delivery system is fabricated. Gelatin-stabilized polypyrrole nanoparticles are reported for the first time. The combination of gelatin-stabilized polypyrrole and cyclodextrin-DOX complexes enabling three-stimuli-controlled drug delivery, including the enzyme-sensitive, pH-sensitive and photothermal-sensitive drug release, exhibiting a new way to equip photothermal agents with precisely controlled drug delivery. Anti-galectin-3 antibodies are utilized as the targeting molecules of nanoparticles in the first time, which surprisingly increase intracellular DOX uptake by enhanced clathrin-mediated endocytosis, showing galectin-3 can be employed as a highly efficient target of drug delivery systems. The nanoparticles achieve excellent photoacoustic imaging effect, enabled chemo-photothermal combined therapy with pinpointed drug delivery. Compared to free DOX, these multifunctional nanoparticles decrease the heart damage, but greatly increase the tumor/heart ratio of DOX concentration by 12.9-fold. The tumors are completely eradicated without any recurrence after the in vivo combined therapy. To the best of the authors' knowledge, this is also the first report to apply photoacoustic imaging-guided chemo-photothermal therapy for thyroid cancer, showing great potential to solve the dilemma in thyroid cancer therapy.

Near-Infrared Cyanine-Loaded Liposome-like Nanocapsules of Camptothecin-Floxuridine Conjugate for Enhanced Chemophotothermal Combination Cancer Therapy.

A dual-in-dual synergistic strategy was proposed based on the self-assembly of combinatorial nanocapsules (NCs) from Janus camptothecin-floxuridine (CF) conjugate and the near-infrared absorber of 1,1'-dioctadecyl-3,3,3',3'-tetramethylindotricarbocyanine iodide (DiR) by introducing PEGylated phospholipid of 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycerol)-2000] to increase the blood circulation time of NCs. Due to the use of amphiphilic CF and DiR themselves to form liposome-like nanocapsules, the obtained CF-DiR NCs owned a significantly high loading content, a stable co-delivery drug combinations, a no premature release, and an excellent photothermal conversion efficiency. The in vivo fluorescence imaging indicated that CF-DiR NCs could achieve a high tumor accumulation after an intravenous injection. The dual drugs of camptothecin and floxuridine could be coordinately released due to the hydrolysis of the ester bond by the esterase in tumor. The in vivo experiments showed that more cytotoxicity of the CF-DiR NCs-mediated chemo- and photothermal dual therapy to tumor cells could be clearly observed than the chemotherapy or photothermal therapy alone due to the synergistic effect, leading to no recurrence in the entire treatment. All of the results highlighted that CF-DiR NCs were highly effective theranostic agents that could be used for imaging-guided cancer chemophotothermal therapy to conquer an intrinsic resistance to chemotherapeutics.

Liposomal nanohybrid cerasomes targeted to PD-L1 enable dual-modality imaging and improve antitumor treatments.

Programmed death ligand-1 (PD-L1) is a central element in cancer therapies targeting immune checkpoints, and its expression is an important predictor of the therapeutic response. With recent approvals of therapeutic antibodies against PD-L1 and PD-1, noninvasive detection methods are now urgently needed to quantify PD-L1 expression in tumors and to evaluate the response to immune therapies. However, only few such methods are available. Thus, we fabricated nanohybrid liposomal cerasome nanoparticles loaded with the chemotherapeutic drug paclitaxel, and evaluated their value as a theranostic agent. The particles are also decorated with PD-L1 antibody to enable specific targeting, and are dual-labeled to enable near-infrared fluorescence (NIRF) and magnetic resonance imaging (MRI) in vivo. Results showed that in vivo NIRF and MRI imaging following intravenous injection of cerasomes revealed a strong positive contrast for tumors, indicating long-lived enhancement of relevant signals. Moreover, the cerasomes were more effective against tumors and metastasis in comparison to simultaneous but nontargeted delivery of PD-L1 antibody and paclitaxel. Taken together, the data indicate that targeted, dual-labeled cerasomes are good theranostic agents for MRI/NIRF dual-mode detection and treatment of solid tumors in situ.

EGFR-targeted liposomal nanohybrid cerasomes: theranostic function and immune checkpoint inhibition in a mouse model of colorectal cancer.

Epidermal growth factor receptor (EGFR) is a major target for the treatment of colorectal cancers (CRCs), and programmed death ligand-1 (PD-L1) is an attractive target for CRC immunotherapy. Herein, we report the synthesis of porphyrin-containing liposomal nanohybrid cerasomes decorated with cetuximab, an anti-EGFR antibody, and conjugated with IRDye800CW and MRI contrast DOTA-Gd, to enable in vivo tumor detection and photodynamic therapy (PDT). Moreover, PD-L1 was added for adjuvant therapy. The antitumor efficacy of PDT combined with PD-L1 immunotherapy was assessed. EGFR-targeted nanoparticles showed the targeted imaging of tumors. EGFR-targeted PDT combined with PD-L1 immunotherapy was more effective against tumor growth than simultaneous albeit nontargeted nanoparticle delivery with laser irradiation plus PD-L1 immunotherapy. Thus, EGFR-targeted nanoparticles exhibited significant potential toward dual-modality imaging-guided precise PDT, combined with immunotherapy.

Self-assembly of porphyrin-grafted lipid into nanoparticles encapsulating doxorubicin for synergistic chemo-photodynamic therapy and fluorescence imaging.

The limited clinical efficacy of monotherapies in the clinic has urged the development of novel combination platforms. Taking advantage of light-triggered photodynamic treatment combined together with the controlled release of nanomedicine, it has been possible to treat cancer without eliciting any adverse effects. However, the challenges imposed by limited drug loading capacity and complex synthesis process of organic nanoparticles (NPs) have seriously impeded advances in chemo-photodynamic combination therapy. In this experiment, we utilize our previously synthesized porphyrin-grafted lipid (PGL) NPs to load highly effective chemotherapeutic drug, doxorubicin (DOX) for synergistic chemo-photodynamic therapy. Methods: A relatively simple and inexpensive rapid injection method was used to prepare porphyrin-grafted lipid (PGL) NPs. The self-assembled PGL NPs were used further to encapsulate DOX via a pH-gradient loading protocol. The self-assembled liposome-like PGL NPs having a hydrophilic core were optimized to load DOX at an encapsulation efficiency (EE) of ~99%. The resultant PGL-DOX NPs were intact, highly stable and importantly these NPs successfully escaped from the endo-lysosomal compartment after laser irradiation to release DOX in the cytosol. The therapeutic efficacy of the aforementioned formulation was validated both in vitro and in vivo. Results: PGL-DOX NPs demonstrated excellent cellular uptake, chemo-photodynamic response, and fluorescence imaging ability in different cell lines. Under laser irradiation, cells treated with a low molar concentration of PGL-DOX NPs reduced cell viability significantly. Moreover, in vivo experiments conducted in a xenograft mouse model further demonstrated the excellent tumor accumulation capability of PGL-DOX NPs driven by the enhanced permeability and retention (EPR) effect. Through fluorescence imaging, the biodistribution of PGL-DOX NPs in tumor and major organs was also easily monitored in real time in vivo. The inherent ability of porphyrin to generate ROS under laser irradiation combined with the cytotoxic effect of the anticancer drug DOX significantly suppressed tumor growth in vivo. Conclusion: In summary, the PGL-DOX NPs combined chemo-photodynamic nanoplatform may serve as a potential candidate for cancer theranostics.