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PEGylated liposomal doxorubicin (PLD) has effectively reduced the cardiac toxicity of free doxorubicin (DOX) due to its unique nanoscale properties. However, an unexpected accumulation of PLD in the skin has led to hand-foot syndrome (HFS), negatively impacting quality of life and psychological well-being. In this study, self-limiting HFS rat models were created to mimic human symptoms through varying dosing schedules and intensities of PLD. The effects of PLD formulation parameters on HFS were also investigated. The results demonstrated that replacing ammonium sulfate with citric buffer, increasing liposome size, or reducing DSPE-mPEG 2000 modification density alleviated HFS. Additionally, liposomes without DSPE-mPEG 2000 modification completely avoided HFS, suggesting that PEGylated phospholipid was the key formulation parameter contributing to PLD-induced HFS. Furthermore, the correlation between liposome pharmacokinetics and HFS indicated that PEGylation, rather than the extended circulation time of liposomes, may mediated PLD-related HFS. Better understanding of the formulation parameters that trigger HFS can guide reformulation strategies to mitigate or prevent this syndrome., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Deuterated drugs are produced by substituting hydrogen atoms with deuterium atoms at specific sites in a drug molecule to prolong its metabolic cycle and reduce the production of toxic metabolites. Deuterated drugs have recently attracted increasing attention from the pharmaceutical industry. Colchicine exhibits a strong anti-tumor activity but has a short half-life, rapid attenuated drug concentration, narrow treatment window, and lack of tumor-specific targeting in vivo, resulting in toxicity and side effects. In this study, we explored whether deuteration could reduce the toxicity of colchicine. We prepared deuterated colchicine liposomes coated with oligo-hyaluronic acid, which can bind to the tumor-specific CD44 receptor and reduce the clearance of immune cells from the blood, resulting in a long blood circulation time and active targeting. We observed that deuteration of the colchicine B ring reduced drug toxicity and improved the anti-tumor response in 4 T1 breast cancer. Liposomes modified with oligo-hyaluronic acid exhibited increased tumor accumulation, further improving the anti-tumor effect of the drugs. Our results provide a basis for the development and application of deuterated drugs in the field of nano-preparations., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022. Published by Elsevier B.V.)

Studies have shown that tumor-associated macrophages (TAMs) are crucial for the establishment and maintenance in immunosuppressive tumor immune microenvironment (TIME), which can help tumor cells to achieve immune escape and attenuate antitumor therapy. Siglecs, the receptors of sialic acid (SA), widely exist in TAMs, which could be targeted to disrupt TIME and inhibit tumor growth at the root. Therefore, a SA-modified VCR liposome was reported (VCR-SSAL). Cellular and pharmacodynamic experiments showed that VCR-SSAL exhibited strong TAMs targeting and tumor-killing ability. Interestingly, VCR-SSAL treatment induced a phenomenon in which the cancerous tissues were "fell off" from the growth site, after which the wound gradually healed. Three months after the wound healed, the mice whose tumors fell off were re-inoculated, and the tumor fell off again without treatment, with an exfoliation rate of 100%. We speculated that this special efficacy might be due to that VCR loaded in VCR-SSAL could activate adaptive immunity by inducing DNA damage, promoting cytotoxic T lymphocytes (CTLs) infiltration into tumor sites, and enhancing the antitumor immune response. Thus, this study might provide new insights into the application of traditional chemotherapeutic drugs., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022. Published by Elsevier B.V.)

Tumor cells are dependent on their microenvironment; thus, targeting the non-cancerous components surrounding the tumor may be beneficial. Neutrophils are important inflammatory cells in the tumor microenvironment that significantly affect tumor cell proliferation, metastasis, and immune regulation. Targeted regulation of tumor-associated neutrophil-related pathways is expected to become a new therapeutic approach. Colchicine compounds are powerful anti-inflammatory drugs that strongly inhibit the chemotaxis of neutrophils to the inflammatory site. We attempted to achieve anticancer effects by utilizing its ability to inhibit neutrophil recruitment rather than killing tumor cells. As such drugs are likely to cause non-specific damages due to the lack of selectivity, we synthesized and used sialic acid and cholesterol derivatives (SA-CH) for surface modification of the newly synthesized low-toxic colchicine derivative (BCS) nanocomposite to improve neutrophil targeting. In vivo and in vitro experiments have shown that SA-CH-modified BCS preparations are effectively absorbed by neutrophils, inhibit cell migration, reduce infiltration of tumor-associated neutrophils, enhance T lymphocyte function, and exhibit good anti-S180 early tumor effect. In addition, in a triple-negative breast cancer model, the agent could strongly inhibit tumor metastasis to the lungs., (Copyright © 2022. Published by Elsevier B.V.)

PEGylation increases the circulation time of the nanocarrier, but also triggers accelerated blood clearance (ABC) phenomenon. It is well-known that the ABC phenomenon results in shortened blood circulation and aberrant increase in liver and spleen accumulation, which greatly limits the application of PEGylated nano-preparations. For many years, researchers have been working hard to find ways to reduce or eliminate the ABC phenomenon. Previous studies have focused on PEG molecular weight and PEG alternative materials, but there has never been any research on the effect of different PEG chain types on the ABC phenomenon. Therefore, 40 kDa molecular weight of linear PEG lipid derivatives (DSPE-mPEG 40k ) and branched PEG lipid derivatives (DSPE-mPEG 2,40k ) were selected to modify nanoemulsions to explore the influence of distinct PEG chain types on avoiding the ABC phenomenon for the first time. We pioneer the use of linear and branched PEG lipid derivatives (DSPE-mPEG 40k and DSPE-mPEG 2,40k ) to modify nanoemulsions (PE 40k and PE 2,40k ). Upon characterization, PE 40k and PE 2,40k showed good physicochemical properties in the aspect of size, polydispersity index (PDI value), and zeta potential. Surprisingly, the pharmacokinetics study indicated that repeated injection of PE 40k and PE 2,40k did not trigger the ABC phenomenon. More importantly, PE 2,40k possessed a long circulation time and did not cause ABC phenomenon after repeated injection. This may be attributed to the fact that PE 2,40k induced noticeably lower anti-PEG IgM levels compared to linear PEG-modified nanocarriers and did not activate the complement system. Therefore, we speculate that DSPE-mPEG 2,40k -modified nanocarriers possess promising prospects in avoiding the ABC phenomenon, which may improve the possibility of wide application of nanoformulations., (Copyright © 2021. Published by Elsevier B.V.)

Combined administration of drugs can improve efficacy and reduce toxicity; therefore, this combination approach has become a routine method in cancer therapy. The main combination regimens are sequential, mixed (also termed "cocktail"), and co-loaded; however, other combinations, such as administration of synergistic drugs and the use of formulations with different mechanisms of action, may exert better therapeutic effects. Tumor-associated macrophages (TAMs) play functional roles throughout tumor progression and exhibit characteristic phenotypic plasticity. Sialic acid (SA)-modified epirubicin liposomes (S-E-L) and SA-modified zoledronate liposomes (S-Z-L) administered separately kill TAMs, reverse their phenotype, and achieve antitumor effects. In this study, we examined the effects of a two-treatment combination for drug delivery, using sequential, mixed, and co-loaded drug delivery. We found that therapeutic effects differed between administration methods: mixed administration of S-E-L and S-Z-L, co-loaded administration of SA-modified liposomes (S-ZE-C), and sequential administration of S-E-L injected 24 h after S-Z-L did not inhibit tumor growth; however, sequential administration of S-Z-L injected 24 h after S-E-L resulted in no tumor growth, no toxicity to noncancerous tissue, and no death of mice, and exhibited 25% tumor shedding. Thus, our results thus encourage the further development of combined therapies for nanomedicines based on the mechanisms investigated here., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Immune checkpoint inhibitors (ICIs), like monoclonal antibodies of PD-1, CTLA-4, and their ligands, are effective only in some populations of patients with cancer, because the immunosuppressive state of the tumor microenvironment (TME) in some patients cannot be effectively reversed after ICI therapy. Sialic acid (SA) receptors in the Siglec family are highly expressed on the surface of tumor-associated macrophages (TAMs) and most have immunosuppressive effects. Therefore, targeting TAMs (the siglec axis) to reverse tumor immunosuppression may provide a new direction for the development of novel tumor immunotherapies. We designed a Zoledronic acid (ZA)-loaded liposome modified by a SA-octadecylamine conjugate (ZA-SL) to act as a novel nanomedicine delivery platform. This platform can efficiently deliver ZA to TAMs through the combination of SA and Siglec-1 and exerts specific cytotoxicity or phenotypic remodeling of M2-like TAMs depending on the drug concentration in TAMs. In vivo experiments showed that ZA-SL had good TAM targeting ability, and after treatment, the S180 tumors of mice were significantly inhibited, and the proportion of M1-like TAMs was significantly higher than that of M2-like TAMs with no significant adverse reactions in mice. Therefore, SA-modified ZA-loaded liposomes may provide a promising strategy for cancer immunotherapy., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Mononuclear phagocytes are efficient drug delivery targets for cancers owing to their cancerous tissue-accumulating nature. As receptors of sialic acid, Siglecs (sialic acid-binding immunoglobulin-type lectins) are noticeably found on peripheral blood monocytes (PBMs) and tumor-associated macrophages (TAMs), which renew by the differentiation of recruited PBMs at the tumor site and positively correlate with tumor growth. Given this, a sialic acid-octadecylamine conjugate (SA-ODA) was synthesized and then modified on the surface of liposomal epirubicin (EPI-SAL) as a potent tumor-targeting delivery strategy. A cellular uptake assay indicated that SA-modified liposomes provided improved distribution of the drug in both PBMs and TAMs. Pharmacodynamic tests demonstrated that the antitumor efficacy of the EPI-SAL group was better than that of the other groups, owing to both inhibition of TAMs by EPI-SAL, and high-efficiency targeting of PBMs by EPI-SAL, after which PBMs containing EPI-SAL were recruited to the tumor site and then killed by EPI. Thus, an SA-based targeted delivery strategy effectively interdicted the generation of TAMs. Our research provides the feasibility of the SA-ODA decorated liposome as an active carrier for cancer immunotherapy., (Copyright © 2019 Elsevier B.V. All rights reserved.)

To overstep the dilemma of chemical drug degradation within powerful lysosomes of tumor associated macrophages (TAMs), a sialic acid-polyethylenimine-cholesterol (SA-PEI-CH) modified liposomal doxorubicin (DOX-SPCL) was designed with both TAMs targeting and smart lysosomal trafficking. The modified liposome DOX-SPCL performed particle size as 103.2 ± 3.1 nm and zeta potential as -4.5 ± 0.9 mV with encapsulation efficiency as 95.8 ± 0.5%. In in vitro cell experiments, compared with conventional liposomal doxorubicin (DOX-CL) and PEGylated liposomal doxorubicin (DOX-PL), DOX-SPCL showed a selective binding on TAMs and a mere lysosomal concentration. In pharmacokinetic study, DOX-SPCL effectively impeded/delayed the disposition of mononuclear phagocyte system (MPS) with a value of AUC 0-t as 796.03 ± 66.93 mg L -1  h. In S180 sarcomas bearing mice, DOX-SPCL showed the greatest tumor inhibition rate (92.7% ± 3.6%) compared with DOX-CL (46.4% ± 2.0%) or DOX-PL (58.8% ± 7.6%). The <0.5% positive region of TAMs in tumor section indicated a super TAMs exhaustion for DOX-SPCL treatment. Conclusively, DOX-SPCL was supposed as a safe and effective liposomal preparation for clinical sarcoma treatment via TAMs targeting/deletion delivery strategy., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Based on the knowledge that poly(sialic acid) is a critical element for tumour development and that the receptors for its monomer are expressed on neutrophils, which play important roles in the progression and invasion of tumours, a poly(sialic acid)-p-octadecylamine conjugate (PSA-p-ODA) was synthesised and used to modify the surface of liposomal pixantrone (Pix-PSL) to improve the delivery of Pix to peripheral blood neutrophils (PBNs). The liposomes were fabricated using a remote loading technology via a pH gradient, and were then assessed for particle size, encapsulation efficiency, in vitro release, in vitro cytotoxicity, and pharmacokinetics. Simultaneously, in vitro and in vivo cellular uptake studies demonstrated that Pix-PSL provided an enhanced accumulation of Pix in PBNs. An in vivo study showed that the anti-tumour activity of Pix-PSL was superior to that of other formulations, probably owing to the efficient targeting of PBNs by Pix-PSL, after which PBNs containing Pix-PSL (Pix-PSL/PBNs) in the circulatory system are recruited by the tumour microenvironment. These findings suggest that PSA-p-ODA-decorated liposomal Pix may provide a neutrophil-mediated drug delivery system (DDS) for the eradication of tumours, and thus represents a promising approach for the tumour targeting of chemotherapeutic treatments., (Copyright © 2018 Elsevier B.V. All rights reserved.)

With the knowledge that the receptors of sialic acid are overexpressed on the surface of tumor-associated macrophages (TAMs), which play a crucial role in the tumor's progression and metastasis, a sialic acid-cholesterol conjugate (SA-CH) was synthesized and modified on the surface of epirubicin (EPI)-loaded liposomes (EPI-SAL) to improve the delivery of EPI to the TAMs. The liposomes were developed using remote loading technology via a pH gradient. The liposomes were evaluated for particle size, encapsulation efficiency, in vitro release, stability, in vitro cytotoxicity and pharmacokinetics. And the in vitro and in vivo cellular uptake studies demonstrated EPI-SAL achieved enhanced accumulation of EPI into TAMs. The antitumor studies indicated that EPI-SAL provided the strongest antitumor activity compared with the other formulations (EPI-S, EPI-CL and EPI-PL represent EPI solution, conventional liposomal EPI, PEGylated liposomal EPI, respectively), and the survival percent of tumor-bearing mice was 83.3%. The superior antitumor efficacy was probably attributed to the killing of TAMs by EPI-SAL, and modulating the tumor microenvironment with the depletion of TAMs. These findings suggested that SA-CH decorated EPI-loaded liposomes may present an effective strategy to eradicate TAMs, which may be a promising approach for cancer therapy., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Polysialic acid (PSA) serves as a hydrophilic polymer and affords conjugated biologically active molecules a longer circulation time in vivo. Furthermore, PSA could potentially target tumor tissues and help achieve better curative effects. In this study, PSA was conjugated with octadecyl dimethyl betaine (BS18) to yield a PSA-BS18 conjugate. The PSA-BS18 modified liposomal epirubicin (EPI-SL), had a particle size of 133.63±0.92nm, a zeta potential of -26.23±1.50mV and an encapsulation efficiency (%EE) of 96.23±1.16%. In vitro release studies showed that PSA-BS18 could delay EPI release from the modified liposomes. The MTT assay suggested that EPI-SL led to stronger cytotoxic activity than that exhibited by common and PEGylated liposomes. The pharmacokinetic study showed that EPI-SL prolonged the residence time of the EPI in the blood compared with that observed from common liposomes. Bio-distribution results obtained from tumor-bearing mice clearly demonstrated that PSA-BS18 increased the accumulation of modified liposomes in tumors compared with that of common liposomes. In the antitumor efficacy study, EPI-SL showed the best antitumor and life-prolonging effects among all of the tested formulations. These findings strongly indicate EPI-SL might have great potential as an effective approach for anticancer therapy., (Copyright © 2016 Elsevier B.V. All rights reserved.)

The present work described the effect of CoQ10 dissolution characteristics in nanocrystals and lipid nanoparticles (LNs) on its oral absorption in rats. Nanocrystals and LNs were prepared by melt-high pressure homogenization and sucrose monolaurate was used as a stabilizer in all formulations. Witepsol(®)W35 and medium-chain triglycerides (MCT) were selected as lipid additives to form LN(CoQ10+W35) and LN(CoQ10+MCT), respectively. From the results obtained, the particle size of CoQ10 nanocrystals was 285 nm, while it was reduced to 150 nm by mixture with an equal amount of lipid additives due to their lower melting points. In vitro dissolution results indicated that the drug release from two LNs was delayed compared with that from nanocrystals, and LN(CoQ10+W35) exhibited the highest drug release over 4h. Finally, in vivo evaluation demonstrated that the oral absorption of CoQ10 was markedly increased by using nanocrystals and LNs compared with a coarse suspension. A good relationship was found between the in vitro dissolution and in vivo evaluation. The enhanced oral absorption of CoQ10 by nanocrystals and LNs was due to improved dissolution. In conclusion, Witepsol(®)W35 was shown to be a better lipid additive for the preparation of LNs to increase the oral absorption of CoQ10., (Copyright © 2011 Elsevier B.V. All rights reserved.)