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Oxidation-Triggerable Liposome Incorporating Poly(Hydroxyethyl Acrylate-co-Allyl methyl sulfide) as an Anticancer Carrier of Doxorubicin.

ABSTRACT: Since cancer cells are oxidative in nature, anti-cancer agents can be delivered to cancer cells specifically without causing severe normal cell toxicity if the drug carriers are designed to be sensitive to the intrinsic characteristic. Oxidation-sensitive liposomes were developed by stabilizing dioleoylphosphatidyl ethanolamine (DOPE) bilayers with folate-conjugated poly(hydroxyethyl acrylate-co-allyl methyl sulfide) (F-P(HEA-AMS)). The copolymer, synthesized by a free radical polymerization, was surface-active but lost its surface activity after AMS unit was oxidized by H2O2 treatment. The liposomes with F-P(HEA-AMS) were sensitive to H2O2 concentration (0%, 0.5%, 1.0%, and 2.0%) in terms of release, possibly because the copolymer lost its surface activity and its bilayer-stabilizing ability upon oxidation. Fluorescence-activated cell sorting (FACS) and confocal laser scanning microscopy (CLSM) revealed that doxorubicin (DOX)-loaded liposomes stabilized with folate-conjugated copolymers markedly promoted the transport of the anti-cancer drug to cancer cells. This was possible because the liposomes were readily translocated into the cancer cells via receptor-mediated endocytosis. This liposome would be applicable to the delivery carrier of anticancer drugs.

SUBMITTER: Kim JA

PROVIDER: S-EPMC7017253 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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Oxidation-Triggerable Liposome Incorporating Poly(Hydroxyethyl Acrylate-<i>co</i>-Allyl methyl sulfide) as an Anticancer Carrier of Doxorubicin.

Kim Jin Ah JA Yoon Dong Youl DY Kim Jin-Chul JC

Cancers 20200110 1

Since cancer cells are oxidative in nature, anti-cancer agents can be delivered to cancer cells specifically without causing severe normal cell toxicity if the drug carriers are designed to be sensitive to the intrinsic characteristic. Oxidation-sensitive liposomes were developed by stabilizing dioleoylphosphatidyl ethanolamine (DOPE) bilayers with folate-conjugated poly(hydroxyethyl acrylate-co-allyl methyl sulfide) (F-P(HEA-AMS)). The copolymer, synthesized by a free radical polymerization, wa ...[more]

PMID: 31936896

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Project description:Background: We have previously shown that alendronate, an amino-bisphosphonate, when reformulated in liposomes, can significantly enhance the efficacy of cytotoxic chemotherapies and help remodel the immunosuppressive tumor microenvironment towards an immune-permissive milieu resulting in increased anticancer efficacy. In addition, we have previously shown that the strong metal-chelating properties of alendronate can be exploited for nuclear imaging of liposomal biodistribution. To further improve anticancer efficacy, a pegylated liposome formulation co-encapsulating alendronate and doxorubicin (PLAD) has been developed. In this study, we examined the effects of PLAD on the tumor immunologic milieu in a mouse fibrosarcoma model in which the tumor microenvironment is heavily infiltrated with tumor-associated macrophages (TAM) that are associated with poor prognosis and treatment resistance. Methods: Doxorubicin biodistribution, characterization of the tumor immunologic milieu, cellular doxorubicin uptake, and tumor growth studies were performed in Balb/c mice bearing subcutaneously implanted WEHI-164 fibrosarcoma cells treated intravenously with PLAD, pegylated liposomal doxorubicin (PLD), free doxorubicin, or vehicle. Results: PLAD delivery resulted in a high level of tumor doxorubicin that was 20 to 30-fold greater than in free doxorubicin treated mice, and non-significantly higher than in PLD treated mice. PLAD also resulted in increased uptake in spleen and slightly lower plasma levels as compared to PLD. Importantly, our results showed that PLAD, and to a lesser extent PLD, shifted cellular drug uptake to TAM and to monocytic myeloid-derived suppressor cells (MDSC), while there was no drug uptake in neutrophilic MDSC or lymphoid cells. Free doxorubicin cellular drug uptake was below detectable levels. PLAD, and to a lesser extent PLD, also induced significant changes in number and functionality of tumor-infiltrating TAM, MDSC, Treg, NKT, and NK cells that are consistent with enhanced antitumor immune responses in the tumor microenvironment. In contrast, free doxorubicin induced moderate changes in the tumor microenvironment that could promote (decreased Treg) or be detrimental to antitumor immune responses (decreased M1 TAM and NK cells). These immune modulatory effects are reflected in the therapeutic study which showed that PLAD and PLD inhibited tumor growth and significantly prolonged survival, while free doxorubicin showed little or no anticancer activity. Conclusion: We show that liposomal delivery of doxorubicin not only alters pharmacokinetics, but also dramatically changes the immune modulatory activity of the drug cargo. In addition, our data support that the PLAD nanotheranostic platform further enhances some immune changes that may act in synergy with its cytotoxic chemotherapy effects.

Dataset Information

Oxidation-Triggerable Liposome Incorporating Poly(Hydroxyethyl Acrylate-co-Allyl methyl sulfide) as an Anticancer Carrier of Doxorubicin.

Publications

Oxidation-Triggerable Liposome Incorporating Poly(Hydroxyethyl Acrylate-<i>co</i>-Allyl methyl sulfide) as an Anticancer Carrier of Doxorubicin.

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