The targeted delivery of therapeutics to sites of rheumatoid arthritis (RA) has been a long-standing challenge. Inspired by the intrinsic inflammation-targeting capacity of macrophages, a macrophage-derived microvesicle (MMV)-coated nanoparticle (MNP) was developed for targeting RA. The MMV was efficiently produced through a novel method. Cytochalasin B (CB) was applied to relax the interaction between the cytoskeleton and membrane of macrophages, thus stimulating MMV secretion. The proteomic profile of the MMV was analyzed by iTRAQ (isobaric tags for relative and absolute quantitation). The MMV membrane proteins were similar to those of macrophages, indicating that the MMV could exhibit bioactivity similar to that of RA-targeting macrophages. A poly(lactic-co-glycolic acid) (PLGA) nanoparticle was subsequently coated with MMV, and the inflammation-mediated targeting capacity of the MNP was evaluated both in vitro and in vivo. The in vitro binding of MNP to inflamed HUVECs was significantly stronger than that of the red blood cell membrane-coated nanoparticle (RNP). Compared with bare NP and RNP, MNP showed a significantly enhanced targeting effect in vivo in a collagen-induced arthritis (CIA) mouse model. The targeting mechanism was subsequently revealed according to the proteomic analysis, indicating that Mac-1 and CD44 contributed to the outstanding targeting effect of the MNP. A model drug, tacrolimus, was encapsulated in MNP (T-RNP) and significantly suppressed the progression of RA in mice. The present study demonstrates MMV as a promising and rich material, with which to mimic macrophages, and demonstrates that MNP is an efficient biomimetic vehicle for RA targeting and treatment.
Zwitterionic nanocarriers have emerged as a new class of biocompatible nanomaterials with outstanding stealth capability in blood circulation. In this work, a novel biodegradable zwitterionic nanogel based on poly(sulfobetaine methacrylate) (PSBMA) was developed for reduction-responsive drug delivery to tumors. PSBMA nanogels were facilely fabricated by one-step reflux precipitation polymerization with the advantage of being surfactant-free and time-saving. The disulfide bond not only endowed the nanogels degradability in a reduction environment but also be modified with a fluorescent group after partial reduction. In vitro release experiments disclosed that doxorubicin (DOX)-loaded PSBMA nanogels could hold the drugs firmly in physiological conditions (only 7% release in 24 h) and release the drugs rapidly and sufficiently in 10 mM glutathione (85% in 8 h). More interestingly, PSBMA nanogels displayed long circulation in blood after intravenous injection, and small change was found in half-life of nanogels between the first (34.1 h) and the second injection (30.5 h), indicating that there was no accelerated blood clearance phenomenon for these nanogels. Meanwhile, no obvious immunogenic response was detected after PSBMA nanogels were injected into BALB/c mice. Furthermore, PSBMA nanogels showed a high accumulation of 9.5 and 10.7% of injected dose per gram of tissue in tumors at 24 and 48 h post intravenous injection, respectively. With outstanding long circulation time, high tumor accumulation, and sufficient drug release in a reduction environment, DOX-loaded PSBMA nanogels demonstrated the strongest tumor growth inhibition effect among all of the treatment groups in human hypopharyngeal carcinoma-bearing mouse models. Therefore, our study provided a facile drug delivery platform based on biodegradable zwitterionic nanogels and may have great potential in tumor drug delivery.
Human neuroscience has made remarkable progress in understanding basic aspects of functional organization; it is a renowned fact that the blood–brain barrier (BBB) impedes the permeation and access of most drugs to central nervous system (CNS) and that many neurological diseases remain undertreated. Therefore, a number of nanocarriers have been designed over the past few decades to deliver drugs to the brain. Among these nanomaterials, dendrimers have procured an enormous attention from scholars because of their nanoscale uniform size, ease of multi-functionalization, and available internal cavities. As hyper-branched 3D macromolecules, dendrimers can be maneuvered to transport diverse therapeutic agents, incorporating small molecules, peptides, and genes; diminishing their cytotoxicity; and improving their efficacy. Herein, the present review will give exhaustive details of extensive researches in the field of dendrimer-based vehicles to deliver drugs through the BBB in a secure and effectual manner. It is also a souvenir in commemorating Donald A. Tomalia on his 80th birthday.
Recently, biomimetic nanoparticles, especially cell membrane-cloaked nanoparticles, have attracted increasing attention in biomedical applications, including antitumor therapy, detoxification, and immune modulation, by imitating the structure and the function of biological systems such as long circulation life in the blood. However, the circulation time of cell membrane-cloaked nanoparticles is far less than that of the original cells, greatly limiting their biomedical applications, while the underlying reasons are seldom demonstrated. In this study, the influence of particle size on the circulation and the biodistribution of red blood cell membrane-coated nanoparticles (RBC-NPs) as model biomimetic nanoparticles were investigated. Differently sized RBC-NPs (80, 120, 160, and 200 nm) were prepared by fusing RBC membranes on poly(lactic-co-glycolic acid) nanoparticles. It was shown that the particle size did not change the cellular uptake of these biomimetic nanoparticles by macrophage cells in vitro and their immunogenic responses in vivo. However, their circulation life in vivo decreased with the particle size, while their accumulation in the liver increased with the particle size, which might be related to their size-dependent filtration through hepatic sinusoids. These findings will provide experimental evidence for the design and the optimization of biomimetic nanoparticles.
As a novel treatment modality of tumors, hypothermal hyperthermia employed relatively lower temperature (<45 °C) to damage cancer cells with mild toxicity to normal tissues. However, beyond that inducible heat resistance of tumor cells, the discounted therapeutic effect of low temperature hyperthermia was also ascribed to poor penetration of exogenous light stimulation and low accumulation of photothermal agents in tumor sites. Herein, we constructed a multifunctional in situ hydrogel of sodium alginate (ALG) via Ca2+ coordinated with ALG to encapsulate the photothermal agent of Ink and azo initiator of 2,2′-azobis[2-(2-imidazolin-2-yl)propane]dihydrochloride (AIPH) for effective tumor treatment. The designed ALG hydrogel was used to improve the therapeutic effect by increased accumulation of Ink and AIPH and avoid potential side-effects caused by the unexpected spread to the surrounding normal tissues. After injection, local low temperature stimulation was generated with near-infrared-II irradiation by a 1064 nm laser, triggering rapid decomposition of AIPH to produce alkyl radicals. The synergistic low temperature photothermal therapy and cytotoxic-free radicals enhanced the apoptosis of tumor cells via physical heat damage and lipid peroxidation. Thus, remarkable inhibition of tumor growth was observed in a subcutaneous colorectal cancer with negligible side effects. Furthermore, the formulation could also exert strong photoacoustic signals, which were utilized to monitor the stability of the composite hydrogel.
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