“Cold” tumor with insufficient CD8+ T cell infiltration and the up-regulated programmed cell death protein 1 (PD-1) on activated T cell surface are the two main obstacles in preventing effective cancer immunotherapy. Herein, we firstly leverage pH-responsive micelles (pRML) with photosensitizer 2-(1-hexyloxyethyl)-2-devinyl pyropheophorbide-a (HPPH) encapsulation (pRML/HPPH) via photodynamic-immunotherapy to pre-activate CD8+ T cells. Subsequently, pH-responsive polymersomes (pRPS) with interleukin-2 (IL-2) encapsulation and anti PD-1 fragment (Fab’) decoration on surface (Fab-pRPS/IL-2) are fabricated to target the pre-activated T cells with immune checkpoint blockade and T cell proliferation. From in vivo study results, the sequential cancer immunotherapy of pRML/HPPH and Fab-pRPS/IL-2 reveals high antitumor activity and abscopal effect in B16F10 tumor-bearing mice, as well as displays more effective antitumor activity than co-injection method. This work provides an approach to enhancing immune response via sequential therapy to target the pre-activated T cells with immune checkpoint blockade.
Abstract The biological barriers have seriously restricted the efficacious responses of oral delivery system in diseases treatment. Utilizing a carrier based on the single construction means is hard to overcome these obstacles simultaneously because the complex gastrointestinal tract environment requires carrier to have different or even contradictory properties. Interestingly, spore capsid (SC) integrates many unique biological characteristics, such as high resistance, good stability etc. This fact offers a boundless source of inspiration for the construction of multi-functional oral nanoplatform based on SC without further modification. Herein, we develop a type of biomimetic spore nanoplatform (SC@DS NPs) to successively overcome oral biological barriers. Firstly, doxorubicin (DOX) and sorafenib (SOR) are self-assembled to form carrier-free nanoparticles (DS NPs). Subsequently, SC is effectively separated from probiotic spores and served as a functional vehicle for delivering DS NPs. As expect, SC@DS NPs can efficaciously pass through the rugged stomach environment after oral administration and further be transported to the intestine. Surprisingly, we find that SC@DS NPs exhibit a significant improvement in the aspects of mucus penetration and transepithelial transport, which is related to the protein species of SC. This study demonstrates that SC@DS NPs can efficiently overcome multiple biological barriers and improve the therapeutic effect.
The use of chemotherapeutic drug paclitaxel (PTX) for the treatment of tumors has several limitations, including multidrug resistance (MDR) and serious adverse reactions. This research aims to co-encapsulate PTX and the chemosensitizer 2-methoxyestradiol (2-ME) into folate-conjugated human serum albumin nanoparticles (FA-HSANPs) to reduce multiple drug resistance and improve antitumor efficiency. The results show PTX/2-ME@FA-HSANPs had uniform particle size (180 ± 12.31 nm) and high encapsulation efficacy. It also exhibited highly potent cytotoxicity and apoptosis-inducing activities in the G2/M phase of PTX-resistant EC109/Taxol cells. Moreover, PTX/2-ME@FA-HSANPs not only displayed better inhibition of tumor growth in S-180 tumor-bearing mice than PTX alone but also reduced pathological damage to normal tissues. In summary, PTX/2-ME@FA-HSANPs could be a promising vehicle for tumor therapy and reducing drug resistance. This research will also provide references for other MDR treatment.
The increasing levels of environmental estrogens are causing negative effects on water, soil, wildlife, and human beings; label-free immunosensors with high specificities and sensitivities are being developed to test estrogeneous chemicals in complex environmental conditions. For the first time, highly fluorescent graphene quantum dots (GQDs) were prepared using a visible-Fenton catalysis reaction with graphene oxide (GO) as a precursor. Different microscopy and spectroscopy techniques were employed to characterize the physical and chemical properties of the GQDs. Based on the fluorescence resonance energy transfer (FRET) between amino-functionalized GQDs conjugated with anti-lipovitellin monoclonal antibodies (Anti-Lv-mAb) and reduced graphene oxide (rGO), an ultrasensitive fluorescent “ON-OFF” label-free immunosensor for the detection of lipovitellin (Lv), a sensitive biomarker derived from Paralichthys olivaceus for environmental estrogen, has been established. The immunosensor has a wide linear test range (0.001–1500 ng/mL), a lower limit of detection (LOD, 0.9 pg/mL), excellent sensitivity (26,407.8 CPS/(ng/mL)), and high selectivity and reproducibility for Lv quantification. The results demonstrated that the visible-Fenton is a simple, mild, green, efficient, and general approach to fabricating GQDs, and the fluorescent “ON-OFF” immunosensor is an easy-to-use, time-saving, ultrasensitive, and accurate detection method for weak estrogenic activity.
Abstract Some manganese‐based nanomaterials quench the fluorescence of photosensitizers, which strongly quenches fluorescence emission and suppresses reactive oxygen species (ROS) production due to the photo‐induced charge transfer from the excited photosensitizer to nanomaterials. In this study, to overcome these disadvantages, amorphous porous manganese phosphate (MnP) nanoparticles are used for loading indocyanine green (ICG), and a broader ICG absorbance width instead of weakened fluorescence profile is observed, resulting in higher stability and phototherapy efficiency under 808 nm irradiation. Moreover, autophagy inhibition obviously weakens the ICG‐mediated phototherapy to breast cancer cells. On this foundation, an autophagy promoter rapamycin (RAPA) and ICG are co‐loaded into the MnP nanoparticles, and further decorated with biocompatible poly(glutamic acid). As expected, this stable nanoplatform released 80.0±4.1% agents at low pH compared to that 32.0±4.8% at normal pH, indicating a clear pH‐responsive release profile. Uniting phototherapy with autophagy promoter by this system is found to achieve synergistic outcomes as evidenced by the smaller relative tumor volume of 1.8±0.4. Overall, this work provides the first photo‐stable manganese‐based nanomaterial without fluorescence quenching profile for achieving multiple desirable therapeutic performances.
Oral drug delivery systems (ODDSs) have attracted considerable attention in relation to orthotopic colon cancer therapy due to certain popular advantages. Unfortunately, their clinical applications are generally limited by the side-effects caused by systemic drug exposure and poor real-time monitoring capabilities. Inspired by the characteristics of pH changes of the gastrointestinal tract (GIT) and specific enzymes secreted by the colonic microflora, we anchored polyacrylic acid (PAA) and chitosan (CS) on Gd3+-doped mesoporous hydroxyapatite nanoparticles (Gd-MHAp NPs) to realize programmed drug release and magnetic resonance imaging (MRI) at the tumor sites. In particular, the grafted PAA, as a pH-responsive switch, could effect controlled drug release in the colon. Further, CS is functionalized as the enzyme-sensitive moiety, which could be degraded by β-glycosidase in the colon. Gadolinium is a paramagnetic lanthanide element used in chelates, working as a contrast medium agent for an MRI system. Interestingly, after oral administration, CS and PAA could protect the drug-loaded nanoparticles (NPs) against variable physiological conditions in the GIT, allowing the drug to reach the colon tumor sites, preventing premature drug release. Enhanced drug concentrations at the colon tumor sites were achieved via this programmed drug release, which subsequently ameliorated the therapeutic effect. In addition, encapsulating both chemotherapeutic (5-fluorouracil, 5-FU) and targeted therapy drug (gefitinib, Gef) within Gd-MHAp NPs produced a synergistic therapeutic effect. In summary, this study demonstrated that such a novel drug system (Gd-MHAp/5-FU/Gef/CS/PAA NPs) could protect, transport, and program drug release locally within the colonic environment; further, this system exhibited a worthwhile therapeutic effect, providing a promising novel treatment strategy for orthotopic colon cancer.
The aim of the paper is to prepare stable antisense oligodeoxynucleotides-loaded cationic liposomes and evaluate the transfection efficiency of asODN to MCF-7 oophoroma cells and study their distribution to different tissues in mice. Antisense oligodeoxynucleotides (asODN)-loaded cationic liposomes were prepared by a thin film-adsorption-lyophilization method which is simple and can overcome crucial pharmaceutical defects (e.g. instability) of liposomes during storage. The morphology was investigated by transmission electron microscope. The size and surface charge of the liposomes were determined by laser particle analyter. The dissociated ligodeoxynucleotides were separated from the liposomes by sephadex column and the entrapment efficiency was determined by using an ultraviolet photometer. Trehalose, mannitol, and glycine were suitable for lyophilization especially trehalose. The resulting liposomes were global microcapsule in a narrow particle size with a mean diameter of 175 nm and 320 nm before and after lyophilization, and a high zeta potentials of +32 mV. The dissociated asODN were separated from the liposomes by sephadex G-50 column and the entrapment coefficient of asODN was 88.4% pre and 83.2% post-lyophilization separately for trehalose. The growth of MCF-7 oophoroma cells were inhibited in vitro obviously (P < 0.05) and transfection efficiency of asODN was 18%, 26%, 44% after 2 h, 4 h and 8 h, respectively. The formulation and method can be used to prepare stable cationic liposomes which can effectively inhibit the growth of MCF-7 oophoroma cells and obtain a high transfection efficiency. This system can improve distribution amount of asODN to tissues especially tumors in mice.
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