Sustained delivery of the bone morphogenetic proteins BMP-2 and BMP-7 for cartilage repair and regeneration in osteoarthritis

Whitty, Ciara; Pernstich, Christian; Marris, Charlotte; McCaskie, Andrew W.; Jones, Michael H.; Henson, Frances

doi:10.1016/j.ocarto.2022.100240

Cited by 19 publications

(17 citation statements)

References 46 publications

(65 reference statements)

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“…Fifteen C57BL/6 mice (Jackson Labs) were divided into three groups of five mice in which each mouse the control group either had no injection or received and injection of 4x10 7 PODS containing enhanced green fluorescent protein (PODS-GFP) in 200µL of PBS. The treatment group received an injection of 4x10 7 PODS-IL-2 in 200µL of PBS.…”

Section: Pods Administration In Melanoma Modelmentioning

confidence: 99%

“…In each experiment Twenty BALB/C mice (Jackson Labs) were divided into four groups of five mice. In the first experiment, each mouse in the treatment groups received an injection of 4x10 7 PODS containing either PODS-IL-2, PODS-IL-15, or PODS-IFN-γ in 200µL of PBS (total 16x10 7 PODS per mouse). The remaining group of five mice were untreated controls.…”

Section: Pods Administration In the Renal Cell Carcinoma Modelmentioning

confidence: 99%

“…In the second experiment each mouse in the treatment groups received an injection of 1x10 7 PODS containing either PODS-IL-2, PODS-IL-15, or PODS-IFN-γ in 200µL of PBS. Human homologs of each cytokine were used.…”

Section: Pods Administration In the Renal Cell Carcinoma Modelmentioning

confidence: 99%

“…In a separate experiment, groups of RCC mice also received a reduced dose of 1x10 7 PODS per injection and a total of four doses (a total of 4x10 7 PODS). This total has the maximum potential to generate 0.2 ug/kg or 2 ng per ml of serum with a maximal burden of 6-19 PODS/circulating monocyte.…”

Section: Determining Dosingmentioning

confidence: 99%

“…The therapeutic potential for sustained release of proteins from PODS has been demonstrated in a mouse model of cartilage repair 7 and a rat model of bone repair 8 in which PODS were locally administered. However, for therapy of non-localized targets, including disseminated cancers, localized drug administration is not feasible.…”

Section: Introductionmentioning

confidence: 99%

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Low-dose cytokine immunotherapy of solid cancers enabled by phagocytic-competent protein co-crystals

Jones

Calla

Smith

et al. 2023

Preprint

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Protein therapeutics are often compromised by sub-optimal biodistribution contributing to poor efficacy and adverse events. Drug delivery mechanisms better able to target protein drugs to the disease site and provide localized, sustained release have the potential to transform therapeutic standards. PODS crystals (PODS) are natural-mimetic, micron-scale protein co-crystals engineered to incorporate a protein cargo that can be sustainably released under the action of resident proteases. PODS are efficiently taken up by phagocytic cells with the cargo protein subsequently released in a bioactive form. Since blood-circulating phagocytic cells, including monocytes, are actively recruited into diseased and inflamed tissue, such as the tumour microenvironment, we postulated that monocyte/macrophage-mediated PODS delivery could be used as a molecular 'Trojan horse' to efficiently deliver therapeutic proteins to target cells. This could improve the pharmacodynamics and pharmacokinetics of protein drug delivery to treat systemic and disseminated diseases. Interleukin-2 (IL-2) is notoriously toxic at the high doses required for therapeutic efficacy. Here, we demonstrate the therapeutic efficacy and tolerability of low doses of PODS containing IL-2 cargo (PODS-IL-2) administered intravenously in a mouse model of melanoma. We further demonstrate the therapeutic benefit of PODS delivering IL-2, interleukin-15 (IL-15) and interferon gamma (IFN-gamma) in a mouse model of renal cell carcinoma at two doses. Efficacy was seen in both doses with the higher dose generating rapid and complete rejection of the tumour in some of the mice treated with each cytokine. This study provides proof-of-concept for the utility of intravenously administered PODS to provide a generalised and widely applicable mechanism to effectively deliver protein drugs for the therapy of cancer and potentially other diseases.

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Section: Pods Administration In Melanoma Modelmentioning

confidence: 99%

Section: Pods Administration In the Renal Cell Carcinoma Modelmentioning

confidence: 99%

Section: Pods Administration In the Renal Cell Carcinoma Modelmentioning

confidence: 99%

Section: Determining Dosingmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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