Yanyu Huang

Rational Design of Cancer-Targeted BSA Protein Nanoparticles as Radiosensitizer to Overcome Cancer Radioresistance

Radiotherapy displays curative potential for cervical cancer management, but radioresistance occurs during long-term therapy. To overcome this limitation, tumor-targeted nanotechnology has been proposed to enhance the radiosensitivity of solid tumors. Herein, we used biocompatible bovine serum albumin nanoparticles (BSANPs) as carriers of organic selenocompound (PSeD) with folate (FA) as the targeting ligand to fabricate a cancer-targeted nanosystem. The combination of PSeD and BSANPs endowed the nanosystem with higher light absorption and reactive oxygen species (ROS) generation owing to their properties of surface plasmon resonance (SPR) effect, heavy metal effect, high refractive index and nanoparticulate interfacial effect. The combined treatment drastically increased the ROS overproduction, VEGF/VEGFR2 inactivation and inhibition of XRCC-1-mediated repair of DNA damage, thus triggering G2/M phase arrest and apoptosis. Taken together, our findings demonstrate the utility of FA-BSANPs as a promising radiosensitizer to improve cancer radiotherapy.

RGD peptide-conjugated selenium nanoparticles: antiangiogenesis by suppressing VEGF-VEGFR2-ERK/AKT pathway

Angiogenesis is essential for tumorigenesis, progression and metastasis. Herein we described the synthesis of RGD peptide-decorated and doxorubicin-loaded selenium nanoparticles (RGD-NPs) targeting tumor vasculature to enhance the cellular uptake and antiangiogenic activities in vitro and in vivo. After internalization by receptor-mediated endocytosis, this nanosystem disassembled under acidic condition with the presence of lysozymes and cell lysate, leading to bioresponsive triggered drug release. Mechanistic investigation revealed that RGD-NPs inhibited angiogenesis through induction of apoptosis and cell cycle arrest in human umbilical vein endothelial cells (HUVECs) via suppression of VEGF-VEGFR2-ERK/AKT signaling axis by triggering ROS-mediated DNA damage. Additionally, RGD-NPs can inhibit MCF-7 tumor growth and angiogenesis in nude mice via down-regulation of VEGF-VEGFR2, effectively reduce the toxicity and prolong the blood circulation in vivo. Our results suggest that the strategy to use RGD-peptide functionalized SeNPs as carriers of anticancer drugs is an efficient way to achieve cancer-targeted antiangiogenesis synergism.

Dual-Functional Nanographene Oxide as Cancer-Targeted Drug-Delivery System to Selectively Induce Cancer-Cell Apoptosis.

Construction of bioresponsive drug-delivery nanosystems could enhance the anticancer efficacy of anticancer agents and reduce their toxic side effects. Herein, by using transferrin (Tf) as a surface decorator, we constructed a cancer-targeted nanographene oxide (NGO) nanosystem for use in drug delivery. This nanosystem (Tf-NGO@HPIP) drastically enhanced the cellular uptake, retention, and anticancer efficacy of loaded drugs but showed much lower toxicity to normal cells. The nanosystem was internalized through receptor-mediated endocytosis and triggered pH-dependent drug release in acidic environments and in the presence of cellular enzymes. Moreover, Tf-NGO@HPIP effectively induced cancer-cell apoptosis through activation of superoxide-mediated p53 and MAPK pathways along with inactivation of ERK and AKT. Taken together, this study demonstrates a good strategy for the construction of bioresponsive NGO drug-delivery nanosystems and their use as efficient anticancer drug carriers.

Size changeable nanosystems for precise drug controlled release and efficient overcoming of cancer multidrug resistance

Multidrug resistance is one of the main causes leading to failure of chemotherapy. Therefore, the rational design of targeting drug systems to reverse multidrug resistance is becoming an important strategy for cancer therapy. Herein, we present a novel copolymer-based nanoparticle that was size changeable and could realize the goal of precise drug controlled release under acidic conditions, and could overcome the multidrug resistance in breast cancer cells. This PCP/uPA nanosystem was formed through the crosslinking between chitosan (CS) and poly(N-isopropylacrylamide) (PNIPAM), followed by surface decoration with polyethylene glycol (mPEG) and a breast cancer targeting peptide uPA, which was then used to encapsulate metal complexes (RuPOP and Fe(PiP)3) to solve their bottleneck of low solubility and stability under physiological conditions. These multifunctional nanosystems (PCP-Ru/uPA and PCP-Fe/uPA) exhibited remarkable anticancer activity and could overcome the poor stability and low solubility of RuPOP and Fe(PiP)3. Noticeably, PCP-Ru/uPA reversed the multidrug resistance of drug-resistant MCF-7 (MCF-7R) human breast cancer cells by enhancing the cellular uptake of RuPOP by MCF-7R cells and inhibiting the expression of ABC family proteins. Furthermore, when PCP-Ru/uPA was at pH 5.3 with lysozyme, the release amount of RuPOP is the largest compared with pH at 5.3 or 7.4, and the release rate of RuPOP reached 75% at 48 h. In other words, the nanosystem with a pH-responsive effect swelled in an acidic environment and released free RuPOP in the lysosome of cancer cells efficiently, which triggered ROS up-regulation and induced apoptosis in MCF-7R cells. Taken together, this study presents a novel size changeable nanosystem for precise drug controlled release and efficient overcoming of cancer multidrug resistance.

A highly selective dual-therapeutic nanosystem for simultaneous anticancer and antiangiogenesis therapy

The rational design of highly selective and cancer-targeted nanodrug delivery systems with attractive anticancer activities is urgently needed for future exploration and translational application of nanomedicine. As angiogenesis and tumor growth could be mutually enhanced, dual therapeutic nanomedicine with simultaneous antiangiogenesis and anticancer activities is practical for cancer therapy. Therefore, herein we have rationally designed functionalized mesoporous silica nanoparticles (MSNs) to realize the dual therapy of tumor growth and angiogenesis based on the biochemical similarity of membranes of cancer cells and angiogenic cells. This nanosystem demonstrates high selectivity in vivo against cancer cells with high integrin expression levels in two-tumor bearing models, and could simultaneously inhibit cancer cell growth and disrupt tumor neovasculature, thus achieving satisfactory in vivo anticancer efficacy. Interestingly, the nanosystem triggers ROS overproduction in both cancer and human umbilical vein endothelial cells, which activates various downstream signaling pathways to regulate cell cycle arrest and apoptosis. Moreover, the nanosystem also effectively reduces the toxic side effects of loaded drugs to normal tissues and prolongs blood circulation in vivo. Therefore, this study provides a simple approach for facile manufacture of a potent nanodrug delivery system that could achieve dual therapy of tumor growth and angiogenesis.

Phycocyanin-based nanocarrier as a new nanoplatform for efficient overcoming of cancer drug resistance

Resistance to chemotherapy remains the primary obstacle for the successful treatment of cancers. Nanotechnology-based studies have developed many smart nanomedicines and efficient strategies to overcome multidrug resistance (MDR), which have brought new horizons to cancer therapy. Among them, protein-based nanomedicine represents an appealing drug delivery platform to realize safe and superior therapeutic effects due to its paramount biocompatibility with minimized toxicity. Herein we describe the rational design and construction of a novel protein-based nanocarrier using the naturally-occurring protein phycocyanin (PC) as the base material, to achieve safe and tumor-specific drug delivery. This cancer-targeting nanosystem (FA-PCNP@DOX) with bio-responsive properties exhibits positive targeting accumulation in resistant cancer cells and overcomes drug efflux by enhancing cellular uptake and retention time. Specifically, FA-PCNP@DOX inhibits the function of pumping proteins of the ABC family and triggers ROS-mediated apoptotic signaling pathways, thereby attaining highly efficient anticancer efficacy and overcoming drug resistance. Pharmaceutical studies demonstrate that FA-PCNP@DOX overwhelms DOX by sustained release in the blood, which verifies its prolonged circulation in vivo. Moreover, FA-PCNP@DOX efficiently accumulates in tumors and strengthens the tumor inhibitory effect of DOX by enhanced tumoral penetration. Importantly, FA-PCNP@DOX effectively reduces the hepatic, pulmonary, renal and cardiac toxicity caused by DOX. Therefore, as a new nanocarrier, this novel nanosystem could be further exploited as a safe and versatile nanoplatform for next-generation cancer therapy.

Bioinspired tumor-homing nanosystem for precise cancer therapy via reprogramming of tumor-associated macrophages

AbstractRational design of smart nanosystems with high biological safety is a critical milestone for realizing precise imaging-guided cancer theranostics. Herein, a bioinspired nanosystem was designed by camouflaging SPIO@DOX-ICG nanoparticles with cancer cell membrane (CCM) to realize precise cancer treatment through simultaneous chemotherapy, hyperthermia-therapy, and radiotherapy. CCM surface decoration preserves the cancer adhesion molecules and surface antigens in the nanosystem, endowing the nanosystem with tumor-homing ability and high biocompatibility. Guided by dual-modal imaging, the nanosystem specifically accumulated in the tumor region and achieved synergistic anticancer effects after combined treatment, without causing toxic side effects in major organs. Interestingly, the combined treatment also antagonized tumor hypoxia and reprogrammed the polarization of tumor associated macrophages to the antitumor M1 phenotype. Taken together, this study offers a smart strategy for designing a bioinspired tumor-homing nanosystem for precise cancer therapy.A bioinspired nanosystem of cancer cell membrane-camouflaged SPIO@DOX-ICG nanoparticles was fabricated to realize precise cancer treatment by simultaneous chemotherapy, hyperthermia-therapy, and radiotherapy. The nanosystem achieved synergistic anticancer effects by antagonizing tumor hypoxia and reprograming the polarization of tumor associated macrophages to anti-tumor M1 phenotype, without causing toxic side effects on major organs. Biomaterials: guiding drugs to tumorsNon-toxic nanoparticles that can target tumors and aid the treatment of cancer have been developed and tested by scientists in China. Nanoparticles injected into the body can improve the resolution of medical scans, or carry therapeutic drugs through the body. Nanoparticles that can achieve both simultaneously are particularly important because they enable multiple different types of therapy. Tianfeng Chen from Jinan University, Zhuang Liu from Soochow University and co-workers made nanoparticles containing the chemotherapeutic drug doxorubicin and the imaging agent indocyanine green, which they coated with membrane from a cancer cell. These nanoparticles accumulated in mouse tumors where they could both deliver drugs for chemotherapy and act as targets for hyperthermia therapy and radiotherapy, all without having any toxic side effects on major organs.