Project description:Combination therapy with multiple chemotherapeutic agents is the main approach for cancer treatment in the clinic. Polyphenol-based materials are found in our diet, demonstrate good biocompatibility, and prevent numerous diseases. In this study, we encapsulate two drugs in a single polyphenol-based polymer with Fe3+ or Mn2+ ions as the cross-linker for cancer therapy. The combination index of two drugs is an essential parameter to evaluate drug combinations. The amphiphilic polymer poly(ethylene glycol)-block-polydopamine (PEG-PDA) was prepared by RAFT polymerization. The nanoparticles were prepared via self-assembly with Fe3+ or Mn2+ ions. Both doxorubicin (DOX) and simvastatin (SV) were encapsulated in the core of the nanoparticles. The cell viability and combination index were evaluated in vitro. The tumor accumulation of the nanoparticles was investigated by positron-emission tomography (PET) and magnetic resonance (MR) imaging. The as-prepared nanoparticles exhibited high drug loading capacity. The drug loaded nanoparticles could kill cancer cells effectively with a combination index <1. Both PET and MRI revealed that the nanoparticles showed long blood circulation time and high tumor accumulation. The nanoparticles could inhibit tumor inhibition via intravenous injection of nanoparticles. The polyphenol-based nanoplatform may serve as a promising theranostic candidate for clinical application.
Project description:We report a novel cancer-targeted nanomedicine platform for imaging and prospect for future treatment of unresected ovarian cancer tumors by intraoperative multimodal phototherapy. To develop the required theranostic system, novel low-oxygen graphene nanosheets were chemically modified with polypropylenimine dendrimers loaded with phthalocyanine (Pc) as a photosensitizer. Such a molecular design prevents fluorescence quenching of the Pc by graphene nanosheets, providing the possibility of fluorescence imaging. Furthermore, the developed nanoplatform was conjugated with poly(ethylene glycol), to improve biocompatibility, and with luteinizing hormone-releasing hormone (LHRH) peptide, for tumor-targeted delivery. Notably, a low-power near-infrared (NIR) irradiation of single wavelength was used for both heat generation by the graphene nanosheets (photothermal therapy [PTT]) and for reactive oxygen species (ROS)-production by Pc (photodynamic therapy [PDT]). The combinatorial phototherapy resulted in an enhanced destruction of ovarian cancer cells, with a killing efficacy of 90%-95% at low Pc and low-oxygen graphene dosages, presumably conferring cytotoxicity to the synergistic effects of generated ROS and mild hyperthermia. An animal study confirmed that Pc loaded into the nanoplatform can be employed as a NIR fluorescence agent for imaging-guided drug delivery. Hence, the newly developed Pc-graphene nanoplatform has the significant potential as an effective NIR theranostic probe for imaging and combinatorial phototherapy.
Project description:Objective: A protein-based leaking-proof theranostic nanoplatform for dual-modality imaging-guided tumor photodynamic therapy (PDT) has been designed. Impact Statement: A site-specific conjugation of chlorin e6 (Ce6) to ferrimagnetic ferritin (MFtn-Ce6) has been constructed to address the challenge of unexpected leakage that often occurs during small-molecule drug delivery. Introduction: PDT is one of the most promising approaches for tumor treatment, while a delivery system is typically required for hydrophobic photosensitizers. However, the nonspecific distribution and leakage of photosensitizers could lead to insufficient drug accumulation in tumor sites. Methods: An engineered ferritin was generated for site-specific conjugation of Ce6 to obtain a leaking-proof delivery system, and a ferrimagnetic core was biomineralized in the cavity of ferritin, resulting in a fluorescent ferrimagnetic ferritin nanoplatform (MFtn-Ce6). The distribution and tumor targeting of MFtn-Ce6 can be detected by magnetic resonance imaging (MRI) and fluorescence imaging (FLI). Results: MFtn-Ce6 showed effective dual-modality MRI and FLI. A prolonged in vivo circulation and increased tumor accumulation and retention of photosensitizer was observed. The time-dependent distribution of MFtn-Ce6 can be precisely tracked in real time to find the optimal time window for PDT treatment. The colocalization of ferritin and the iron oxide core confirms the high stability of the nanoplatform in vivo. The results showed that mice treated with MFtn-Ce6 exhibited marked tumor-suppressive activity after laser irradiation. Conclusion: The ferritin-based leaking-proof nanoplatform can be used for the efficient delivery of the photosensitizer to achieve an enhanced therapeutic effect. This method established a general approach for the dual-modality imaging-guided tumor delivery of PDT agents.
Project description:Triple-negative breast cancer is a highly aggressive and metastatic tumor; diagnosing it in the early stages is still difficult, and the prognosis for conventional radio-chemotherapy and immunotreatment is not promising due to cancer's immunosuppressive microenvironment. The utilization of protein-based nanosystem has proven to be effective in delivering agents with limited adverse effects, yet the combination of diagnosis and treatment remains a difficult challenge. This research took advantage of natural albumin and organic molecules to construct a self-assemble core-shell nanostructure combining with superparamagnetic iron oxide nanocrystals and heptamethine cyanine dye IR780 through non-covalent interactions. This nanocomposite successfully decreased the transverse relaxation time of the magnetic resonance hydrogen nucleus, resulting in outstanding T2 imaging, as well as emitting near-infrared II fluorescence, thereby the resulting dual-modality imaging tool was applied to improve diagnostic competency. It is noteworthy that the nanocomposites exhibited impressive enzyme-like catalytic and photothermal capabilities, resulting in a successful activation of the immune system to efficiently suppress distant metastatic lesions in vivo. Consequently, this nano-drug-based therapy could be an advantageous asset in reinforcing the immune system and hindering the growth and reappearance of the immune-cold breast cancer.
Project description:Chemodynamic therapy (CDT), designed to trigger a tumor-specific hydrogen peroxide (H2O2) reaction generating highly toxic hydroxyl radicals (·OH), has been investigated for cancer treatment. Unfortunately, the limited Fenton or Fenton-like reaction rate and the significant impact of excessive reducing glutathione (GSH) in the tumor microenvironment (TME) have severely compromised the effectiveness of CDT. To address this issue, we designed a dual-responsive nanoplatform utilizing a metal-polyphenol network (MPN) -coated multi-caged IrOx for efficient anti-tumor therapy in response to the acidic TME and intracellular excess of GSH, in which MPN composed of Fe3+ and tannic acid (TA). Initially, the acidic TME and intracellular excess of GSH lead to the degradation of the MPN shell, resulting in the release of Fe3+ and exposure of the IrOx core, facilitating the efficient dual-pathway CDT. Subsequently, the nanoplatform can mitigate the attenuation of CDT by consuming the excessive GSH within the tumor. Finally, the multi-caged structure of IrOx is advantageous for effectively implementing photothermal therapy (PTT) in coordination with CDT, further enhancing the therapeutic efficacy of tumors. Moreover, the outstanding Computed Tomography (CT) and Magnetic Resonance Imaging (MRI) (T1/T2) multimodal imaging capabilities of IrOx@MPN enable early diagnosis and timely treatment. This work provides a typical example of the construction of a novel multifunctional platform for dual-responsive treatment of tumors.
Project description:Tunable, ultra-pH responsive fluorescent nanoparticles with multichromatic emissions are highly valuable in a variety of biological studies, such as endocytic trafficking, endosome/lysosome maturation, and pH regulation in subcellular organelles. Small differences (e.g., <1 pH unit) and yet finely regulated physiological pH inside different endocytic compartments present a huge challenge to the design of such a system. Herein, we report a general strategy to produce pH-tunable, highly activatable multicolored fluorescent nanoparticles using commonly available pH-insensitive dyes with emission wavelengths from green to near IR range. The primary driving force of fluorescence activation between the ON (unimer) and OFF (micelle) states is the pH-induced micellization. Among three possible photochemical mechanisms, homo Förster resonance energy transfer (homoFRET)-enhanced decay was found to be the most facile strategy to render ultra-pH response over the H-dimer and photoinduced electron transfer (PeT) mechanisms. Based on this insight, we selected several fluorophores with small Stoke shifts (<40 nm) and established a panel of multicolored nanoparticles with wide emission range (500-820 nm) and different pH transitions. Each nanoparticle maintained the sharp pH response (ON/OFF < 0.25 pH unit) with corresponding pH transition point at pH 5.2, 6.4, 6.9, and 7.2. Incubation of a mixture of multicolored nanoparticles with human H2009 lung cancer cells demonstrated sequential activation of the nanoparticles inside endocytic compartments directly correlating with their pH transitions. This multicolored, pH-tunable nanoplatform offers exciting opportunities for the study of many important cell physiological processes, such as pH regulation and endocytic trafficking of subcellular organelles.
Project description:Many cancer treatments including photodynamic therapy (PDT) utilize reactive oxygen species (ROS) to kill tumor cells. However, elevated antioxidant defense systems in cancer cells result in resistance to the therapy involving ROS. Here we describe a highly effective phototherapy through regulation of redox homeostasis with a biocompatible and versatile nanotherapeutic to inhibit tumor growth and metastasis. We systematically explore and exploit methylene blue adsorbed polydopamine nanoparticles as a targeted and precise nanocarrier, oxidative stress amplifier, photodynamic/photothermal agent, and multimodal probe for fluorescence, photothermal and photoacoustic imaging to enhance anti-tumor efficacy. Remarkably, following the glutathione-stimulated photosensitizer release to generate exogenous ROS, polydopamine eliminates the endogenous ROS scavenging system through depleting the primary antioxidant, thus amplifying the phototherapy and effectively suppressing tumor growth in vitro and in vivo. Furthermore, this approach enables a robust inhibition against breast cancer metastasis, as oxidative stress is a vital impediment to distant metastasis in tumor cells. Innovative, safe and effective nanotherapeutics via regulation of redox balance may provide a clinically relevant approach for cancer treatment.
Project description:Tumor hypoxia diminishes the effectiveness of traditional type II photodynamic therapy (PDT) due to oxygen consumption. Type I PDT, which can operate independently of oxygen, is a viable option for treating hypoxic tumors. In this study, we have designed and synthesized JSK@PEG-IR820 NPs that are responsive to the tumor microenvironment (TME) to enhance type I PDT through glutathione (GSH) depletion. Our approach aims to expand the sources of therapeutic benefits by promoting the generation of superoxide radicals (O2-.) while minimizing their consumption. The diisopropyl group within PEG-IR820 serves a dual purpose: it functions as a pH sensor for the disassembly of the NPs to release JSK and enhances intermolecular electron transfer to IR820, facilitating efficient O2-. generation. Simultaneously, the release of JSK leads to GSH depletion, resulting in the generation of nitric oxide (NO). This, in turn, contributes to the formation of highly cytotoxic peroxynitrite (ONOO-.), thereby enhancing the therapeutic efficacy of these NPs. NIR-II fluorescence imaging guided therapy has achieved successful tumor eradication with the assistance of laser therapy.
Project description:The extreme complexity and heterogeneity of fatal tumors requires the development of combination phototherapy considering the limited therapeutic efficiency of conventional monomodal photodynamic therapy (PDT) or photothermal therapy (PTT). However, tumor-specific drug administration and the accompanying hypoxia-restrained PDT present the main obstacles for executing an efficient combination phototherapy. Developing a highly biocompatible, tumor-specific, near infrared absorbing, and oxygen (O2)-evolving multifunctional nanoplatform is thus crucial for an effective PDT-based combination therapy. In this contribution, a multifunctional ZIF-8-gated polydopamine nanoparticle (PDA) carrier was synthesized for simultaneously delivering a photosensitizer and a catalase (CAT) into tumor cells, thus realizing a cooperatively enhanced combination photodynamic and photothermal therapy, as systematically demonstrated in vitro and in vivo. The ZIF-8 gatekeeper facilitates the simultaneous and effective delivery of these functional payloads, and the subsequent tumor acidic pH-stimulated drug release. This leads to a significant improvement of combination efficacy by ameliorating tumor hypoxic conditions since the CAT-mediated self-sufficient O2 generation could substantially promote an efficient PDT operation. In addition, this nanoplatform can effectively convert near infrared photoradiation into heat, resulting in thermally induced elimination of cancerous cells. As an intelligent multi-mode therapeutic nanosystem, this inorganic/organic hybrid nanosystem showed great potential for accurate cancer diagnosis and immediate therapy.
Project description:Multiply responsive protein nanoparticles are interesting for a variety of applications. Herein, we describe the synthesis of a vault nanoparticle that responds to both temperature and pH. Specifically, poly(N-isopropylacrylamide-co-acrylic acid) with a pyridyl disulfide end group was prepared by reversible addition-fragmentation chain transfer (RAFT) polymerization. The polymer had a lower critical solution temperature (LCST) of 31.9 °C at pH 5, 44.0 °C at pH 6 and above 60 °C at pH 7. The polymer was conjugated to human major vault protein (hMVP), and the resulting nanoparticle was analyzed by UV-Vis, dynamic light scattering (DLS) and electron microscopy. The data demonstrated that poly(N-isopropylacrylamide-co-acrylic acid)-vault conjugate did not respond to temperatures below 60 °C at pH 7, while the nanoparticles reversibly aggregated at pH 6. Furthermore, it was shown that the vault nanoparticle structure remained intact for at least three heat and cooling cycles. Thus, these dually responsive nanoparticles may serve as a platform for drug delivery and other applications.