Dendrimer-encapsulated naphthalocyanine as a single agent-based theranostic nanoplatform for near-infrared fluorescence imaging and combinatorial anticancer phototherapy

Multifunctional theranostic platforms capable of concurrent near-infrared (NIR) fluorescence imaging and phototherapies are strongly desired for cancer diagnostic and treatment. However, integration of separate imaging and therapeutic components into nanocarriers results in complex theranostic systems with limited translational potential. A single agent-based theranostic nanoplatform, therefore, was developed for concurrent NIR fluorescence imaging and combinatorial phototherapy with dual photodynamic (PDT) and photothermal (PTT) therapeutic mechanisms. The transformation of substituted silicon naphthalocyanine (SiNc) into biocompatible nanoplatform (SiNc-NP) was achieved by SiNc encapsulation into the hydrophobic interior of the generation 5 polypropylenimine dendrimer following surface modification with polyethylene glycol. Encapsulation provides aqueous solubility to SiNc and preserves its NIR fluorescence, PDT and PTT properties. Moreover, impressive photostability of dendrimer-encapsulated SiNc have been detected. Under NIR irradiation (785 nm, 1.3 W/cm²), SiNc-NP manifested robust heat generation capability (ΔT = 40 °C) and efficiently produced reactive oxygen species essential for PTT and PDT, respectively, without releasing SiNc from the nanopaltform. By varying laser power density from 0.3 W/cm² to 1.3 W/cm² the therapeutic mechanism of SiNc-NP could be switched from PDT to combinatorial PDT-PTT treatment. In vitro and in vivo studies confirmed that phototherapy mediated by SiNc can efficiently destroy chemotherapy resistant ovarian cancer cells. Remarkably, solid tumors treated with a single dose of SiNc-NP combined with NIR irradiation were completely eradicated without cancer recurrence. Finally, the efficiency of SiNc-NP as an NIR imaging agent was confirmed by recording the strong fluorescence signal in the tumor, which was not photobleached during the phototherapeutic procedure.Keywords: photothermal therapy, photostability, near-infrared imaging, theranostic, naphthalocyanine, photodynamic therap

Multifunctional Nanomedicine Platform for Concurrent Delivery of Chemotherapeutic Drugs and Mild Hyperthermia to Ovarian Cancer Cells

A multifunctional tumor-targeting delivery system was developed and evaluated for an efficient treatment of drug-resistant ovarian cancer by combinatorial therapeutic modality based on chemotherapy and mild hyperthermia. The engineered iron oxide nanoparticle (IONPs)-based nanocarrier served as an efficient delivery vehicle for doxorubicin and provided the ability to heat cancer cells remotely upon exposure to an alternating magnetic field (AMF). The nanocarrier was additionally modified with polyethylene glycol and LHRH peptide to improve its biocompatibility and ability to target tumor cells. The synthesized delivery system has an average size of 97.1 nm and a zeta potential close to zero, both parameters favorable for increased stability in biological media and decreased elimination by the immune system. The nanocarrier demonstrated faster drug release in acidic conditions that mimic the tumor environment. It was also observed that the LHRH targeted delivery system could effectively enter drug resistant ovarian cancer cells, and the fate of doxorubicin was tracked with fluorescence microscope. Mild hyperthermia (40 °C) generated by IONPs under exposure to AMF synergistically increased the cytotoxicity of doxorubicin delivered by the developed nanocarrier to cancer cells. Thus, the developed IONPs-based delivery system has high potential in the effective treatment of ovarian cancer by combinatorial approach.This is an author's peer-reviewed final manuscript, as accepted by the publisher. The published article is copyrighted by Elsevier and can be found at: http://www.journals.elsevier.com/international-journal-of-pharmaceutics/.Keywords: Mild hyperthermia, Iron oxide nanoparticles, Ovarian cancer, Combinatorial treatment, Alternating magnetic field (AMF), Doxorubici

Intraperitoneal Nanotherapy for Metastatic Ovarian Cancer Based on siRNA-Mediated Suppression of DJ-1 Protein Combined with a Low Dose of Cisplatin

Herein, we report an efficient combinatorial therapy for metastatic ovarian cancer based on siRNA-mediated suppression of DJ-1 protein combined with a low dose of cisplatin. DJ-1 protein modulates, either directly or indirectly, different oncogenic pathways that support and promote survival, growth, and invasion of ovarian cancer cells. To evaluate the potential of this novel therapy, we have engineered a cancer-targeted nanoplatform and validated that DJ-1 siRNA delivered by this nanoplatform after intraperitoneal injection efficiently downregulates the DJ-1 protein in metastatic ovarian cancer tumors and ascites. In vivo experiments revealed that DJ-1 siRNA monotherapy outperformed cisplatin alone by inhibiting tumor growth and increasing survival of mice with metastatic ovarian cancer. Finally, three cycles of siRNA-mediated DJ-1 therapy in combination with a low dose of cisplatin completely eradicated ovarian cancer tumors from the mice, and there was no cancer recurrence detected for the duration of the study, which lasted 35 weeks

Naphthalocyanine-Based Biodegradable Polymeric Nanoparticles for Image-Guided Combinatorial Phototherapy

Image-guided phototherapy is extensively considered as a promising therapy for cancer treatment. To enhance translational potential of this modality, we developed a single agent-based biocompatible nanoplatform that provides both real time near-infrared (NIR) fluorescence imaging and combinatorial phototherapy with dual photothermal and photodynamic therapeutic mechanisms. The developed theranostic nanoplatform consists of two building blocks: (1) silicon naphthalocyanine (SiNc) as NIR fluorescence imaging and phototherapeutic agent and (2) a copolymer, poly(ethylene glycol)-block-poly(ε-caprolactone) (PEG-PCL) as the biodegradable SiNc carrier. Our simple, highly reproducible and robust approach results in preparation of spherical, monodisperse SiNc-loaded PEG-PCL polymeric nanoparticles (SiNc-PNP) with a hydrodynamic size of 37.66 ± 0.26 nm (polydispersity index = 0.06) and surface charge of -2.76 ± 1.83 mV. The SiNc-loaded nanoparticles exhibit a strong NIR light absorption with an extinction coefficient of 2.8 x 10⁵ M⁻¹cm⁻¹ and efficiently convert the absorbed energy into fluorescence emission (Φ[subscript F] = 11.8%), heat (ΔT ~ 25 °C) and reactive oxygen species. Moreover, the SiNc-PNP are characterized by superior photostability under extensive photoirradiation and structure integrity during storage at room temperature over a period of 30 days. Following intravenous injection, the SiNc-PNP accumulated selectively in tumors and provided high lesion-to-normal tissue contrast for sensitive fluorescence detection. Finally, Adriamycin-resistant tumors treated with a single intravenous dose of SiNc-PNP (1.5 mg/kg) combined with 10 min of a 785 nm light irradiation (1.3 W/cm²) were completely eradicated from the mice without cancer recurrence or side effects. The reported characteristics make the developed SiNc-PNP a promising platform for future clinical application.This is the author's peer-reviewed final manuscript, as accepted by the publisher. The published article is copyrighted by the American Chemical Society and can be found at: https://doi.org/10.1021/acs.chemmater.5b0312

Intraperitoneal Nanotherapy for Metastatic Ovarian Cancer Based on siRNA-Mediated Suppression of DJ-1 Protein Combined with a Low Dose of Cisplatin

Herein, we report an efficient combinatorial therapy for metastatic ovarian cancer based on siRNA-mediated suppression of DJ-1 protein combined with a low dose of cisplatin. DJ-1 protein modulates, either directly or indirectly, different oncogenic pathways that support and promote survival, growth, and invasion of ovarian cancer cells. To evaluate the potential of this novel therapy, we have engineered a cancer-targeted nanoplatform and validated that DJ-1 siRNA delivered by this nanoplatform after intraperitoneal injection efficiently downregulates the DJ-1 protein in metastatic ovarian cancer tumors and ascites. In vivo experiments revealed that DJ-1 siRNA monotherapy outperformed cisplatin alone by inhibiting tumor growth and increasing survival of mice with metastatic ovarian cancer. Finally, three cycles of siRNA-mediated DJ-1 therapy in combination with a low dose of cisplatin completely eradicated ovarian cancer tumors from the mice, and there was no cancer recurrence detected for the duration of the study, which lasted 35 weeks

Targeted Nanocarriers for Systemic Delivery of IRAK4 Inhibitors to Inflamed Tissues

Persistent and uncontrolled inflammation is the root cause of various debilitating diseases. Given that interleukin-1 receptor–associated kinase 4 (IRAK4) is a critical modulator of inflammation, inhibition of its activity with selective drug molecules (IRAK4 inhibitors) represents a promising therapeutic strategy for inflammatory disorders. To exploit the full potential of this treatment approach, drug carriers for efficient delivery of IRAK4 inhibitors to inflamed tissues are essential. Herein, the first nanoparticle-based platform for the targeted systemic delivery of a clinically tested IRAK4 inhibitor, PF-06650833, with limited aqueous solubility (57 μg mL-1) is presented. The developed nanocarriers increase the intrinsic aqueous dispersibility of this IRAK4 inhibitor by 40 times. A targeting peptide on the surface of nanocarriers significantly enhances their accumulation after intravenous injection in inflamed tissues of mice with induced paw edema and ulcerative colitis when compared to non-targeted counterparts. The delivered IRAK4 inhibitor markedly abates inflammation and dramatically suppresses paw edema, mitigates colitis symptoms, and reduces proinflammatory cytokine levels in the affected tissues. Importantly, repeated injections of IRAK4 inhibitor-loaded nanocarriers have no acute toxic effect on major organs of mice. Therefore, the developed nanocarriers have the potential to significantly improve the therapeutic efficacy of IRAK4 inhibitors for different inflammatory diseases

Novel Nanoparticle-Based Treatment and Imaging Modalities

Over the last twenty years, nanomaterials have been widely used in cancer research [...

Mechanistic Nanotherapeutic Approach Based on siRNA-Mediated DJ-1 Protein Suppression for Platinum-Resistant Ovarian Cancer

We report an efficient therapeutic modality for platinum resistant ovarian cancer based on siRNAmediated suppression of a multifunctional DJ-1 protein that is responsible for the proliferation, growth, invasion, oxidative stress and overall survival of various cancers. The developed therapeutic strategy can work alone or in concert with a low dose of the first line chemotherapeutic agent cisplatin, to elicit a maximal therapeutic response. To achieve an efficient DJ-1 knockdown, we constructed the polypropylenimine dendrimer-based nanoplatform targeted to LHRH receptors overexpressed on ovarian cancer cells. The quantitative PCR and western immunoblotting analysis, revealed that the delivered DJ-1 siRNA downregulated the expression of targeted mRNA and corresponding protein by more than 80% in various ovarian cancer cells. It was further demonstrated that siRNA-mediated DJ-1 suppression dramatically impaired proliferation, viability and migration of the employed ovarian cancer cells. Finally, the combinatorial approach led to the most pronounced therapeutic response in all the studied cell lines, outperforming both siRNAmediated DJ-1 knockdown and cisplatin treatment alone. It is noteworthy that the platinumresistant cancer cells (A2780/CDDP) with the highest basal level of DJ-1 protein are most susceptible to the developed therapy and this susceptibility declines with decreasing basal levels of DJ-1. Finally, we interrogate the molecular underpinnings of the DJ-1 knockdown effects in the treatment of the ovarian cancer cells. By using various experimental techniques, it was revealed that DJ-1 depletion: (1) decreases the activity of the Akt pathway, thereby reducing cellular proliferation, migration and increasing the antiproliferative effect of cisplatin on ovarian cancer cells; (2) enhances the activity of p53 tumor suppressor protein therefore restoring cell cycle arrest functionality and upregulating the Bax-caspase pathway, triggering cell death; and (3) weakens the cellular defense mechanisms against inherited oxidative stress thereby increasing toxic intracellular radicals and amplifying the reactive oxygen species created by the administration of cisplatin