Tumor-targeting semiconducting polymer nanoparticles: efficient adjuvant photothermal therapy using ultra-low laser power inhibits recurrences after breast-conserving surgery.

The need for adjuvant therapy to inhibit local recurrence after breast-conserving surgery with minimal side effects is great. Adjuvant photothermal therapy (aPTT) has the potential to replace radiotherapy and eliminates its inherent damage to healthy tissues. Herein, we functionalized semiconducting polymer nanoparticles (SPNs) with cRGD-peptide and silicon 2,3-naphthalocyanine bis(trihexylsilyloxide) (NIR775) to target breast cancer and perform aPTT under an ultra-low laser power (0.2 W cm-2) after breast-conserving surgery (BCS). The synthesized RGD-SPNNIR775 showed an excellent photothermal conversion efficiency and biocompatibility and was demonstrated to accumulate in tumors specifically. The BCS could be performed with confidence under the guidance of preoperative and postoperative fluorescence imaging. Notably, the aPTT completely inhibited the local recurrence after the BCS without compromising the cosmetic effect of the BCS. These results indicate the prospect of RGD-SPNNIR775 as a theranostic nanoplatform for efficient aPTT using an ultra-low laser power to control recurrence after BCS.

Disrupting stromal barriers to enhance photothermal-chemo therapy using a halofuginone-loaded Janus mesoporous nanoplatform.

Dense tumor stroma is the physiological barrier in drug delivery that prevents anticancer drugs from entering the tumor, thereby seriously limiting the drugs' therapeutic effect. In this study, a Janus nanoplatform consisting of periodic mesoporous organosilica-coated platinum nanoplatforms (JPMO-Pt) and anti-stroma drug halofuginone (HF) (denoted as JPMO-Pt-HF), was developed to deplete the tumor stroma and synergistically treat breast cancer in BALB/c mice. The prepared JPMO-Pt had a uniform size of 245 nm, a good dispersion, an excellent in vitro and in vivo biocompatibility, and a high loading capacity for HF (up to 50 µg/mg). The antitumor experiments showed that the survival rate of 4 T1 cells exhibited an obvious downward trend when the cells were incubated with the JPMO-Pt-HF and irradiated with 808 nm laser. Moreover, the cell survival rate was only about 10% at 48 h when the HF concentration was 2.0 µg/mL. Notably, JPMO-Pt-HF under irradiation had an excellent synergistic therapeutic effect on tumor cells. In vivo antitumor experiment further showed that the JPMO-Pt-HF, in combination with laser irradiation, could minimize tumor growth, showing significantly better effects than those observed for the case of monotherapy involving photothermal therapy (PTT) (152 vs. 670 mm3, p < 0.0001) and HF (152 vs. 419 mm3, p = 0.0208). In addition, immunohistochemistry of tumor tissues indicated that JPMO-Pt-HF obviously reduced the relative collagen and α-smooth muscle actin (α-SMA) area fraction. Taken together, this research designs a new platform that not only possesses the ability to degrade the tumor matrix but also combines PTT and chemotherapeutic effects, and holds promise for effective tumor treatment.

Dye-loaded mesoporous polydopamine nanoparticles for multimodal tumor theranostics with enhanced immunogenic cell death.

BACKGROUND: Tumor phototherapy especially photodynamic therapy (PDT) or photothermal therapy (PTT), has been considered as an attractive strategy to elicit significant immunogenic cell death (ICD) at an optimal tumor retention of PDT/PTT agents. Heptamethine cyanine dye (IR-780), a promising PDT/PTT agent, which can be used for near-infrared (NIR) fluorescence/photoacoustic (PA) imaging guided tumor phototherapy, however, the strong hydrophobicity, short circulation time, and potential toxicity in vivo hinder its biomedical applications. To address this challenge, we developed mesoporous polydopamine nanoparticles (MPDA) with excellent biocompatibility, PTT efficacy, and PA imaging ability, facilitating an efficient loading and protection of hydrophobic IR-780. RESULTS: The IR-780 loaded MPDA (IR-780@MPDA) exhibited high loading capacity of IR-780 (49.7 wt%), good physiological solubility and stability, and reduced toxicity. In vivo NIR fluorescence and PA imaging revealed high tumor accumulation of IR-780@MPDA. Furthermore, the combined PDT/PTT of IR-780@MPDA could induce ICD, triggered immunotherapeutic response to breast tumor by the activation of cytotoxic T cells, resulting in significant suppression of tumor growth in vivo. CONCLUSION: This study demonstrated that the as-developed compact and biocompatible platform could induce combined PDT/PTT and accelerate immune activation via excellent tumor accumulation ability, offering multimodal tumor theranostics with negligible systemic toxicity.

Anti-EGFR Peptide-Conjugated Triangular Gold Nanoplates for Computed Tomography/Photoacoustic Imaging-Guided Photothermal Therapy of Non-Small Cell Lung Cancer.

Non-small cell lung cancer (NSCLC) is difficult to cure because of the high recurrence rate and the side effects of current treatments. It is urgent to develop a new treatment that is safer and more effective than current treatments against NSCLC. Herein, we constructed anti-epidermal growth factor receptor (EGFR) peptide-conjugated PEGylated triangular gold nanoplates (TGN-PEG-P75) as a targeting photothermal therapy (PTT) agent to treat NSCLC under the guidance of computed tomography (CT) and photoacoustic (PA) imaging. The surface of TGNs is successfully conjugated with a novel peptide P75 that has the specific affinity to epidermal growth factor receptor (EGFR). It is found that the EGFR is overexpressed in NSCLC cells. The TGN-PEG-P75 has uniform edge length (77.9 ± 7.0 nm) and neutrally charged surface. The cell uptake experiments demonstrate remarkable affinity of the TGN-PEG-P75 to high EGFR expression cells than low EGFR expression cells (5.1-fold). Thanks to the strong near-infrared absorbance, high photothermal conversion efficiency, and the increased accumulation in tumor cells via the interaction of P75 and EGFR, TGN-PEG-P75 exhibits 3.8-fold superior therapeutic efficacy on HCC827 cells than TGN-PEG. The in vivo CT/PA dual-modal imaging of the TGN-PEG-P75 is helpful in selecting the optimal treatment time and providing real-time visual guidance of PTT. Furthermore, treatments on HCC827 tumor-bearing mouse model demonstrate that the growth of NSCLC cells can be effectively inhibited by the TGN-PEG-P75 through PTT, indicating the great promise of the nanoplatform for treating NSCLC in vivo.

Timely coordinated phototherapy mediated by mesoporous organosilica coated triangular gold nanoprisms.

A variety of nanocarriers have been designed to deliver photosensitizers (PSs) and promote the clinical applications of photodynamic therapy (PDT). However, most of them suffer from insufficient loading capability, premature leakage, and/or unstable therapeutic efficacy. Herein, we constructed a novel nanocomposite (TGP@MOS) with a benzene-bridged mesoporous organosilica shell and a triangular gold nanoprism core. The TGP@MOS could load model PS molecules, zinc phthalocyanine (ZnPc), with high loading capacity (11.8 wt%) and minimal premature leakage (only 2.6% after incubation in PBS with 10% FBS for 60 h) viaπ-π stacking interactions and hydrophobic interactions. We demonstrated that the obtained TGP@MOS-ZnPc could realize timely coordinated photodynamic/photothermal therapy upon single irradiation, and thus stabilize and maximize the therapeutic efficacy of phototherapy both in vitro and in vivo. Other advantages of TGP@MOS-ZnPc include excellent water solubility, stability, hemocompatibility and biocompatibility.

Adjuvant Photothermal Therapy Inhibits Local Recurrences after Breast-Conserving Surgery with Little Skin Damage.

Adjuvant treatments following breast-conserving surgery (BCS) are essential to reduce the risk of local recurrences in patients with breast cancer. However, current adjuvant treatments are based on ionizing radiation, which brings radiation-induced damage and amplifies the risk of death. Here we explore the feasibility of using non-ionizing light to induce photothermal therapy as an adjuvant treatment to BCS. In an orthotopic breast cancer mice model, we demonstrate that adjuvant photothermal therapy (aPTT) decreases the incidence of local recurrences after BCS with no expense of cosmetic outcome. In comparison with conventional photothermal therapy, the technique used in aPTT provides more uniformly distributed light energy and less risk of skin burns and local recurrences. Overall, this work represents a departure from the traditional concept of using PTT as an alternative to surgery and reveals the potential of using PTT as an alternative to adjuvant radiation therapy, which is valuable especially for patients susceptible to radiation damage.

Photosensitizer-loaded biomimetic platform for multimodal imaging-guided synergistic phototherapy.

Photodynamic therapy (PDT) has attracted much attention as a strategy for tumor therapy. However, the insolubility and poor tumor-targeting ability of most photosensitizers (PSs) hinder PDT from further development. Therefore, it is necessary to explore new carriers with good water solubility and biocompatibility to deliver PSs to tumors. Melanin nanoparticles are novel biomimetic nanocarriers with excellent biocompatibility, loading capacity, photothermal therapy (PTT) and magnetic resonance (MR)/photoacoustic (PA) imaging properties. Here we designed polydopamine melanin nanoparticles (PDMNs) as a delivery platform for the photosensitizer Chlorin e6 (PDMN-Ce6) and realized its application as a theranostic agent for tumor therapy. The PDMN-Ce6 exhibited excellent biocompatibility, good water solubility and high loading capability (35.2 wt%) for Ce6. Compared with the free Ce6, PDMN-Ce6 showed higher cellular internalization and superior synergistic phototherapy effects in an in vitro study. An in vivo study indicated that the accumulation of PDMN-Ce6 at tumor sites was 2.8-fold higher than that of free Ce6 at 24 h post-injection, which was beneficial for MR/PA imaging. Moreover, the synergetic therapy significantly inhibited tumor growth, causing tumor necrosis and tumor angiogenesis suppression. These results suggest that our biomimetic and biocompatible platform could improve the delivery of Ce6 to tumors and realize multimodal imaging-guided tumor synergetic phototherapy.

Gold nanorod embedded large-pore mesoporous organosilica nanospheres for gene and photothermal cooperative therapy of triple negative breast cancer.

To date, clinicians still lack an effective strategy to treat triple negative breast cancer (TNBC). In this work, we design for the first time a gold nanorod embedded large-pore mesoporous organosilica (GNR@LPMO) nanoplatform for gene and photothermal cooperative therapy of TNBC. The synthesized GNR@LPMOs possess a uniform size (175 nm), high surface area (631 m2 g-1), large pore size, excellent photothermal efficiency, and good biocompatibility. Thanks to the large-pore mesoporous organosilica layer, the GNR@LPMO nanoplatforms display much higher loading capacity of siRNA compared with traditional liposome and bare gold nanorods. Thus, functional siRNA can be efficiently delivered into TNBC cells by GNR@LPMOs, causing much higher cell apoptosis through knocking down the PLK1 proteins. By combining the effective gene delivery and photothermal abilities, the GNR@LPMO nanoplatforms are further used for gene and photothermal cooperative therapy of TNBC, which induce a 15 fold higher mice tumor inhibition rate than sole therapy modality, indicating the potential clinical use of this novel nanoplatform in treating TNBC.

Selectively Sensitizing Malignant Cells to Photothermal Therapy Using a CD44-Targeting Heat Shock Protein 72 Depletion Nanosystem.

Selectively enhance the therapeutic efficacy to malignancy is one of the most important issues for photothermal therapy (PTT). However, most solid tumors, such as triple negative breast cancer (TNBC), do not have identifiable surface markers to distinguish themselves from normal cells, thus it is challenging to selectively identify and eliminate those malignances by PTT. In this report, we hypothesized that, by targeting CD44 (one TNBC-overexpressed surface molecule) and depleting heat shock protein 72 (HSP72, one malignancy-specific-overexpressed thermotolerance-related chaperone) subsequently, the TNBC could be selectively sensitized to PTT and improve the accuracy of treatment. To this end, a rationally designed nanosystem gold nanostar (GNS)/siRNA against HSP72 (siHSP72)/hyaluronic acid (HA) was successfully constructed using a layer-by-layer method. Hydrodynamic diameter and zeta potential analysis demonstrated the formation of GNS/siHSP72/HA having a particle size of 73.2 ± 3.8 nm and a negative surface charge of -18.3 ± 1.6 mV. The CD44-targeting ability of GNS/siHSP72/HA was confirmed by the flow cytometer, confocal microscopic imaging, and competitive binding analysis. The HSP72 silencing efficacy of GNS/siHSP72/HA was ∼95% in complete culture medium. By targeting CD44 and depleting HSP72 sequentially, GNS/siHSP72/HA could selectively sensitize TNBC cells to hyperthermia and enhance the therapeutic efficacy to TNBC with minimal side effect both in vitro and in vivo. Other advantages of GNS/siHSP72/HA included easy synthesis, robust siRNA loading capacity, endosome/lysosome escaping ability, high photothermal conversion efficacy and superior hemo- and biocompatibility.

Synergistic Chemo-Photothermal Therapy of Breast Cancer by Mesenchymal Stem Cell-Encapsulated Yolk-Shell GNR@HPMO-PTX Nanospheres.

Mesenchymal stem cells (MSCs) have attracted increasing attention as vehicles for cancer treatment. Herein, MSC-based synergistic oncotherapy strategy is presented for the first time. To achieve this goal, yolk-shell structured gold nanorod embedded hollow periodic mesoporous organosilica nanospheres (GNR@HPMOs) with high paclitaxel (PTX) loading capability and excellent photothermal transfer ability upon near-infrared (NIR) light irradiation are first prepared. Cytotoxicity and migration assays show that the viability and tumor-homing capability of MSCs are well-retained after internalization of high content of PTX loaded GNR@HPMOs (denoted as GNR@HPMOs-PTX). In vitro experiments show the GNR@HPMOs-PTX loaded MSCs (GNR@HPMOs-PTX@MSCs) possess synergistic chemo-photothermal killing effects for breast cancer cells. Also, photoacoustic imaging shows that the MSCs can improve dispersion and distribution in tumor tissue for GNR@HPMOs-PTX after intratumoral injection. In vivo experiments in breast cancer model of nude mice further demonstrate that the GNR@HPMOs-PTX@MSCs significantly inhibit tumor growth, suggesting their great potential for synergistic therapy of cancer.

Metabolomics-Based Screening of Biofilm-Inhibitory Compounds against Pseudomonas aeruginosa from Burdock Leaf.

Screening of anti-biofilm compounds from the burdock leaf based on metabolomics is reported here. The crystal violet assay indicated 34% ethanol elution fraction of burdock leaf could completely inhibit biofilm formation of Pseudomonas aeruginosa at 1 mg·mL(-1). Then, the chemical composition of burdock leaf fraction was analyzed by ultra-performance liquid chromatography-mass spectrometry (UPLC-MS) and 11 active compounds (chlorogenic acid, caffeic acid, p-coumaric acid, quercetin, ursolic acid, rutin, cynarin, luteolin, crocin, benzoic acid, and Tenacissoside I) were identified. Lastly, UPLC-MS analysis was employed to obtain the metabolic fingerprints of burdock leaf fractions before and after inhibiting the biofilm of Pseudomonas aeruginosa. The metabolic fingerprints were transformed to data, analyzed with PLS-DA (partial least squares discriminant analysis) and the peaks whose area was significantly changed were found out. Thus, 81 compounds were screened as potential anti-biofilm ingredients. Among them, rutin, ursolic acid, caffeic acid, p-coumaric acid and quercetin were identified and confirmed as the main anti-biofilm compounds in burdock leaf. The study provided basic anti-biofilm profile data for the compounds in burdock leaf, as well as provided a convenient method for fast screening of anti-biofilm compounds from natural plants.

Tumor-Specific Formation of Enzyme-Instructed Supramolecular Self-Assemblies as Cancer Theranostics.

Despite the effort of developing various nanodelivery systems, most of them suffer from undesired high uptakes by the reticuloendothelial system, such as liver and spleen. Herein we develop an endogenous phosphatase-triggered coassembly strategy to form tumor-specific indocyanine green (ICG)-doped nanofibers (5) for cancer theranostics. Based on coordinated intermolecular interactions, 5 significantly altered near-infrared absorbance of ICG, which improves the critical photoacoustic and photothermal properties. The phosphatase-instructed coassembly process, as well as its theranostic capability, was successfully conducted at different levels ranging from in vitro, living cell, tissue mimic, to in vivo. Specifically, the tumor uptake of ICG was markedly increased to 15.05 ± 3.78%ID/g, which was 25-fold higher than that of free ICG (0.59 ± 0.24%ID/g) at 4 h after intravenous injection. The resulting ultrahigh T/N ratios (>15) clearly differentiated tumors from the surrounding normal tissue. Complete tumor elimination with high therapeutic accuracy has been successfully achieved upon laser irradiation (0.8 W/cm(2), 5 min) within 24-48 h postinjection. As the first example, in vivo formation of tumor-specific ICG-doped nanofiber for PTT theranostics owns the immense potential for clinical translation of personalized nanomedicine with targeted drug delivery as well as for cancer theranostics.

An aptamer-targeting photoresponsive drug delivery system using "off-on" graphene oxide wrapped mesoporous silica nanoparticles.

We have developed a novel aptamer-targeting photoresponsive drug delivery system by non-covalent assembly of a Cy5.5-AS1411 aptamer conjugate on the surface of graphene oxide wrapped doxorubicin (Dox)-loaded mesoporous silica nanoparticles (MSN-Dox@GO-Apt) for light-mediated drug release and aptamer-targeted cancer therapy. The two "off-on" switches of the MSN-Dox@GO-Apt were controlled by aptamer targeting and light triggering, respectively. The Cy5.5-AS1411 ligand provides MSN-Dox@GO-Apt with nucleolin specific targeting and real-time indicator abilities by "off-on" Cy5.5 fluorescence recovery. The GO acts as a gatekeeper to prevent the loaded Dox from leaking in the absence of laser irradiation, and to control the Dox release in response to laser irradiation. When the GO wrapping falls off upon laser irradiation, the "off-on" photoresponsive drug delivery system is activated, thus inducing chemotherapy. Interestingly, with an increase in laser power, the synergism of chemotherapy and photothermal therapy in a single MSN-Dox@GO-Apt platform led to much more effective cancer cell killing than monotherapies, providing a new approach for treatment against cancer.