Assembly of bioactive multilayered nanocoatings on pancreatic islet cells: incorporation of α1-antitrypsin into the coatings

Zheng, Zhi; Singh, Jashandeep; Austin, Amazon; Hope, David; King, Aileen; Persaud, Shanta J.; Jones, Peter M.

doi:10.1039/c5cc02570b

Cited by 14 publications

(14 citation statements)

References 26 publications

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“…This process approximates layer-by-layer (LBL) assembly, which has been used to create functional cell surface coatings through sequential adsorption of oppositely charged components that form thin polyelectrolyte multilayer films. This approach has been explored primarily in the modification of pancreatic islets [35][36][37] to dampen host immune reactivity and not for the intracellular delivery of therapeutics. Furthermore, previous LBL approaches have almost entirely utilized polycations to modify negatively charged cell surfaces, which is associated with significant cytotoxicity 38 .…”

Section: Discussionmentioning

confidence: 99%

An anionic, endosome-escaping polymer to potentiate intracellular delivery of cationic peptides, biomacromolecules, and nanoparticles

et al. 2019

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Peptides and biologics provide unique opportunities to modulate intracellular targets not druggable by conventional small molecules. Most peptides and biologics are fused with cationic uptake moieties or formulated into nanoparticles to facilitate delivery, but these systems typically lack potency due to low uptake and/or entrapment and degradation in endolysosomal compartments. Because most delivery reagents comprise cationic lipids or polymers, there is a lack of reagents specifically optimized to deliver cationic cargo. Herein, we demonstrate the utility of the cytocompatible polymer poly(propylacrylic acid) (PPAA) to potentiate intracellular delivery of cationic biomacromolecules and nano-formulations. This approach demonstrates superior efficacy over all marketed peptide delivery reagents and enhances delivery of nucleic acids and gene editing ribonucleoproteins (RNPs) formulated with both commercially-available and our own custom-synthesized cationic polymer delivery reagents. These results demonstrate the broad potential of PPAA to serve as a platform reagent for the intracellular delivery of cationic cargo.

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Section: Discussionmentioning

confidence: 99%

An anionic, endosome-escaping polymer to potentiate intracellular delivery of cationic peptides, biomacromolecules, and nanoparticles

et al. 2019

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“…PEG grafting could also be leveraged to tether and present bioactive agents to the host. For example, others have linked anti‐inflammatory motifs such as heparin, alpha1‐antitrypsin, urokinase, thrombomodulin, and human soluble complement receptor 1 (sCR1) with observed benefits in vitro and in rodent models . In one NHP trial, Park et al observed improved engraftment in fully immunosuppressed NHP recipients when heparin was linked to PEGylated allogenic islets .…”

Section: Discussionmentioning

confidence: 99%

“…For example, others have linked anti-inflammatory motifs such as heparin, alpha1-antitrypsin, urokinase, thrombomodulin, and human soluble complement receptor 1 (sCR1) with observed benefits in vitro and in rodent models. 41,[65][66][67][68][69] In one NHP trial, Park et al observed improved engraftment in fully immunosuppressed NHP recipients when heparin was linked to PEGylated allogenic islets. 39 Thus, bioactivity can be incorporated onto PEGylated islets in future work to impart additional benefits.…”

Section: Discussionmentioning

confidence: 99%

Transplantation of PEGylated islets enhances therapeutic efficacy in a diabetic nonhuman primate model

Stabler

Giraldo

Berman

et al. 2020

American Journal of Transplantation

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Islet cell transplantation can lead to insulin independence, reduced hypoglycemia, and amelioration of diabetes complications in patients with type 1 diabetes. The systemic delivery of anti‐inflammatory agents, while considered crucial to limit the early loss of islets associated with intrahepatic infusion, increases the burden of immunosuppression. In an effort to decrease the pharmaceutical load to the patient, we modified the pancreatic islet surface with long‐chain poly(ethylene glycol) (PEG) to mitigate detrimental host‐implant interactions. The effect of PEGylation on islet engraftment and long‐term survival was examined in a robust nonhuman primate model via three paired transplants of dosages 4300, 8300, and 10 000 islet equivalents per kg body weight. A reduced immunosuppressive regimen of anti‐thymocyte globulin induction plus tacrolimus in the first posttransplant month followed by maintenance with sirolimus monotherapy was employed. To limit transplant variability, two of the three pairs were closely MHC‐matched recipients and received MHC‐disparate PEGylated or untreated islets isolated from the same donors. Recipients of PEGylated islets exhibited significantly improved early c‐peptide levels, reduced exogenous insulin requirements, and superior glycemic control, as compared to recipients of untreated islets. These results indicate that this simple islet modification procedure may improve islet engraftment and survival in the setting of reduced immunosuppression.

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“…We are therefore currently focusing on strategies that will deliver anti-inflammatory agents to the site of implantation. To do this we have applied a layer-by-layer nanoencapsulation method which can incorporate anti-inflammatory peptides such as α1-anti-trypsin ( 59 ). It is possible that this strategy combined with using insulinotropic peptides will lead to better function and survival of islets in a transplantation setting.…”

Section: Discussionmentioning

confidence: 99%

Imatinib prevents beta cell deathin vitrobut does not improve islet transplantation outcome

King

Griffiths

Persaud

et al. 2016

Upsala Journal of Medical Sciences

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Introduction Improving islet transplantation outcome could not only bring benefits to individual patients but also widen the patient pool to which this life-changing treatment is available. Imatinib has previously been shown to protect beta cells from apoptosis in a variety of in vitro and in vivo models. The aim of this study was to investigate whether imatinib could be used to improve islet transplantation outcome.Methods Islets were isolated from C57Bl/6 mice and pre-cultured with imatinib prior to exposure to streptozotocin and cytokines in vitro. Cell viability and glucose-induced insulin secretion were measured. For transplantation experiments, islets were pre-cultured with imatinib for either 72 h or 24 h prior to transplantation into streptozotocin-diabetic C57Bl/6 mice. In one experimental series mice were also administered imatinib after islet transplantation.Results Imatinib partially protected islets from beta cell death in vitro. However, pre-culturing islets in imatinib or administering the drug to the mice in the days following islet transplantation did not improve blood glucose concentrations more than control-cultured islets.Conclusion Although imatinib protected against beta cell death from cytokines and streptozotocin in vitro, it did not significantly improve syngeneic islet transplantation outcome.

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Assembly of bioactive multilayered nanocoatings on pancreatic islet cells: incorporation of α1-antitrypsin into the coatings

Cited by 14 publications

References 26 publications

An anionic, endosome-escaping polymer to potentiate intracellular delivery of cationic peptides, biomacromolecules, and nanoparticles

An anionic, endosome-escaping polymer to potentiate intracellular delivery of cationic peptides, biomacromolecules, and nanoparticles

Transplantation of PEGylated islets enhances therapeutic efficacy in a diabetic nonhuman primate model

Imatinib prevents beta cell deathin vitrobut does not improve islet transplantation outcome

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