Yunlei Zhang

Smart Cancer Cell Targeting Imaging and Drug Delivery System by Systematically Engineering Periodic Mesoporous Organosilica Nanoparticles

The integration of diagnosis and therapy into one nanoplatform, known as theranostics, has attracted increasing attention in the biomedical areas. Herein, we first present a cancer cell targeting imaging and drug delivery system based on engineered thioether-bridged periodic mesoporous organosilica nanoparticles (PMOs). The PMOs are stably and selectively conjugated with near-infrared fluorescence (NIRF) dye Cyanine 5.5 (Cy5.5) and anti-Her2 affibody on the outer surfaces to endow them with excellent NIRF imaging and cancer targeting properties. Also, taking the advantage of the thioether-group-incorporated mesopores, the release of chemotherapy drug doxorubicin (DOX) loaded in the PMOs is responsive to the tumor-related molecule glutathione (GSH). The drug release percentage reaches 84.8% in 10 mM of GSH solution within 24 h, which is more than 2-fold higher than that without GSH. In addition, the drug release also exhibits pH-responsive, which reaches 53.6% at pH 5 and 31.7% at pH 7.4 within 24 h. Confocal laser scanning microscopy and flow cytometry analysis demonstrate that the PMOs-based theranostic platforms can efficiently target to and enter Her2 positive tumor cells. Thus, the smart imaging and drug delivery nanoplatforms induce high tumor cell growth inhibition. Meanwhile, the Cy5.5 conjugated PMOs perform great NIRF imaging ability, which could monitor the intracellular distribution, delivery and release of the chemotherapy drug. In addition, cell viability and histological assessments show the engineered PMOs have good biocompatibility, further encouraging the following biomedical applications. Over all, the systemically engineered PMOs can serve as a novel cancer cell targeting imaging and drug delivery platform with NIRF imaging, GSH and pH dual-responsive drug release, and high tumor cell targeting ability.

Periodic Mesoporous Organosilica Coated Prussian Blue for MR/PA Dual‐Modal Imaging‐Guided Photothermal‐Chemotherapy of Triple Negative Breast Cancer

Complete eradication of highly aggressive triple negative breast cancer (TNBC) remains a notable challenge today. In this work, an imaging‐guided photothermal‐chemotherapy strategy for TNBC is developed for the first time based on a periodic mesoporous organosilica (PMO) coated Prussian blue (PB@PMO) nanoplatform. The PB@PMOs have organic‐inorganic hybrid frameworks, uniform diameter (125 nm), high surface area (866 m2 g−1), large pore size (3.2 nm), excellent photothermal conversion capability, high drug loading capacity (260 µg mg−1), and magnetic resonance (MR) and photoacoustic (PA) imaging abilities. The MR and PA properties of the PB@PMOs are helpful for imaging the tumor and showing the accumulation of the nanoplatform in the tumor region. The bioluminescence intensity and tumor volume of the MDA‐MB‐231‐Luc tumor‐bearing mouse model demonstrate that TNBC can be effectively inhibited by the combined photothermal‐chemotherapy than monotherapy strategy. Histopathological analysis further reveals that the combination therapy results in most extensive apoptotic and necrotic cells in the tumor without inducing obvious side effect to major organs.

pH-Dependent Transmembrane Activity of Peptide-Functionalized Gold Nanostars for Computed Tomography/Photoacoustic Imaging and Photothermal Therapy

Progress in multifunctional nanomaterials for tumor therapy mostly depends on the development of tumor-targeting delivery strategies. One approach is to explore a pH-responsive strategy to target the slightly acidic solid tumor microenvironment. A novel class of pH (low) insertion peptides (pHLIPs) with pH-dependent transmembrane activity can fold and rapidly insert into the lipid bilayer of tumor cells triggered by acidity, facilitating the cellular internalization of nanomaterials synchronously. Here, we innovatively decorated gold nanostars (GNSs) with pHLIPs (GNS-pHLIP) to improve their targeting ability and photothermal therapeutic (PTT) efficiency. The obtained GNS-pHLIP exhibited the excellent characteristics of uniform size and good biocompatibility. As compared to GNS-mPEG, the cellular internalization of GNS-pHLIP was 1-fold higher after a 2 h incubation with cells in media at pH 6.4 than at pH 7.4. Moreover, the tumor accumulation of the GNS-pHLIP was 3-fold higher than that of GNS-mPEG after intravenous injection into MCF-7 breast tumor animal models for 24 h. Furthermore, GNS-pHLIP exhibited stronger signals than the GNS-mPEG through computed tomography (CT) and photoacoustic (PA) imaging. Simultaneously, the desirable targeting efficiency significantly improved the PTT efficacy to tumors, with low side effects on normal tissues. The results clearly demonstrate that the GNS-pHLIP successfully took advantage of the tumor-targeting ability of pHLIPs and the good characteristics of GNSs, which may contribute to the study of tumor imaging and therapy.

NIR photoresponsive drug delivery and synergistic chemo-photothermal therapy by monodispersed-MoS2-nanosheets wrapped periodic mesoporous organosilicas

Two-dimensional (2D) MoS2 nanosheets have attracted increasing attention in recent years owing to their various fascinating properties, particularly excellent near-infrared (NIR) photothermal feature. In this study, we synthesized a novel NIR-light-triggered drug-delivery system by wrapping MoS2 nanosheets around doxorubicin (Dox)-loaded periodic mesoporous organosilicas (PMOs) and then decorating with polyethylene glycol (PEG) to form a PMO-Dox@MoS2-PEG nanoplatform for the first time. The obtained PMO-Dox@MoS2-PEG nanoplatforms had a uniform diameter (326 nm), high Dox loading capacity (160 μg mg-1 PMOs), excellent photothermal transformation ability, and good dispersibility in physiological conditions. Note that the Dox was almost completely blocked in the PMO-Dox@MoS2-PEG nanoplatforms, and the photothermal effect of the MoS2 nanosheets could efficiently trigger the release of Dox under an 808 nm laser irradiation. Simultaneously, the PMO-Dox@MoS2-PEG nanoplatforms realized a combined chemotherapy and photothermal therapy for liver cancer cells and breast cancer cells upon NIR laser irradiation. Compared with the single photothermal therapy or chemotherapy, the combined treatment had an improved synergistic therapeutic efficacy. We believe the NIR-light-triggered drug-delivery system with synergistic chemo-photothermal therapeutic property provides a promising strategy for cancer treatment.

Mesoporous organosilica nanoparticles with large radial pores via an assembly-reconstruction process in bi-phase

Mesoporous organosilica nanoparticles (MONs) have attracted increasing interest for guest molecule delivery. In this work, we prepared MONs with radially oriented large pores for the first time in a water-ethanol/n-hexane biphasic reaction system. The MONs possess ethane-incorporated organosilica frameworks, large radial pores with openings of 17-78 nm, a high surface area (1219 cm2 g-1), a large pore volume (2.2 cm3 g-1), tunable diameters (124-287 nm), and excellent biocompatibility. We reveal that the formation of large pore MONs in the biphasic reaction system undergoes a surfactant-directed self-assembly following mesostructure reconstruction, providing a new mechanism for the preparation of large mesoporous nanoparticles. Also, the effects of the reaction parameters including temperature and the stirring rate on the pore size are systemically investigated. Furthermore, large pore MONs were loaded with bovine serum albumin (BSA) and small interference RNA (siRNA), which exhibit high protein loading and siRNA delivery capabilities, suggesting the potential of the MONs for biomedical applications.

Cisplatin and doxorubicin high-loaded nanodrug based on biocompatible thioether- and ethane-bridged hollow mesoporous organosilica nanoparticles

Herein, a mesoporous organosilica nanoparticle (MON) based nanodrug highly loaded with cisplatin (CDDP) and doxorubicin (DOX) (denoted as MONs/CDDP/DOX) has been successfully prepared for the first time. The MONs are characterized with core-contained double hollow shells, thioether and ethane groups separately incorporated frameworks, uniform diameter (420 nm), large surface area (592 m2/g), and ordered pore size (2.5 nm). The safety evaluation of the MONs based on cell viability, haemolytic activity, histological change, and serum biochemical index demonstrates that they have excellent biological compatibility. The efficient uptake of the MONs by human breast cancer MCF-7 cells is further confirmed via confocal laser scanning imaging and flow cytometry. Importantly, the contents of CDDP and DOX in the MONs/CDDP/DOX nanodrug are as high as 120 mg/g and 85 mg/g, respectively. Therefore, the MONs/CDDP/DOX shows a significant improved killing effect against human breast cancer MCF-7 cells compared with sole DOX or CDDP loaded MONs, demonstating the promise of the nanodrug for cancer treatment.

Tumor Acidic Microenvironment Targeted Drug Delivery Based on pHLIP-Modified Mesoporous Organosilica Nanoparticles

Enhancing the tumor-targeting delivery of chemotherapeutic drugs is important yet challenging for improving therapeutic efficacy and reducing the side effects. Here, we first construct a drug delivery system for targeting tumor acidic microenvironment by modification of pH (low) insertion peptide (pHLIP) on mesoporous organosilica nanoparticles (MONs). The MONs has thioether-bridged framework, uniform diameter (60 nm), good biocompatibility, and high doxorubicin (DOX) loading capacity (334 mg/g). The DOX loaded in the pHLIP modified MONs can be released responsive to glutathione and low pH circumstance, ensuring the chemotherapeutic drug exerts higher cytotoxic effects to cancer cells than normal cells because of high intracellular GSH of tumor cells and low pH of tumor microenvironment. Moreover, the engineered MONs exhibit higher cellular uptake in pH 6.5 medium by MDA-MB-231 and MCF-7 cells than the particles decorated with polyethylene glycol (PEG). Importantly, the pHLIP-mosaic MONs with DOX displays better cytotoxic effects against the breast cancer cells in pH 6.5 medium than pH 7.4 medium. The in vivo experiments demonstrate that the pHLIP modified MONs are accumulated in the orthotopic breast cancer via targeting to acidic tumor microenvironment while no serious pathogenic effects was observed. After loading DOX, the pHLIP-modified MONs display better therapeutic effects than the control groups on the growth of MCF-7 breast cancers, showing promise for enhancing chemotherapy.

High and low molecular weight hyaluronic acid-coated gold nanobipyramids for photothermal therapy

Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer. It is known that hyaluronic acid (HA) binds CD44 receptors, which are overexpressed on the surface of TNBC cells. To optimize the targeting ability of HA, in this study we coated gold nanobipyramids (GBPs) with high and low molecular weight HA (380 kDa and 102 kDa), named GBPs@h-HA and GBPs@l-HA, respectively. GBPs@l-HA and GBPs@h-HA had excellent stability when dispersed in water and PBS (pH 7.4) for seven days. The HA density was calculated by the ratio of HA to GBPs@l-HA and GBPs@h-HA, which was 13.22 and 4.77, respectively. The two nanoparticles displayed good photostability, which was evaluated by their photothermal performance and similar biocompatibility. Inductively coupled plasma atomic emission spectrometry (ICP-AES) revealed superior cellular uptake of GBPs@h-HA over GBPs@l-HA. Upon 808 nm laser irradiation, the GBPs@h-HA also showed higher therapeutic efficacy than GBPs@l-HA both in vitro and in vivo. Overall, our study demonstrates that the molecular weight of HA plays an important role in the targeting ability and thus photothermal therapeutic efficacy of HA-coated gold nanobipyramids.

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.

In Situ shRNA Synthesis on DNA–Polylactide Nanoparticles to Treat Multidrug Resistant Breast Cancer

Nanomedicine has shown unprecedented potential for cancer theranostics. Nucleic acid (e.g., DNA and RNA) nanomedicines are of particular interest for combination therapy with chemotherapeutics. However, current nanotechnologies to construct such nucleic acid nanomedicines, which rely on chemical conjugation or physical complexation of nucleic acids with chemotherapeutics, have restrained their clinical translation due to limitations such as low drug loading efficiency and poor biostability. Herein, in situ rolling circle transcription (RCT) is applied to synthesize short hairpin RNA (shRNA) on amphiphilic DNA-polylactide (PLA) micelles. Core-shell PLA@poly-shRNA structures that codeliver a high payload of doxorubicin (Dox) and multidrug resistance protein 1 (MDR1) targeted shRNA for MDR breast cancer (BC) therapy are developed. DNA-PLA conjugates are first synthesized, which then self-assemble into amphiphilic DNA-PLA micelles; next, using the conjugated DNA as a promoter, poly-shRNA is synthesized on DNA-PLA micelles via RCT, generating PLA@poly-shRNA microflowers; and finally, microflowers are electrostatically condensed into nanoparticles using biocompatible and multifunctional poly(ethylene glycol)-grafted polypeptides (PPT-g-PEG). These PLA@poly-shRNA@PPT-g-PEG nanoparticles are efficiently delivered into MDR breast cancer cells and accumulated in xenograft tumors, leading to MDR1 silencing, intracellular Dox accumulation, potentiated apoptosis, and enhanced tumor therapeutic efficacy. Overall, this nanomedicine platform is promising to codeliver anticancer nucleic acid therapeutics and chemotherapeutics.