Multiple administration of PEG-coated liposomal oxaliplatin enhances its therapeutic efficacy: A possible mechanism and the potential for clinical application

Lila, Amr S. Abu; Eldin, Noha Essam; Ichihara, Masako; Ishida, Tatsuhiro; Kojima, Hiroshi

doi:10.1016/j.ijpharm.2012.08.030

Cited by 34 publications

(19 citation statements)

References 34 publications

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“…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]. The immune modulatory effects of PEG are increasingly recognized, and the use of PEG in cancer drug delivery has become a controversy [69] that is unlikely to be resolved until the precise mechanisms, and its impact on anticancer efficacy of the payload drug, are clarified.…”

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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“…Another factor that has been shown to influence the extent of ABC is the cargo inside the NPs [95-97]. For example, IgM production against PEG was decreased when doxorubicin-loaded liposomes were administered compared to empty PEGylated liposomes [90, 98].…”

Section: Nanoparticle Pegylation For Improved Systemic Deliverymentioning

confidence: 99%

PEGylation as a strategy for improving nanoparticle-based drug and gene delivery

Suk

Kim

et al. 2016

Advanced Drug Delivery Reviews

3,169

2,076

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Coating the surface of nanoparticles with polyethylene glycol (PEG), or “PEGylation”, is a commonly used approach for improving the efficiency of drug and gene delivery to target cells and tissues. Building from the success of PEGylating proteins to improve systemic circulation time and decrease immunogenicity, the impact of PEG coatings on the fate of systemically administered nanoparticle formulations has, and continues to be, widely studied. PEG coatings on nanoparticles shield the surface from aggregation, opsonization, and phagocytosis, prolonging systemic circulation time. Here, we briefly describe the history of the development of PEGylated nanoparticle formulations for systemic administration, including how factors such as PEG molecular weight, PEG surface density, nanoparticle core properties, and repeated administration impact circulation time. A less frequently discussed topic, we then describe how PEG coatings on nanoparticles have also been utilized for overcoming various biological barriers to efficient drug and gene delivery associated with other modes of administration, ranging from gastrointestinal to ocular. Finally, we describe both methods for PEGylating nanoparticles and methods for characterizing PEG surface density, a key factor in the effectiveness of the PEG surface coating for improving drug and gene delivery.

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“…In addition, some studies have shown that methylation of the methoxy group on PEG conjugates to eliminate the anionic group, can dramatically reduce the immune response [51,52]. Furthermore, recent work has demonstrated that accelerated clearance is not observed at high doses of PEGylated liposomes containing cytotoxic drugs due to destruction of the B cells in the spleen responsible for the subsequent antibody response [53,54]. Interestingly, lower doses of the drug exhibited ABC behavior, presumably due to inefficient killing of B cells involved in triggering anti-PEG antibodies.…”

mentioning

confidence: 99%

Questioning the use of PEGylation for drug delivery

Verhoef

Anchordoquy

2013

Drug Deliv. and Transl. Res.

291

242

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Polyethylene glycol (PEG) is widely utilized in drug delivery and nanotechnology due to its reported “stealth” properties and biocompatibility. It is generally thought that PEGylation allows particulate delivery systems and biomaterials to evade the immune system and thereby prolong circulation lifetimes. However, numerous studies over the past decade have demonstrated that PEGylation causes significant reductions in drug delivery, including enhanced serum protein binding, reduced uptake by target cells, and the elicitation of an immune response that facilitates clearance in vivo. This report reviews some of the extensive literature documenting the detrimental effects of PEGylation, and thereby questions the wisdom behind employing this strategy in drug development.

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Multiple administration of PEG-coated liposomal oxaliplatin enhances its therapeutic efficacy: A possible mechanism and the potential for clinical application

Cited by 34 publications

References 34 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

PEGylation as a strategy for improving nanoparticle-based drug and gene delivery

Questioning the use of PEGylation for drug delivery

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