Gd-metallofullerenol drug delivery system mediated macrophage polarization enhances the efficiency of chemotherapy
Graphical abstract
Introduction
Treatment of solid tumors by chemotherapy is usually failed in clinical because of the low effectiveness and side effects of chemodrugs [1]. Recent years' success of cancer immunotherapy, including monoclonal antibodies, cancer vaccines, adoptive cancer therapy and immune checkpoint therapy, has revolutionized traditional cancer treatment [[2], [3], [4]]. Manipulating of immune response in the tumor microenvironment becomes a powerful method for cancer treatment. However, challenges still exist in cancer immunotherapy [5]. Conventional cancer immunotherapeutic drugs with specific proteins or small molecular, whose therapeutic effect varies greatly in different patients because of the tumor heterogeneity with different antigen expression levels [6]. Also, the main components of traditional immunotherapy usually lose their bioactivity or target and lead to fail in vivo [7]. Preliminary evidences indicated that there will be promising synergistic effects when combining other types of therapies with immunotherapy [[8], [9], [10]].
As is now principally recognized, nanoparticle-based drug delivery system has the capacity to improve cancer treatment by packaging and protecting chemodrugs, and delivering them to the target cells [11,12]. Polymer nanoparticles usually offer great advantages by delivering a higher concentration of chemodrugs to tumor microenvironment [13]. However, the encapsulation of some hydrophilic drugs in polymer carriers is still not up to scratch. Researchers have developed nanoscale liposomal polymeric gels co-delivery TGF-β inhibitor and immunostimulatory IL-2 to increase the survival of tumor-bearing mice [14]. Also, Toll-like-receptor-7 agonist and indocyanine green were co-encapsulated by traditional poly(lactic-co-glycolic) acid (PLGA) polymer cargo to generate immunological responses in tumor metastasis inhibition [15]. However, the chemotherapeutics seldom co-delivered with the immunomodulatory protein due to the intricacy of manipulating the different pharmacokinetics of small molecule and protein without external force.
Macrophage is a fundamental part of the innate immune defense mechanisms and an essential component of tumor microenvironment [16]. It can be characterized as pro-inflammatory M1 or anti-inflammatory M2 macrophage [17,18]. M1 macrophage secretes pro-inflammatory cytokines promote specific immunity to provoke antitumor immunity by inducing T cell recruitment and activation, while M2 macrophages produce anti-inflammatory cytokines which would support tumorigenesis [[19], [20], [21]]. Accumulating evidences have assumed that some specific nanoparticles, like iron oxide and polymer, have implication in macrophage polarization [[22], [23], [24]]. Fullerene derivatives, including fullerenol [C60(OH)22] and Gd-metallofullerenol [Gd@C82(OH)22], have also been reported as efficient immunoadjuvants for HIV-1 DNA vaccines and cancer therapeutic agents [25,26]. In our previous studies, Fullerene and its derivatives have been identified as imaging agents [27], metalloproteinase inhibitors [28] and radical scavengers [29]. Also, both fullerenol and Gd-metallofullerenol nanoparticles can arouse both strong immune responses and highly delivery capacity against malignant disease [30,31]. Nevertheless, the role of Gd-metallofullerenol mediated immune response in cancer treatment especially combining with chemodrugs is remained obscure.
Herein, we developed a co-delivery nanosystem which utilized PEG-PLGA polymer to envelop Gd-metallofullerenol and Dox drug that realized combined cancer treatment with chemo-toxic effect and immunomodulation. Via this elaborate design, the Dox treatment effectiveness was significantly enhanced in vivo. By regulating the ratio of M2 to M1 phenotype in tumor microenvironment, Gd-metallofullerenol nanoparticles achieved the immune modulation with potential anti-tumor activity and significantly improved the encapsulation efficiency of Dox in polymer cargo. Furthermore, the combined delivery of Dox and Gd-metallofullerenol attained synergistic anti-tumor effect of chemo-immunotherapy. Therefore, our strategy that combining Gd-metallofullerenol immune-provoking with chemotherapy will be benefit for improving the effectiveness of cancer therapy.
Section snippets
Nanoparticles synthesis and characterization
Water-soluble Gd-metallofullerenol nanoparticles were synthesized by the Kraschmer-Huffman method with further hydroxylation as described previously [30]. D:Gd-pNPs (Dox and Gd-metallofullerenol co-delivered in polymer nanoparticles) were prepared by using the double emulsion (W/O/W) method. In brief, 40 mg of PEG-PLGA (MW: 5000, 15,000, Jinan Daigang Biomaterial Co., Ltd) were dissolved in 2 mL of methylene chloride and 0.4 mL of D:Gd complex solution (Dox, 0.7vmmol; Gd-metallofullerenol,
Synthesis and characterization of D:Gd-pNPs
The Gd-metallofullerenol nanoparticles were synthesized by Kratschmer-Huffman method and make them hydroxylation by the alkaline reaction as previously described [30]. The number of hydroxyl groups on the surface of Gd-metallofullerenol is about 22 and mainly located at the polar site according to the theoretical predictions [32]. Because of the hydroxyl groups, the Gd-metallofullerenol nanoparticles were negative charged (Fig. 1C). Thus, the Dox could be tightly absorbed on the
Conclusions
In summary, we developed a biocompatible and reliable nanoplatform by combining nanoparticle-induced immune modulation and chemotherapy with controlled and sustained drug release, which subsequently triggers systemic antitumor immune responses for the effective inhibition of tumor growth. We also identified the ability of Gd-metallofullerenol to polarize macrophage differentiation and applied to co-deliver Dox with higher encapsulation efficiency for cancer therapy. Hence, the integration of
Declaration of Competing Interest
The authors declare that they have no competing financial interests.
Acknowledgements
This work was financially supported by the Ministry of Science and Technology of China (National Basic Research Program 2016YFA0201600 and 2016YFE0133100), the National Science Foundation of China (81872651, 31571027, 21705151), the Science Fund for Creative Research Groups of the National Natural Science Foundation of China (11621505), the CAS Key Research Program for Frontier Sciences (QYZDJ-SS-SLH022), and the CAS Interdisciplinary Innovation Team.
References (52)
- et al.
Intratumoral fate of functional nanoparticles in response to microenvironment factor: implications on cancer diagnosis and therapy
Adv. Drug Deliv. Rev.
(2019) - et al.
Macrophages, innate immunity and cancer: balance, tolerance, and diversity
Curr. Opin. Immunol.
(2010) - et al.
Macrophage polarization in tumour progression
Semin. Cancer Biol.
(2008) - et al.
Macrophage polarization: tumor-associated macrophages as a paradigm for polarized M2 mononuclear phagocytes
Trends Immunol.
(2002) - et al.
Gadolinium metallofullerenol nanoparticles inhibit cancer metastasis through matrix metalloproteinase inhibition: imprisoning instead of poisoning cancer cells
Nanomed.-Nanotechnol.
(2012) - et al.
Nucleosome-inspired nanocarrier obtains encapsulation efficiency enhancement and side effects reduction in chemotherapy by using fullerenol assembled with doxorubicin
Biomaterials
(2018) - et al.
Chitosan nanoparticles as delivery systems for doxorubicin
J. Control. Release
(2001) - et al.
The scavenging of reactive oxygen species and the potential for cell protection by functionalized fullerene materials
Biomaterials
(2009) - et al.
Effects by doxorubicin on the myocardium are mediated by oxygen free radicals
Life Sci.
(2001) - et al.
The effect of Gd@C82(OH)(22) nanoparticles on the release of Th1/Th2 cytokines and induction of TNF-alpha mediated cellular immunity
Biomaterials
(2009)
Regulatory T cells and toll-like receptors in tumor immunity
Semin. Immunol.
Humoral immunity, inflammation and cancer
Curr. Opin. Immunol.
Immunological effects of conventional chemotherapy and targeted anticancer agents
Cancer Cell
Polarization profiles of human M-CSF-generated macrophages and comparison of M1-markers in classically activated macrophages from GM-CSF and M-CSF origin
Cell. Immunol.
Th1 cytokine-based immunotherapy for cancer
Hepatob. Pancreat. Dis.
Cellular senescence promotes adverse effects of chemotherapy and cancer relapse
Cancer Discov.
Novel cancer immunotherapy agents with survival benefit: recent successes and next steps
Nat. Rev. Cancer
Neoantigens in cancer immunotherapy
Science
Chemokines in the cancer microenvironment and their relevance in cancer immunotherapy
Nat. Rev. Immunol.
Nanoparticle immunotherapy combo combat
Nat. Mater.
A pathology atlas of the human cancer transcriptome
Science
Designer vaccine nanodiscs for personalized cancer immunotherapy
Nat. Mater.
Prospects for combining targeted and conventional cancer therapy with immunotherapy
Nat. Rev. Cancer
Evolving synergistic combinations of targeted immunotherapies to combat cancer
Nat. Rev. Cancer
Combining immunotherapy and targeted therapies in cancer treatment
Nat. Rev. Cancer
Principles of nanoparticle design for overcoming biological barriers to drug delivery
Nat. Biotechnol.
Cited by (0)
- 1
These authors contributed equally.