Qingpo Li

Appropriate Size of Magnetic Nanoparticles for Various Bioapplications in Cancer Diagnostics and Therapy

The development of multifunctional nanoparticles has attracted increasing attention. The versatility of nanoparticles largely depends on their physiochemical properties (especially size). However, the optimized size range may be different for the bioapplications of each function associated with multifunctional nanoparticles. It is important to investigate every optimized size range to ascertain which size enables the best function of the nanoparticles before deciding their final size. In this work, we synthesized a series of monodisperse Fe3O4 nanoparticles with identical surface properties ranging in size from 60 to 310 nm and systematically investigated their biobehavior and application. Our data indicate that compared to their large counterparts, small Fe3O4 nanoparticles exhibited greater cellular internalization and deeper penetration into multicellular spheroids, thus enabling a higher photothermal ablation efficacy in vitro. Interestingly, larger Fe3O4 nanoparticles showed greater accumulation in tumors, thereby inducing more efficient tumor growth inhibition. In addition, 120 nm may be the optimal diameter of Fe3O4 nanoparticles for magnetic resonance imaging and photoacoustic tomography in vitro. However, more efficient in vivo imaging mediated by Fe3O4 nanoparticles will predominantly depend on their high accumulation. Our work presents a different appropriate size range for each biofunction of Fe3O4 nanoparticles, which could be a valuable reference for future nanoparticle design.

Gold Nanospheres-Stabilized Indocyanine Green as a Synchronous Photodynamic–Photothermal Therapy Platform That Inhibits Tumor Growth and Metastasis

Both photothermal therapy (PTT) and photodynamic therapy (PDT) are phototherapeutic approaches, which have been widely investigated for cancer therapy mediated by an external light source. Here, a nanosystem presenting the synchronous PTT and PDT effect realized through one-step near-infrared (NIR) light irradiation is reported. This system was fabricated by conjugating indocyanine green (ICG) on hollow gold nanospheres (HAuNS) using branched-polyethylenimine (PEI, MW = 10 kDa) as optimal linker, which provided a high ICG payload as well as a covering layer with suitable thickness on HAuNS to maintain ICG fluorescence and reactive oxygen species (ROS) productivity. The resulting system (ICG-PEI-HAuNS) had the molar ratio of ICG:PEI:Au = 3:0.33:5. Compared with free ICG, ICG-PEI-HAuNS exhibited dramatically enhanced stability of ICG molecules and greater intratumoral accumulation. The conjugation of ICG caused significantly higher plasmon absorption of ICG-PEI-HAuNS in the NIR region compared with HAuNS alone, inducing remarkably enhanced photothermal conversion efficiency and synchronous photodynamic effect under NIR light irradiation. Interestingly, compared with PTT or PDT alone, synchronous PTT and PDT produced by ICG-PEI-HAuNS upon NIR light irradiation induced significantly stronger antitumor and metastasis inhibition effects both in vitro and in vivo, which might be a promising strategy for cancer treatment.

External Magnetic Field-Enhanced Chemo-Photothermal Combination Tumor Therapy via Iron Oxide Nanoparticles

The development of multifunctional nanoplatforms based on magnetic nanoparticles (MNPs) has attracted increasing attention. MNPs especially exhibit excellent responsiveness under the guidance of an external magnetic field (MF), resulting in tumor-specific, targeted delivery. The behavior and magnetic-targeting efficiency of MNPs largely depend on their physiochemical properties, especially the particle size; however, the optimal size range may vary across the multiple bioapplications associated with multifunctional nanoparticles. The optimal size range of nanoparticles for external MF-mediated targeted delivery has rarely been reported. In this work, we synthesized a series of monodisperse Fe3O4 nanoparticles with identical surface properties ranging in size from 10 to 310 nm, and we systematically investigated their behavior and MF-assisted antitumor efficacy. Our data indicated that smaller Fe3O4 nanoparticles exhibited greater cellular internalization, while larger Fe3O4 nanoparticles showed greater tumor accumulation. Larger Fe3O4 nanoparticles exhibited stronger magnetic responsiveness both in vitro and in vivo, which could be used to further induce increased accumulation of nanoparticles and their payload (e.g., doxorubicin) into the tumor site under the guidance of an external MF. Our work demonstrated that larger Fe3O4 nanoparticles, with a diameter of up to 310 nm, exhibited the best magnetic-targeting efficiency mediated by an external MF and the strongest antitumor efficacy from combination photothermal-chemotherapy. Our results could serve as a valuable reference for the future design of MNPs and their targeted delivery via the modulation of an external MF.

Synchronous delivery of oxygen and photosensitizer for alleviation of hypoxia tumor microenvironment and dramatically enhanced photodynamic therapy

Abstract Photosensitizer, proper laser irradiation, and oxygen are essential components for effective photodynamic therapy (PDT) in clinical cancer therapy. However, native hypoxic tumoral microenvironment is a major barrier hindering photodynamic reactions in vivo. Thus, we have prepared biocompatible liposomes by loading complexes of oxygen-carrier (hemoglobin, Hb) and photosensitizer (indocyanine green, ICG) for enhanced PDT against hypoxic tumor. Ideal oxygen donor Hb, which is an oxygen-carried protein in red blood cells, makes such liposome which provide stable oxygen supply. ICG, as a photosensitizer, could transfer energy from lasers to oxygen to generate cytotoxic reactive oxygen species (ROS) for treatment. The liposomes loading ICG and Hb (LIH) exhibited efficient tumor homing upon intravenous injection. As revealed by T2-weighted magnetic resonance imaging and immunohistochemical analysis, the intratumoral hypoxia was greatly alleviated, and the level of hypoxia inducible factor-1α (HIF-1α) and vascular endothelial growth factor (VEGF) in tumor was obviously down-regulated. A weak PDT efficiency was found in cells incubated in simulated hypoxia condition in vitro, while PDT effect was dramatically enhanced in LIH treated hypoxia cells under near-infrared (NIR) laser, which was mainly attributed to massive generation of ROS with sufficient oxygen supply. ROS trigger oxidative damage of tumors and induce complete suppression of tumor growth and 100% survival rate of mice, which were also in good health condition. Our work highlights a liposome-based nanomedicine that could effectively deliver oxygen to tumor and alleviate tumor hypoxia state, inducing greatly improved efficacy compared to conventional cancer PDT and demonstrates the promise of modulating unfavorable tumor microenvironment with nanotechnology to overcome limitations of cancer therapies.

Specifically increased paclitaxel release in tumor and synergetic therapy by a hyaluronic acid-tocopherol nanomicelle

Recently, interest in tumor-targeted and site-specific drug release from nanoparticles as a means of drug delivery has increased. In this study, we report a smart nanosized micelle formed by hyaluronic acid (HA) conjugated with d-α-tocopherol succinate (TOS) using a disulfide bond as the linker (HA-SS-TOS, HSST). HSST micelles can specifically bind to the CD44 receptors that are overexpressed by cancer cells. The high levels of glutathione (GSH) in tumor cells selectively break the disulfide bond linker. This effect results in the synchronous release of the payload and a TOS fragment. These two components subsequently demonstrate synergetic anticancer activity. First, we demonstrate that drug release from HSST occurs rapidly in physiological high redox conditions and inside cancer cells. Significant GSH-triggered drug release was also observed in vivo. Furthermore, an in vivo biodistribution study indicated that the HSST micelles efficiently accumulated at the tumor sites, primarily due to an enhanced permeability and retention effect and the efficient binding to the cancer cells that overexpressed the CD44 receptor. Interestingly, the synchronous release of paclitaxel (PTX) and the TOS fragment from the PTX-loaded HSST caused synergetic tumor cell killing and tumor growth inhibition. Our work presents a useful candidate for a drug delivery system that can specifically accumulate at tumor tissue, selectively release its payload and a TOS fragment, and thus display a synergetic anticancer effect.

Specific Photothermal Ablation Therapy of Endometriosis by Targeting Delivery of Gold Nanospheres

Endometriosis is difficult to treat since the side effects of the current therapeutic method and the high recurrence rate; thus, newer and safer therapeutic approaches are urgently needed. This work investigates the enhanced permeability and retention effect of CdTe quantum dots (QDs) and hollow gold nanospheres (HAuNS) in endometriosis to increase the delivery of HAuNS into lesion cells. The surface of HAuNS is successfully conjugated with a TNYL peptide that has specific affinity for the EphB4 receptor, which is a member of the Eph family of receptor tyrosine kinases. It is found that the EphB4 receptor is overexpressed in endometriosis lesions. The data indicate that both QDs and HAuNS can efficiently accumulate in endometriotic lesions through permeable vessels and the TNYL-conjugated HAuNS (TNYL-HAuNS) accumulate more via the interaction with EphB4. The specific photothermal ablation therapy based on TNYL-HAuNS significantly inhibits the growth of the endometriotic volume and induces the atrophy and degeneration of ectopic endometrium with no detectable toxicity to the normal organs. The level of TNF-α and estradiol also significantly decreases in the endometriotic lesions, indicating that the treatment enables a recovery from hormonal imbalance and inflammatory injury. This work can be a valuable reference for future endometriosis therapy.

Sustained release of anti-PD-1 peptide for perdurable immunotherapy together with photothermal ablation against primary and distant tumors

ABSTRACT Immune checkpoint PD‐1/PD‐L1 blockade has emerged as a successful immunotherapy strategy for treating several types of malignant tumors. A constant and proper drug concentration during the treatment is important because the long‐term activation of the immune system is urgently needed to perdurably recognize and attack cancer cells for a better therapeutic effect with minimum side effects. However, practically few related studies have been reported to date. In this study, we constructed a therapeutic strategy combining PD‐1 blocking with photothermal ablation for malignant tumors by co‐encapsulating anti‐PD‐1 peptide (APP) and hollow gold nanoshell (HAuNS) into biodegradable Poly (d, l‐lactic‐co‐glycolide) nanoparticles (APP‐ and HAuNS‐loaded PLGA nanoparticles, AA@PN). Slow and continuous release of APP from AA@PN could be obtained from 0 to 40days, and this release was easily accelerated by illumination with a near‐infrared (NIR) laser. A clear killing effect on distant tumor cells was observed after treatment of the co‐culture system of PMBCs and tumor cells with AA@PN plus an NIR laser, reflecting the activated immune response. AA@PN followed by multiple irradiations with an NIR laser showed the strongest antitumor effect, with the elimination of most primary tumors compared with other treatments, and significantly inhibited the growth of the distant uninjected primary tumors, similarly to free APP with frequent injections, which induced the longest survival time for the mice in this group.

A photosensitive liposome with NIR light triggered doxorubicin release as a combined photodynamic-chemo therapy system

&NA; The targeted drug delivery with the help of nanocarriers and the controlled drug release at the lesion sites are the most effective ways to enhance therapeutic efficacy and reduce side effects. Here, we built a light sensitive liposome (Her2‐I&D‐LSL) which was formed by a special phospholipid (PLsPC) and a hydrophobically modified photosensitizer (ICG‐ODA). DOX was employed as the therapeutic drug, encapsulating in the internal phase of the liposome whose surface was modified by Her2 antibodies for recognizing tumor cells with high Her2 receptor expression. Mediated by NIR light, Her2‐I&D‐LSL was proved to generate sufficient ROS to realize PDT, which then triggered the release of DOX for combined chemotherapy. The ROS generation and DOX release were verified to be strictly controlled by NIR light and the proportion of ICG‐ODA. Thanks to the mediation of Her2 receptor, the specific DOX release and the combination of PDT‐chemotherapy triggered by NIR light, Her2‐I&D‐LSL showed a significant accumulation in MCF7 and SKOV3 tumors, thus leading to the strongest tumor growth inhibition effect compared to PDT alone (I‐LSL) or chemotherapy alone (D‐LSL). Her2‐I&D‐LSL also possessed a great biocompatibility due to the targeted treatment, holding promise for future cancer therapy in clinic.

Suppress orthotopic colon cancer and its metastasis through exact targeting and highly selective drug release by a smart nanomicelle

The treatment of metastatic cancer is a huge challenge at the moment. Highly precise targeting delivery and drug release in tumor have always been our pursuit in cancer therapy, especially to advance cancer with metastasis, for increasing the efficacy and biosafety. We established a smart nanosized micelle, formed by tocopherol succinate (TOS) conjugated hyaluronic acid (HA) using a disulfide bond linker. The micelle (HA-SS-TOS, HSST) can highly specifically bind with CD44 receptor over-expressed tumor, and response selectively to high GSH level in the cells, inducing disulfide bond breakage and the release of the payload (paclitaxel, PTX). To predict the antitumor efficacy of the micelles more clinically, we established an orthotopic colon cancer model with high metastasis rate, which could be visualized by the luciferase bioluminescence. Our data confirmed CD44 high expression in the colon cancer cells. Highly matching between the micellar fluorescence and bioluminescence of cancer cells in intestines demonstrated an exact recognition of our micelles to orthotopic colon tumor and its metastatic cells, attributing to the mediation of CD44 receptors. Furthermore, the fluorescence of the released Nile Red from the micelles was found only in the tumor and its metastatic cells, and almost completely overlapped with the bioluminescence of the cancer cells, indicating a highly selective drug release. Our micelles presented an excellent therapeutic effect against metastatic colon cancer, and induced significantly prolonged survival time for the mice, which might become a promising nanomedicine platform for the future clinical application against advanced cancers with high CD44 receptor expression.

Low molecular weight polyethylenimine-conjugated gold nanospheres: a platform for selective gene therapy controlled by near-infrared light

AIM Whether PEI2k-HAuNS could promote gene transfection efficiency controlled by near-infrared (NIR) light. MATERIALS & METHODS This safe nonviral gene delivery system was obtained by conjugating low molecular weight (2 kDa) polyethylenimine (PEI) onto hollow gold nanospheres (PEI2k-HAuNS). Upon NIR laser irradiation, there was a conspicuous increase both in the in vitro and in vivo transfection achieved by the nanocomplexes. Furthermore, a plasmid encoding the tumor suppressor TP53 (pTP53) was applied to test antitumor activity. RESULTS The enhanced gene transfection efficiency and therapy of PEI2k-HAuNS were achieved via the mediation of an NIR laser compared with the other treatments in vitro and in vivo. CONCLUSION The application of NIR laser irradiated PEI2k-HAuNS can be used as a promising gene delivery systems in vitro and in vivo.