This is high demand to enhance the accumulation of near-infrared theranostic agents in the tumor region, which is favorable to the effective phototherapy. Compared with indocyanine green (a clinically applied dye), IR-780 iodide possesses higher and more stable fluorescence intensity and can be utilized as an imaging-guided PTT agent with laser irradiation. However, lipophilicity and short circulation time limit its applications in cancer imaging and therapy. Moreover, solid lipid nanoparticles (SLNs) conjugated with c(RGDyK) was designed as efficient carriers to improve the targeted delivery of IR-780 to the tumors. The multifunctional cRGD-IR-780 SLNs exhibited a desirable monodispersity, preferable stability and significant targeting to cell lines overexpressing αβ integrin. Additionally, the in vitro assays such as cell viability and in vivo PTT treatment denoted that U87MG cells or U87MG transplantation tumors could be eradicated by applying cRGD-IR-780 SLNs under laser irradiation. Therefore, the resultant cRGD-IR-780 SLNs may serve as a promising NIR imaging-guided targeting PTT agent for cancer therapy.
Background:The purpose of this work was to develop nanostructured lipid carriers (NLCs) loaded simultaneously with oleanolic acid and gentiopicrin. Methods: An aqueous dispersion of NLCs was prepared successfully using a film-ultrasonic method, with glycerin monostearate as the solid lipid and oleic acid as the liquid lipid. Poloxamer 188 was used as the surfactant. A central composite design was used to optimize the technologic parameters. The characteristics of the NLCs were then investigated. Results: The encapsulation efficiency was 48.34% ± 2.76%, drug loading was 8.06% ± 0.42%, particle size was 111.0 ± 1.56 nm, polydispersity index was 0.287 ± 0.01, and zeta potential was −23.8 ± 0.36 mV for the optimized NLCs. The other physicochemical properties were characterized by transmission electron microscopy and differential scanning calorimetry. Drug release followed first-order kinetics and release studies confirmed that oleanolic acid and gentiopicrin fitted a sustained-release model. Compared with NLCs loaded with oleanolic acid or gentiopicrin alone, NLCs loaded with both oleanolic acid and gentiopicrin produced drug concentrations which persisted for a significantly longer time in plasma, with a linear decrement following second-order kinetics. Aspartate and alanine aminotransferase levels were significantly lower on exposure to NLCs loaded with both oleanolic acid and gentiopicrin than in negative controls. Conclusion:The results of this study confirm that oleanolic acid and gentiopicrin can be loaded simultaneously into NLCs. Compared with oleanolic acid and gentiopicrin loaded alone, sustained release and protective effects against hepatic injury were observed using NLCs loaded with both oleanolic acid and gentiopicrin.
There was much interest in the development of nanoscale delivery vehicles based on polymeric micelles to realize the diagnostic and therapeutic applications in biomedicine. Here, with the purpose of constructing a micellar magnetic resonance imaging (MRI) contrast agent (CA) with well biocompatibility and targeting specificity, two types of amphiphilic diblock polymers, mPEG-PG(DOTA(Gd))-b-PCL and FA-PEG-b-PCL, were synthesized to form mixed micelles by coassembly. The nanostructure of the resulting micellar system consisted of poly(caprolactone) (PCL) as core and poly(glycerol) (PG) and poly(ethylene glycol) (PEG) as shell, simultaneously modified with DOTA(Gd) chelates and folic acid (FA), which afforded functions of MRI contrast enhancement and tumor targeting. The mixed micelles in aqueous solution presented a hydrodynamic diameter of about 85 nm. Additionally, this mixed micelles exhibited higher r relaxivity (14.01 mM S) compared with commercial Magnevist (3.95 mM S) and showed negligible cytotoxicity estimated by WST assay. In vitro and in vivo MRI experiments revealed excellent targeting specificity to tumor cells and tissue. Furthermore, considerably enhanced signal intensity and prominent positive contrast effect were achieved at tumor region after tumor-bearing mice were intravenously injected with the mixed micelles. These preliminary results indicated the potential of the mixed micelle as T MRI CA for tumor-targeted imaging.
Circulating tumor cell (CTC) isolation has attracted a great deal of research interest in recent years. However, there are still some challenges, including purity as well as viability of the captured CTCs, resulting from nanoscale structures and inorganic nanomaterials. Here, a chitosan nanoparticle surface is first fabricated by electrospray to provide a cellular compatible interface. The "soft" substrate, further modified by polyethylene glycol (PEG) as an antifouling molecule and DNA aptamer as a specific capture molecule, has a hydrophilic nature and is capable of specific capture of viable rare CTCs from artificial white blood cell (WBC) samples. Furthermore, a subsequent in situ culture strategy based on the developed cellular compatible soft interface is introduced for further purification and proliferation of the captured rare number target cells. The WBCs are weeded out after 2 d, and after a 7 d proliferation nearly 200 MCF-7 cells are obtained from 7 target cells with more than 90% purity. This work provides a promising strategy for viable isolation and purification of rare CTCs and it has great potential for achieving clinical validity.
Lanthanide (Ln(3+) )-doped upconversion nanoparticles (UCNPs) as a new generation of multimodal bioprobes have attracted great interest for theranostic purpose. Herein, red emitting nonstoichiometric Na0.52 YbF3.52 :Er UCNPs of high luminescence intensity and color purity are synthesized via a facile solvothermal method. The red UC emission from the present nanophosphors is three times more intense than the well-known green emission from the ≈30 nm sized hexagonal-phase NaYF4 :Yb,Er UCNPs. By utilizing Na0.52 YbF3.52 :Er@SrF2 UCNPs as multifunctional nanoplatforms, highly efficient in vitro and in vivo 915 nm light-triggered photodynamic therapies are realized for the first time, with dramatically diminished overheating yet similar therapeutic effects in comparison to those triggered by 980 nm light. Moreover, by virtue of the high transverse relaxivity (r 2 ) and the strong X-ray attenuation ability of Yb(3+) ions, these UCNPs also demonstrate good performances as contrast agents for high contrast magnetic resonance and X-ray computed tomography dual-modal imaging. Our research shows the great potential of the red emitting Na0.52 YbF3.52 :Er UCNPs for multimodal imaging-guided photodynamic therapy of tumors.
Background Anti-angiogenic therapy has been widely applied to the clinical treatment of malignant tumors. However, the efficacy of such treatments has been called into question, especially in triple-negative breast cancer (TNBC). Bevacizumab, the first anti-angiogenic agent approved by FDA, actually increases invasive and metastatic properties of TNBC cells, resulting from the activation of Wnt/β-catenin signaling in response to hypoxia. As a critical receptor of Wnt/β-catenin signaling, Frizzled-7 (Fzd7) is aberrantly expressed in TNBC, indicating Fzd7 a potential target for developing drugs to be combined with anti-angiogenic agents. Methods Hybridoma technique and antibody humanization technique were utilized to generate a Fzd7-targeting antibody (SHH002-hu1). Biolayer interferometry (BLI) assay and near infrared (NIR) imaging were conducted to detect the affinity and targeting ability of SHH002-hu1. Next, whether SHH002-hu1 could suppress the invasion and migration of TNBC cells induced by Bevacizumab were validated, and the underlying molecular mechanisms were elucidated by luciferase reporter and western blot assays. The nude-mice transplanted TNBC models were established to assess the anti-TNBC activities of SHH002-hu1 when combined with Bevacizumab. Then, the effects on putative TNBC stem-like cells and Wnt/β-catenin signaling were evaluated by immunofluorescence (IF). Further, the tumor-initiating and self-renew capacity of TNBC cells were studied by secondary nude mouse xenograft model and sphere formation assay. In addition, the effects of SHH002-hu1 on the adaptation of TNBC cells to hypoxia were evaluated by the detection of vasculogenic mimicry (VM) and hypoxia-inducible factor-1α (HIF-1α) transcriptional activity. Results The novel humanized antibody targeting Fzd7 (SHH002-hu1) exhibited extremely high affinity with Fzd7, and specifically targeted to Fzd7+ cells and tumor tissues. SHH002-hu1 repressed invasion, migration and epithelial-mesenchymal cell transformation (EMT) of TNBC cells induced by Bevacizumab through abating Wnt/β-catenin signaling. SHH002-hu1 significantly enhanced the capacity of Bevacizumab to inhibit the growth of TNBC via reducing the subpopulation of putative TNBC stem-like cells, further attenuating Bevacizumab-enhanced tumor-initiating and self-renew capacity of TNBC cells. Moreover, SHH002-hu1 effectively restrained the adaptation of TNBC cells to hypoxia via disrupting Wnt/β-catenin signaling. Conclusion SHH002-hu1 significantly enhances the anti-TNBC capacity of Bevacizumab, and shows the potential of preventing TNBC recurrence, suggesting SHH002-hu1 a good candidate for the synergistic therapy together with Bevacizumab.
A novel aptamer modified thermosensitive liposome was designed as an efficient magnetic resonance imaging probe. In this paper, Gd-DTPA was encapsulated into an optimized thermosensitive liposome (TSL) formulation, followed by conjugation with AS1411 for specific targeting against tumor cells that overexpress nucleolin receptors. The resulting liposomes were extensively characterized in vitro as a contrast agent. As-prepared TSLs-AS1411 had a diameter about 136.1 nm. No obvious cytotoxicity was observed from MTT assay, which illustrated that the liposomes exhibited excellent biocompatibility. Compared to the control incubation at 37 °C, the liposomes modified with AS1411 exhibited much higher T1 relaxivity in MCF-7 cells incubated at 42 °C. These data indicate that the Gd-encapsulated TSLs-AS1411 may be a promising tool in early cancer diagnosis.
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