Nanocapsule Delivery of IL-12

Markel, Justin E.; Lacinski, Ryan A.; Lindsey, Brock A.

doi:10.1007/978-3-030-43032-0_13

Cited by 6 publications

(7 citation statements)

References 43 publications

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“…Unfortunately, recombinant IL-12 cytokine therapy thus far has produced underwhelming results in human patients. Clinical trials conducted in the 1990s required high loading doses of IL-12 to achieve adequate tissue biodistribution and resulted in TCE, SIRS, and ultimately worse outcomes [ 13 ]. In contrast, low-dose IL-12 given over prolonged periods has been shown to induce tumor regression without overstimulation, though there are currently few cases reported in the literature using this treatment strategy [ 64 , 65 ].…”

Section: Discussionmentioning

confidence: 99%

“…Unfortunately, clinical use of recombinant IL-12 systemically has been complicated by inadvertent overstimulation in the form of systemic inflammatory response syndrome (SIRS) and T cell exhaustion (TCE) [ 12 ], as high loading doses of free protein were needed to ensure adequate distribution to target tissues. Nevertheless, while the side-effect profiles of systemic high-dose IL-12 administration are toxic, low doses of IL-12 are generally safe [ 13 ]. If formulated correctly, recombinant IL-12 may be used to alter the local cytokine environment and encourage antitumor immunity at a point far enough upstream in the inflammatory cascade to induce a multimodal downstream response, ultimately leading to a decreased likelihood of treatment resistance.…”

Section: Introductionmentioning

confidence: 99%

“…Furthermore, to be used in systemic settings (versus intratumoral injections), nanospheres must be able to achieve safe and effective travel through the microvasculature of an organism (with capillaries being approximately 4-9 μ m in diameter) with minimal risk of forming emboli [ 18 ]. Encapsulating IL-12 within PLGA nanospheres is a potential strategy to achieve adequate biodistribution and tissue deposition of sensitive protein molecules without the need for toxic loading doses that resulted in the failure of clinical trials in the past [ 13 ]. While there have been several studies describing the synthesis of IL-12-loaded microspheres [ 19 – 35 ], to date, successful submicron encapsulation and elution of a structurally intact protein have not been well established.…”

Section: Introductionmentioning

confidence: 99%

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Synthesis, Characterization, and In Vivo Cytokinome Profile of IL-12-Loaded PLGA Nanospheres

Lacinski

Markel

Noore

et al. 2022

Journal of Immunology Research

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We report the successful encapsulation and elution of recombinant murine IL-12 (rmIL-12) from poly(lactide-co-glycolic) acid (PLGA) nanospheres (IL-12-NS) synthesized using the double emulsion/solvent evaporation (DESE) technique with microsphere depletion through ultracentrifugation. Images obtained with scanning electron microscopy (SEM) showcased a characteristic spherical shape with a mean particle diameter of 138.1 ± 10.8 nm and zeta potential of − 15.1 ± 1.249 mV . These values suggest minimal flocculation when in solution, which was reflected in an in vivo biodistribution study that reported no observed morbidity/mortality. Encapsulation efficiency (EE) was determined to be 0.101 ± 0.009 % with average particle concentration obtained per batch of 1.66 × 10 9 ± 4.45 × 10 8 particles/mL. Disparate zeta (ζ) potentials obtained from both protein-loaded and protein-unloaded batches suggested surface adsorption of protein, and confocal microscopy of BSA-FITC-loaded nanospheres confirmed the presence of protein within the polymeric shell. Furthermore, elution of rmIL-12 from IL-12-NS at a concentration of 500 million particles/mL was characterized using enzyme-linked immunosorbent assay (ELISA). When IL-12-NS was administered in vivo to female BALB/c mice through retroorbital injection, IL-12-NS produced a favorable systemic cytokine profile for tumoricidal activity within the peripheral blood. Whereas IFN-γ nadir occurred at 72 hours, levels recovered quickly and displayed positive correlations postburst out to 25 days postinjection. IL-12-NS administration induced proinflammatory changes while prompting minimal counterregulatory increases in anti-inflammatory IL-10 and IL-4 cytokine levels. Further, while IL-6 levels increased to 30 folds of the baseline during the burst phase, they normalized by 72 hours and trended negatively throughout the sill phase. Similar trends were observed with IL-1β and CXCL-1, suggesting a decreased likelihood of progression to a systemic inflammatory response syndrome-like state. As IL-12-NS delivers logarithmically lower amounts of IL-12 than previously administered during human clinical trials, our data reflect the importance of IL-12-NS which safely create a systemic immunostimulatory environment.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Synthesis, Characterization, and In Vivo Cytokinome Profile of IL-12-Loaded PLGA Nanospheres

Lacinski

Markel

Noore

et al. 2022

Journal of Immunology Research

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“…IL-12 is now recognized as a key regulator of cell-mediated immune response and a bridge between innate and adaptive immunity [ 41 ]. Because of its role as major orchestrator of Th1-type immune response against cancer [ 40 ], IL-12 is an attractive protein candidate for cancer therapies [ 42 ]. Studies conducted in a rat model of thyroid cancer showed that delivery of IL-12 gene with adenovirus (AdIL-12) was efficacious to elicit systemic anti-tumor immunity, unlike treatment with AdGM-CSF with cells expressing IL-12 or GM–CSF, which elicited only local effects.…”

Section: Exploring the Tumor Microenvironment And Its Modulation Bmentioning

confidence: 99%

Oncolytic Adenoviruses for Cancer Therapy

Tripodi

Vitale

Cerullo

et al. 2021

IJMS

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Many immuno-therapeutic strategies are currently being developed to fight cancer. In this scenario, oncolytic adenoviruses (Onc.Ads) have an interesting role for their peculiar tumor selectivity, safety, and transgene-delivery capability. The major strength of the Onc.Ads is the extraordinary immunogenicity that leads to a strong T-cell response, which, together with the possibility of the delivery of a therapeutic transgene, could be more effective than current strategies. In this review, we travel in the adenovirus (Ads) and Onc.Ads world, focusing on a variety of strategies that can enhance Onc.Ads antitumoral efficacy, passing through tumor microenvironment modulation. Onc.Ads-based therapeutic strategies constitute additional weapons in the fight against cancer and appear to potentiate conventional and immune checkpoint inhibitors (ICIs)-based therapies leading to a promising scenario.

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“…Furthermore, the IL-12 cytokine mediates anti-angiogenesis activity in a CXCR3-dependent manner by acting on endothelial cells while enhancing T cells' expression [78]. Wang [79,80]. However, the application of cytokines in cancer therapy is thwarted by the therapeutic agent's potential side effects, such as metabolic disturbances, myelosuppression and serum sickness [13].…”

Section: Cytokine Therapymentioning

confidence: 99%

Nanomedicine-Mediated Optimization of Immunotherapeutic Approaches in Cervical Cancer

Venkatas

Singh

2021

Nanomedicine (Lond.)

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Cervical cancer shows immense complexity at the epigenetic, genetic and cellular levels, limiting conventional treatment. Immunotherapy has revolutionized nanomedicine and rejuvenated the field of tumor immunology. Although several immunotherapeutic approaches have shown favorable clinical responses, their efficacies vary, with subsets of patients benefitting. The success of cancer immunotherapy requires the enhancement of cytokines and antitumor effector cell production and activation. Recently, the feasibility of nanoparticle-based cytokine approaches in tumor immunotherapy has been highlighted. Immunotherapeutic nanoparticle-based platforms form a novel strategy enabling researchers to co-deliver immunomodulatory agents, target tumors, improve pharmacokinetics and minimize collateral toxicity to healthy cells. This review looks at the potential of immunotherapy and nanotechnologically enhanced immunotherapeutic approaches for cervical cancer.

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Nanocapsule Delivery of IL-12

Cited by 6 publications

References 43 publications

Synthesis, Characterization, and In Vivo Cytokinome Profile of IL-12-Loaded PLGA Nanospheres

Synthesis, Characterization, and In Vivo Cytokinome Profile of IL-12-Loaded PLGA Nanospheres

Oncolytic Adenoviruses for Cancer Therapy

Nanomedicine-Mediated Optimization of Immunotherapeutic Approaches in Cervical Cancer

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