Yuqing Su

Accelerated blood clearance phenomenon upon cross-administration of PEGylated nanocarriers in beagle dogs

The cross-administration of nanocarriers modified by poly(ethylene glycol) (PEG), named PEGylated nanocarriers, a type of combination therapy, is becoming an increasingly important method of long-term drug delivery, to decrease side effects, avoid multidrug resistance, and increase therapeutic efficacy. However, repeated injections of PEGylated nanocarriers induces the accelerated blood clearance (ABC) phenomenon, prevents long circulation, and can cause adverse effects owing to alterations in the biodistribution of the drug. Although the nature of the ABC phenomenon that is induced by repeated injections of PEGylated nanocarriers has already been studied in detail, there are few reports on the immune response elicited by the cross-administration of PEGylated nanocarriers. In this study, we investigated the ABC phenomenon induced by the intravenous cross-administration of various PEGylated nanocarriers, including PEGylated liposomes (PL), PEG micelles (PM), PEGylated solid lipid nanoparticles (PSLN), and PEGylated emulsions (PE), in beagle dogs. The results indicated that the magnitude of the immune response elicited by the cross-administration was in the following order (from the strongest to the weakest): PL, PE, PSLN, PM. It is specifically PEG in the brush structure that elicits a significant immune response, in both the induction phase and the effectuation phase. Furthermore, the present study suggests that there is a considerable difference between the effect of repeated injections and cross-administration, depending on the colloidal structure. This work is a preliminary investigation into the cross-administration of PEGylated nanocarriers, and our observations can have serious implications for the design of combination therapies that use PEGylated vectors.

Are PEGylated liposomes better than conventional liposomes? A special case for vincristine

Abstract Cancer poses a significant threat to human health worldwide, and many therapies have been used for its palliative and curative treatments. Vincristine has been extensively used in chemotherapy. However, there are two major challenges concerning its applications in various tumors: (1) Vincristines antitumor mechanism is cell-cycle-specific, and the duration of its exposure to tumor cells can significantly affect its antitumor activity and (2) Vincristine is widely bio-distributed and can be rapidly eliminated. One solution to these challenges is the encapsulation of vincristine into liposomes. Vincristine can be loaded into conventional liposomes, but it quickly leak out owing to its high membrane permeability. Numerous approaches have been attempted to overcome this problem. Vincristine has been loaded into PEGylated liposomes to prolong circulation time and improve tumor accumulation. These liposomes indeed prolong circulation time, but the payout characteristic of vincristine is severer, resulting in a compromised outcome rather than a better efficacy compared to conventional sphingomyelin (SM)/cholesterol (Chol) liposomes. In 2012, the USA Food and Drug Administration (FDA) approved SM/Chol liposomal vincristine (Marqibo®) for commercial use. In this review, we mainly focus on the drugs rapid leakage problem and the potentially relevant solutions that can be applied during the development of liposomal vincristine and the reason for conventional liposomal vincristine rather than PEGylated liposomes has access to the market.

Tolerance-like innate immunity and spleen injury: a novel discovery via the weekly administrations and consecutive injections of PEGylated emulsions

There has been an increasing interest in the study of the innate immune system in recent years. However, few studies have focused on whether innate immunity can acquire tolerance. Therefore, in this study, we investigated tolerance in the innate immune system via the consecutive weekly and daily injections of emulsions modified with polyethylene glycol (PEG), referred to as PEGylated emulsions (PE). The effects of these injections of PE on pharmacokinetics and biodistribution were studied in normal and macrophage-depleted rats. Additionally, we evaluated the antigenic specificity of immunologic tolerance. Immunologic tolerance against PE developed after 21 days of consecutive daily injections or the fourth week of PE administration. Compared with a single administration, it was observed that the tolerant rats had a lower rate of PE clearance from the blood, which was independent of the stress response. In addition, weekly PE injections caused injury to the spleen. Furthermore, the rats tolerant to PEs with the methoxy group (–OCH3) of PEG, failed to respond to the PEs with a different terminal group of PEG or to non-PEG emulsions. Innate immunity tolerance was induced by PE, regardless of the mode of administration. Further study of this mechanism suggested that monocytes play an essential role in the suppression of innate immunity. These findings provide novel insights into the understanding of the innate immune system.

Neutrophil-mediated delivery of pixantrone-loaded liposomes decorated with poly(sialic acid)–octadecylamine conjugate for lung cancer treatment

Abstract Poly(sialic acid) (PSA) is a natural hydrophilic biodegradable and non-immunogenic biopolymer, receptors for its monomer are expressed on peripheral blood neutrophils (PBNs), which plays important roles in the progression and invasion of tumors. A poly(sialic acid)–octadecylamine conjugate (PSA–ODA) was synthesized and then anchor it on the surface of liposomal pixantrone (Pix-PSL), to achieve an improved anticancer effect. The liposomes were prepared using a remote loading method via a pH gradient, and then assessed for particle size, zeta potential encapsulation efficiency, in vitro release, and in vitro cytotoxicity. Simultaneously, in vitro and in vivo cellular uptake studies confirmed that PSA-decorated liposomes provided an enhanced accumulation of liposomes in PBNs. An in vivo study presented that the anti-tumor activity of Pix-PSL was superior to that of other Pix formulations, probably due to the efficient targeting of PBNs by Pix-PSL, after which PBN containing Pix-PSL (Pix-PSL/PBNs) in the blood circulation are recruited by the tumor microenvironment. These findings suggest that PSA-decorated liposomal Pix may provide a neutrophil-mediated drug delivery system (DDS) for the eradication of tumors, which represents a promising approach for the tumor targeting of chemotherapeutic treatments.

The accelerated blood clearance phenomenon of PEGylated nanoemulsion upon cross administration with nanoemulsions modified with polyglycerin

Graphical Abstract The first dose of the 1,2-distea-royl-sn-glycero-3-phosphoethanolamine-n-polygly-cerine-610 modified nanoemulsions can induce the ABC phenomenon of the second dose of the PEGylated nanoemulsions. We synthesized polycarboxyl compound via the esterification reaction of 1,2-distea-royl-sn-glycero-3-phosphoethan-olamine-n-polyglycerine-610 and succinic anhydride. The polycarboxyl structure in the new modified compound we synthesized can circumvent the ABC phenomenon of the second dose of the PEGylated nanoemulsions.Unlabelled image

Effects of complement inhibition on the ABC phenomenon in rats

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Enhanced Opsonization-Independent Phagocytosis and High Response Ability to Opsonized Antigen–Antibody Complexes: A New Role of Kupffer Cells in the Accelerated Blood Clearance Phenomenon upon Repeated Injection of PEGylated Emulsions

The accelerated blood clearance (ABC) phenomenon is an immune response against the first injection of PEGylated colloidal drug delivery systems (CDDSs), which causes the accelerated clearance of the second dose. The enhanced complement-mediated phagocytic activity of Kupffer cells is responsible for accelerated second-dose clearance. Nevertheless, few studies have focused on the role of Kupffer cells in the induction phase of the ABC phenomenon. In this study, the intrinsic phagocytic activity of Kupffer cells was significantly enhanced at 6 days after the initial injected PEGylated emulsions (PEs) using the carbon clearance test and single-pass liver perfusion experiment. Furthermore, PE could stimulate Kupffer cells activation, leading to enhanced cell viability of Kupffer cells and opsonization-independent cellular uptake. It was also found that the response ability of Kupffer cells to the antigen-antibody complexes was augmented by the first injection of PE. Conclusively, we proposed that, besides anti-PEG IgM and complement activation-mediated hepatic uptake, enhanced opsonization-independent phagocytosis of Kupffer cells and the high response ability to opsonized antigen-antibody complexes contribute to the accelerated clearance of the second administration. The results indicated that Kupffer cells play an indispensable role in the ABC phenomenon and provided novel insights into the current view on the mechanism of the ABC effect.

Comparison among different “revealers” in the study of accelerated blood clearance phenomenon

Abstract The markers are the “revealers” of accelerated blood clearance (ABC) phenomenon. PEGylated nanocarriers labeled with various markers have been used to explore the mechanism of ABC. However, different markers were labeled on different nanocarriers, and the influence of different markers on ABC phenomenon is questionable. In this study, tocopheryl nicotinate (TN), N‐(7‐nitrobenz‐2‐oxa‐1,3‐diazol‐4‐yl)‐1,2‐dihexadecanoyl‐sn‐glycero‐3‐phosphoethanolamine, triethylammonium salt (NBD‐DPPE), and 1,1′‐dioctadecyl‐3,3,3′,3′‐tetra‐methylindotricarbocyanine iodide (DiR) were selected as markers. ABC index(0–30 min) was used as an evaluation indicator to reveal ABC phenomenon after repeated injections of PEGylated emulsions (PEs) in Wistar rats. No significant difference was observed in ABC index(0–30 min) of PE labeled with the three markers (P > 0.05), suggesting that the results of previous studies using these markers were comparable and interchangeable. Of the three markers, TN required tedious analytical method and showed proliferative effect on liver cells, while NBD‐DPPE fluorescence was easily interfered by tissues and its phospholipid composition affected ABC analysis. On the contrary, DiR was deemed superior due to its near‐infrared fluorescence, high‐sensitivity, and convenient analytical detection. Graphical abstract Figure. No caption available.

Mixed PEGylated surfactant modifying system decrease the accelerated blood clearance phenomenon of nanoemulsions in rats

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