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

Anchordoquy, Thomas J.; Barenholz, Yechezkel; Boraschi, Diana; Chorny, Michael; Decuzzi, Paolo; Dobrovolskaia, Marina A.; Farhangrazi, Z. Shadi; Farrell, Dorothy; Gabizón, Alberto; Ghandehari, Hamidreza; Godin, Biana; La‐Beck, Ninh M.; Ljubimova, Julia Y.; Moghimi, S. Moein; Pagliaro, L; Park, Ji Ho; Peer, Dan; Ruoslahti, Erkki; Serkova, Natalie J.; Simberg, Dmitri

doi:10.1021/acsnano.6b08244

Cited by 265 publications

(168 citation statements)

References 39 publications

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“…In protein therapeutics, PEG suppressed antibody responses against conjugated antigens thereby inducing a tolerogenic state [58] and this approach has been utilized to optimize pharmacokinetics of therapeutic proteins ( e.g. PEG-asparaginase) [11]. In organ transplantation, the addition of PEG to organ preservation solutions significantly improved organ function and decreased inflammation and fibrosis through suppression of the host immune responses against the transplanted organ [28,67].…”

Section: Discussionmentioning

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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Section: Discussionmentioning

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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“…This has led to the design of liposome formulations with great potential in cancer therapy. However, despite the sound pharmacologic basis, many of the liposomal drugs as well as other nanoparticle-based drug formulations have failed to meet regulatory criteria for approval or have shown modest effects in phase 3 clinical studies (3–8). In fact, some of the approvals have been based on reduced toxicity rather than increased efficacy.…”

Section: Introductionmentioning

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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“…9 Complement is implicated in a variety of disease conditions; 18 therefore, its enhanced activation could potentially result in pathophysiological misbalances and worsening of the disease rather than its alleviation. 19 …”

Section: Introductionmentioning

confidence: 99%

Variability of Complement Response toward Preclinical and Clinical Nanocarriers in the General Population

Benasutti

Wang

et al. 2017

Bioconjugate Chem.

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Opsonization (coating) of nanoparticles with complement C3 component is an important mechanism that triggers immune clearance and downstream anaphylactic and proinflammatory responses. The variability of complement C3 binding to nanoparticles in the general population has not been studied. We examined complement C3 binding to dextran superparamagnetic iron oxide nanoparticles (superparamagnetic iron oxide nanoworms, SPIO NWs, 58 and 110 nm) and clinically approved nanoparticles (carboxymethyl dextran iron oxide ferumoxytol (Feraheme, 28 nm), highly PEGylated liposomal doxorubicin (LipoDox, 88 nm), and minimally PEGylated liposomal irinotecan (Onivyde, 120 nm)) in sera from healthy human individuals. SPIO NWs had the highest variation in C3 binding (n = 47) between subjects, with a 15−30 fold range in levels of C3. LipoDox (n = 12) and Feraheme (n = 18) had the lowest levels of variation between subjects (an approximately 1.5-fold range), whereas Onivyde (n = 18) had intermediate between-subject variation (2-fold range). There was no statistical diﬀerence between males and females and no correlation with age. There was a significant correlation in complement response between small and large SPIO NWs, which are similar structurally and chemically, but the correlations between SPIO NWs and other types of nanoparticles, and between LipoDox and Onivyde, were not significant. The calculated average number of C3 molecules bound per nanoparticle correlated with the hydrodynamic diameter but was decreased in LipoDox, likely due to the PEG coating. The conclusions of this study are (1) all nanoparticles show variability of C3 opsonization in the general population; (2) an individual’s response toward one nanoparticle cannot be reliably predicted based on another nanoparticle; and (3) the average number of C3 molecules per nanoparticle depends on size and surface coating. These results provide new strategies to improve nanomedicine safety.

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

Cited by 265 publications

References 39 publications

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

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

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

Variability of Complement Response toward Preclinical and Clinical Nanocarriers in the General Population

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