Subcutaneous nanotherapy repurposes the immunosuppressive mechanism of rapamycin to enhance allogeneic islet graft viability

Burke, Jacqueline A.; Zhang, Xiaomin; Bobbala, Sharan; Frey, Molly; Fuentes, Carolina Bohorquez; Haddad, Helena; Allen, Shannon A.; Richardson, Reese A.K.; Amaral, Luís A. Nues; Scott, Evan A.

doi:10.1101/2020.09.03.281923

Cited by 3 publications

(6 citation statements)

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“…21,22,37 These systems have been extensively studied in terms of their sustained drug release kinetics, toxicity, and cell uptake both in vitro and in vivo. 22,30,39 In our previous study, we showed that an anti-integrin (anti-αvβ3) SDV heptapeptide bound to PEG-b-PPS MCs could efficiently inhibit angiogenesis with less peptide concentration in micellar form compared to the bare peptide. 37 This demonstrated the new approach where the targeting ligand can act as therapeutic moiety as well.…”

Section: Discussionmentioning

confidence: 99%

“…The PEG‐ b ‐PPS block‐copolymer is a versatile delivery platform that can self‐assemble into thermodynamically stable structures like MCs, polymersomes, and filomicelles 21,22,37 . These systems have been extensively studied in terms of their sustained drug release kinetics, toxicity, and cell uptake both in vitro and in vivo 22,30,39 . In our previous study, we showed that an anti‐integrin (anti‐αvβ3) SDV heptapeptide bound to PEG‐ b ‐PPS MCs could efficiently inhibit angiogenesis with less peptide concentration in micellar form compared to the bare peptide 37 .…”

Section: Discussionmentioning

confidence: 99%

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In vitro assessment of varying peptide surface density on the suppression of angiogenesis by micelles displaying αvβ3 blocking peptides

et al. 2022

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Ligand targeted therapy (LTT) is a precision medicine strategy that can selectively target diseased cells while minimizing off‐target effects on healthy cells. Integrin‐targeted LTT has been developed recently for angiogenesis‐related diseases. However, the clinical success is based on the optimal design of the nanoparticles for inducing receptor clustering within the cell membrane. The current study focused on determining the surface density of Ser‐Asp‐Val containing anti‐integrin heptapeptide on poly (ethylene glycol)‐b‐poly(propylene sulfide) micelles (MC) required for anti‐angiogenic effects on HUVECs. Varying peptide density on PEG‐b‐PPS/Pep‐PA MCs (Pep‐PA‐Peptide‐palmitoleic acid) was used in comparison to a random peptide (SGV) and cRGD (cyclic‐Arginine‐Glycine‐Aspartic acid) construct at 5%‐density on MCs. Immunocytochemistry using CD51/CD31 antibody was performed to study the integrin blocking by MCs. In addition, the expression of VWF and PECAM‐1, cell migration and tube formation was evaluated in the presence of PEG‐b‐PPS/Pep‐PA MCs. The results show PEG‐b‐PPS/SDV‐PA MCs with 5%‐peptide density to achieve significantly higher αvβ3 blocking compared to random peptide as well as cRGD. In addition, αvβ3 blocking via MCs further reduced the expression of vWF and PECAM‐1 angiogenesis protein expression in HUVECs. Although a significant level of integrin blocking was observed for 1%‐peptide density on MCs, the cell migration and tube formation were not significantly affected. In conclusion, the results of this study demonstrate that the peptide surface density on PEG‐b‐PPS/Pep‐PA MCs has a significant impact in integrin blocking as well as inhibiting angiogenesis during LTT. The outcomes of this study provides insight into the design of ligand targeted nanocarriers for various disease conditions.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

In vitro assessment of varying peptide surface density on the suppression of angiogenesis by micelles displaying αvβ3 blocking peptides

et al. 2022

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“…8 They synthesized a MECA79 monoclonal antibody (mAb)-coated NP that carries an anti-CD3 payload (MECA79-anti-CD3-NP). MECA-79-anti-CD3-NPs 15 Rapamycin is a potent immunosuppressive drug and, yet, is not readily used in the perioperative period due to a host of adverse side effects when administered systemically. 16 By encapsulating rapamycin in PS nanocarriers, rPS achieved antigen-specific tolerance for transplanted pancreatic islets in a major histocompatibility complex (MHC)-mismatched, allogeneic, intraportal (liver) transplantation model during the treatment of type I diabetes.…”

Section: Bahmani Et Al Reported On a Novel Intravascular Delivery Plat-mentioning

confidence: 99%

“…Typically, an immunosuppressive agent is encapsulated inside the NP, and cell or tissue targeted delivery is achieved by conjugating antibodies or aptamers or peptides or cyclic peptides on the surface of the NPs. Some examples of each NP developed and/or tested for transplantation are shown 8,9,12,14,15,[31][32][33][34] | 1295 AJT PLUMBLEE Et aL.…”

Section: F I G U R Ementioning

confidence: 99%

“…Burke et al designed poly(ethylene glycol)‐b‐poly(propylene sulfide) (PEG‐b‐PPS) polymersome (PS) nanocarriers for subcutaneous delivery of rapamycin (rPS) 15 . Rapamycin is a potent immunosuppressive drug and, yet, is not readily used in the perioperative period due to a host of adverse side effects when administered systemically 16 .…”

Section: Introductionmentioning

confidence: 99%

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Nanotherapeutics in transplantation: How do we get to clinical implementation?

Plumblee

Atkinson

Jaishankar

et al. 2022

American Journal of Transplantation

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Patients undergoing organ transplantation transition from one life‐altering issue (organ dysfunction) to a lifelong commitment—immunosuppression. Regimens of immunosuppressive agents (ISAs) come with significant side effects and comorbidities. Recently, the use of nanoparticles (NPs) as a solution to the problems associated with the long‐term and systemic use of ISAs in transplantation has emerged. This minireview describes the role of NPs in organ transplantation and discusses obstacles to clinical implementation and pathways to clinical translation.

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Targeted modulation of immune cells and tissues using engineered biomaterials

Yousefpour

Irvine

2023

Nat Rev Bioeng

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system. We focus on approaches targeting immune cells and lymphoid organs, excluding direct targeting of pathogens such as viruses or bacteria, followed by a discussion on prospects and challenges for developments in this area. Targeting lymphoid organsLymphoid organs coordinate the maturation and migration of immune cells while organizing and regulating immune responses (Fig. 1a). Primary lymphoid organs in adults include the bone marrow and thymus, which serve as niches for lymphocyte development. Secondary lymphoid organs -which include 600-800 lymph nodes distributed across the body, the spleen and the mucosa-associated lymphoid tissue -house and organize T cells, B cells and antigen-presenting cells (APCs). These organs serve as command centres of adaptive immunity where activation of naive B and T lymphocytes occurs (Fig. 1a,b) and are thus natural targets for vaccines and immunotherapies. Principles of lymph node targetingPassive targeting of therapeutics to lymphatic vessels. Lymph nodes interface with peripheral tissues through lymphatic vessels, which drain lymph fluid from all tissues and provide a conduit for immune cell trafficking. Drugs and vaccines can be targeted to lymph nodes through lymphatic uptake following parenteral injection. A major factor influencing lymphatic targeting is the physical size of the injected agents: following injection into tissue (including tumours), particles larger than 50-100 nm in diameter become trapped in the extracellular matrix (ECM), whereas particles in the size range of 5-50 nm convect with lymph into the lymphatic vessels and flow to draining lymph nodes (dLNs). By contrast, particles smaller than 5 nm partition preferentially into the blood rather than the lymph 9,10 (Fig. 2a). These approximate size ranges depend on the tissue site of injection (which can vary in ECM and lymphatic composition) and factors such as injection volume and rate (which can cause mechanical expansion of the flaps mediating entry into lymphatic vessels), especially in small-animal models, where tissue volume relative to injection volume is much smaller. Furthermore, particle shape, charge and surface chemistry can also play a part by promoting or hindering convection through the tissue and lymphatic entry 11 . Notably, capture of particles at the downstream dLN is a less studied but equally important prerequisite for lymph node modulation, as evidenced by data showing that proteins 12 and small hydrophilic nanoparticles 13 can pass through the entire lymphatic chain, reach the thoracic duct and enter the systemic circulation following a parenteral injection. In this regard, using adjuvants that promote compound entry into lymph nodes 14 , or designing carriers that stimulate recognition by macrophages lining the subcapsular and medullary sinuses, can prove useful 15 .Protein nanoparticles with surface-arrayed antigens and a size optimized for efficient lymphatic uptake enhance the immunogenicity of vaccines [16][17][18][19][20] . Protein nanoparticle vaccines are currently in clinic...

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Subcutaneous nanotherapy repurposes the immunosuppressive mechanism of rapamycin to enhance allogeneic islet graft viability

Cited by 3 publications

References 65 publications

In vitro assessment of varying peptide surface density on the suppression of angiogenesis by micelles displaying αvβ3 blocking peptides

In vitro assessment of varying peptide surface density on the suppression of angiogenesis by micelles displaying αvβ3 blocking peptides

Nanotherapeutics in transplantation: How do we get to clinical implementation?

Targeted modulation of immune cells and tissues using engineered biomaterials

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