Liposome promotion of tumor growth is associated with angiogenesis and inhibition of antitumor immune responses

Sabnani, Manoj K; Rajan, Robin; Rowland, Bradley; Mavinkurve, Vikram; Wood, Laurence M.; Gabizón, Alberto; La‐Beck, Ninh M.

doi:10.1016/j.nano.2014.08.010

Cited by 47 publications

(32 citation statements)

References 10 publications

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“…However, other attendees stressed that products of the complement activation also induce strong pro-inflammatory responses that could nullify the therapeutic efficacy of the payload. Indeed, there is evidence that some nanocarriers actually promote tumor growth, 9 likely due to liberation of C5a and subsequent recruitment of pro-inflammatory macrophages and regulatory T-cells. 10 While some of these effects may be due to the presence of anti-PEG antibodies, which elicit complement activation in a proportion of patients, it is likely that there are other mechanisms that remain to be elucidated.…”

Section: Immune System: Friend or Foe?mentioning

confidence: 99%

Mechanisms and Barriers in Cancer Nanomedicine: Addressing Challenges, Looking for Solutions

Barenholz²,

et al. 2017

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Remarkable progress has recently been made in the synthesis and characterization of engineered nanoparticles for imaging and treatment of cancers, resulting in several promising candidates in clinical trials. Despite these advances, clinical applications of nanoparticle-based therapeutic/imaging agents remain limited by biological, immunological, and translational barriers. In order to overcome the existing status quo in drug delivery, there is a need for open and frank discussion in the nanomedicine community on what is needed to make qualitative leaps toward translation. In this Nano Focus, we present the main discussion topics and conclusions from a recent workshop: “Mechanisms and Barriers in Nanomedicine”. The focus of this informal meeting was on biological, toxicological, immunological, and translational aspects of nanomedicine and approaches to move the field forward productively. We believe that these topics reflect the most important issues in cancer nanomedicine.

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Section: Immune System: Friend or Foe?mentioning

confidence: 99%

Mechanisms and Barriers in Cancer Nanomedicine: Addressing Challenges, Looking for Solutions

Barenholz²,

et al. 2017

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“…The tumor microenvironment is complex, and tumors are often infiltrated by immune cells such as monocytes, macrophages, and MDSCs, which are believed to have protumoral functions through their inhibition of T cell antitumor responses and enhancement of tumor angiogenesis (28, 29). Interestingly, it was recently reported that a pegylated liposomal drug carrier, similar to that used in patients, significantly enhanced tumor growth in a mouse model of HPV-induced cancer (30). This was associated with suppression of antitumor immunity as indicated by decreased interferon-γ production by tumor-associated macrophages and cytotoxic T cells, diminished tumor infiltration of tumor antigen-specific T cells, and decreased number of dendritic cells in tumor-draining lymph nodes.…”

Section: Potential Impact On Cancer Progression and Regressionmentioning

confidence: 99%

Nanoparticle Interactions with the Immune System: Clinical Implications for Liposome-Based Cancer Chemotherapy

La‐Beck

Gabizón

2017

Front. Immunol.

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The development of stable and long-circulating liposomes provides protection of the drug cargo from degradation and increases tumor drug delivery, leading to the design of liposome formulations with great potential in cancer therapy. However, despite the sound pharmacologic basis, many liposomal as well as other nanoparticle-based drug formulations have failed to meet regulatory criteria for approval. The question that arises is whether we have missed key liposome–host interactions that can account for the gap between the major pharmacologic advantages in preclinical studies and the modest impact of the clinical effects in humans. We will discuss here the nanoparticle–immune system interactions that may undermine the antitumor effect of the nanodrug formulations and contribute to this gap. To overcome this challenge and increase clinical translation, new preclinical models need to be adopted along with comprehensive immunopharmacologic studies and strategies for patient selection in the clinical phase.

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“…The resulting nanomedicines are within the nanometer scale, usually in the range of 10 to 200 nm in diameter. Nanoparticles are used as drug carriers for cancer therapies since they have pharmacological advantages such as increased tumor drug delivery through the enhanced permeability and retention (EPR) effect, protection of the drug cargo from degradation, and in most cases improved tolerability of cytotoxic drugs [3,20,50]. There are now nine nanoparticle drugs approved for the treatment of cancer (Supplemental Table S1), and most utilize liposomal nanoparticles because the lipid components are considered biocompatible and safe materials and liposomes have been manufactured in bulk and met regulatory criteria.…”

Section: Introductionmentioning

confidence: 99%

Liposome-induced immunosuppression and tumor growth is mediated by macrophages and mitigated by liposome-encapsulated alendronate

Rajan

Sabnani

Mavinkurve

et al. 2018

Journal of Controlled Release

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Liposomal nanoparticles are the most commonly used drug nano-delivery platforms. However, recent reports show that certain pegylated liposomal nanoparticles (PLNs) and polymeric nanoparticles have the potential to enhance tumor growth and inhibit antitumor immunity in murine cancer models. We sought herein to identify the mechanisms and determine whether PLN-associated immunosuppression and tumor growth can be reversed using alendronate, an immune modulatory drug. By conducting in vivo and ex vivo experiments with the immunocompetent TC-1 murine tumor model, we found that macrophages were the primary cells that internalized PLN in the tumor microenvironment and that PLN-induced tumor growth was dependent on macrophages. Treatment with PLN increased immunosuppression as evidenced by increased expression of arginase-1 in CD11b+Gr1+ cells, diminished M1 functionality in macrophages, and globally suppressed T-cell cytokine production. Encapsulating alendronate in PLN reversed these effects on myeloid cells and shifted the profile of multi-cytokine producing T-cells towards an IFNγ+ perforin+ response, suggesting increased cytotoxic functionality. Importantly, we also found that PLN-encapsulated alendronate (PLN-alen), but not free alendronate, abrogated PLN-induced tumor growth and increased progression-free survival. In summary, we have identified a novel mechanism of PLN-induced tumor growth through macrophage polarization and immunosuppression that can be targeted and inactivated to improve the anticancer efficacy of PLN-delivered drugs. Importantly, we also determined that PLN-alen not only reversed protumoral effects of the PLN carrier, but also had moderate antitumor activity. Our findings strongly support the inclusion of immune-responsive tumor models and in-depth immune functional studies in the preclinical drug development paradigm for cancer nanomedicines, and the further development of chemo-immunotherapy strategies to co-deliver alendronate and chemotherapy for the treatment of cancer.

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Liposome promotion of tumor growth is associated with angiogenesis and inhibition of antitumor immune responses

Cited by 47 publications

References 10 publications

Mechanisms and Barriers in Cancer Nanomedicine: Addressing Challenges, Looking for Solutions

Mechanisms and Barriers in Cancer Nanomedicine: Addressing Challenges, Looking for Solutions

Nanoparticle Interactions with the Immune System: Clinical Implications for Liposome-Based Cancer Chemotherapy

Liposome-induced immunosuppression and tumor growth is mediated by macrophages and mitigated by liposome-encapsulated alendronate

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