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  1. Article ; Online: Liposomal Targeting Modifies Endosomal Escape: Design and Mechanistic Implications.

    Mejia, Franklin / Khan, Sabrina / Bilgicer, Basar

    ACS biomaterials science & engineering

    2022  Volume 8, Issue 3, Page(s) 1067–1073

    Abstract: Development of effective targeted nanoparticle (TNP) therapeutics requires rational design of targeted and endosomolytic moieties. Nevertheless, endosomal escape of TNPs is poorly understood, relying on extrapolation of knowledge from nontargeted (NP) ... ...

    Abstract Development of effective targeted nanoparticle (TNP) therapeutics requires rational design of targeted and endosomolytic moieties. Nevertheless, endosomal escape of TNPs is poorly understood, relying on extrapolation of knowledge from nontargeted (NP) systems. Here, we describe how incorporation of targeting elements on endosomolytic nanoparticles alters the endosomal escape mechanism. We demonstrated that NP and TNP systems react differently to addition of precise length oligohistidines and showcase the effects of alternating spatial arrangements of targeting and endosomolytic elements. The results established that these elements act cooperatively and must be incorporated as individual moieties, rather than a single multifunctional moiety, for optimal internalization by target cells.
    MeSH term(s) Endosomes/metabolism ; Liposomes/metabolism ; Liposomes/pharmacology ; Nanoparticles/therapeutic use
    Chemical Substances Liposomes
    Language English
    Publishing date 2022-02-16
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ISSN 2373-9878
    ISSN (online) 2373-9878
    DOI 10.1021/acsbiomaterials.2c00100
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Determination of immunogenic epitopes in major house dust mite allergen, Der p 2, via nanoallergens.

    Sjoerdsma, Jenna / Mejia, Franklin / Bilgicer, Basar

    Annals of allergy, asthma & immunology : official publication of the American College of Allergy, Asthma, & Immunology

    2022  Volume 129, Issue 2, Page(s) 231–240.e2

    Abstract: Background: Despite the high prevalence of allergic asthma, currently, avoidance of the responsible allergens, which is nearly impossible for allergens such as house dust mite (HDM), remains among the most effective treatment. Consequently, ... ...

    Abstract Background: Despite the high prevalence of allergic asthma, currently, avoidance of the responsible allergens, which is nearly impossible for allergens such as house dust mite (HDM), remains among the most effective treatment. Consequently, determination of the immunogenic epitopes of allergens will aid in developing a better understanding of the condition for diagnostic and therapeutic purposes. Current methods of epitope identification, however, only evaluate immunoglobulin E-epitope binding interactions, which is not directly related to epitope immunogenicity.
    Objective: To determine and rank the immunogenicity of the epitopes of major HDM allergen, Der p 2.
    Methods: We performed degranulation assays with RBL-SX38 cells primed using patient plasma and challenged with nanoallergens which multivalently displayed epitopes to study the relative immunogenicity of various epitopes of Der p 2. Nanoallergens were used to evaluate epitopes individually or in combination.
    Results: When evaluated using 3 patient samples, 3 epitopes in 2 distal regions of Der p 2 were identified as highly immunogenic when presented in combination, whereas no individual epitope triggered relevant degranulation. One of the epitopes (69-DPNACHYMKCPLVKGQQY-86) was identified to be cooperatively immunogenic when combined with other epitopes.
    Conclusion: Our study highlights the importance of conformational epitopes in HDM-related allergies. This study also provides further evidence of the versatility of nanoallergens and their value for functional characterization of allergy epitopes, by ranking the Der p 2 epitopes according to immunogenicity. We believe that nanoallergens, by aiding in identification and understanding of immunogenic epitopes, will provide a better understanding of the manifestation of the allergic condition and potentially aid in developing new treatments.
    MeSH term(s) Allergens ; Animals ; Antigens, Dermatophagoides ; Arthropod Proteins ; Dust ; Epitopes/chemistry ; Humans ; Pyroglyphidae
    Chemical Substances Allergens ; Antigens, Dermatophagoides ; Arthropod Proteins ; Dermatophagoides pteronyssinus antigen p 2 ; Dust ; Epitopes
    Language English
    Publishing date 2022-04-09
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 1228189-x
    ISSN 1534-4436 ; 0003-4738 ; 1081-1206
    ISSN (online) 1534-4436
    ISSN 0003-4738 ; 1081-1206
    DOI 10.1016/j.anai.2022.04.003
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Identification and optimization of tunable endosomal escape parameters for enhanced efficacy in peptide-targeted prodrug-loaded nanoparticles.

    Mejia, Franklin / Khan, Sabrina / Omstead, David T / Minetos, Christina / Bilgicer, Basar

    Nanoscale

    2022  Volume 14, Issue 4, Page(s) 1226–1240

    Abstract: Endosomal escape of nanoparticles (NPs) is a weighty consideration for engineering successful nanomedicines. Although it is well-established that incorporation of histidine (His) in particle design improves endosomal escape for NPs, our understanding of ... ...

    Abstract Endosomal escape of nanoparticles (NPs) is a weighty consideration for engineering successful nanomedicines. Although it is well-established that incorporation of histidine (His) in particle design improves endosomal escape for NPs, our understanding of its effects for ligand-targeted nanoparticles (TNPs) remains incomplete. Here, we systematically evaluated the cooperativity between targeting ligands and endosomolytic elements using liposomal TNPs with precise stoichiometric control over functional moieties (>90% loading efficiency). We synthesized endosomolytic lipid conjugates consisting of 1 to 10 consecutive His residues presented at the end of linkers between 2 to 45 repeating units of ethylene glycol (His
    MeSH term(s) Drug Delivery Systems ; Endosomes ; Nanoparticles ; Peptides ; Prodrugs/pharmacology
    Chemical Substances Peptides ; Prodrugs
    Language English
    Publishing date 2022-01-27
    Publishing country England
    Document type Journal Article
    ZDB-ID 2515664-0
    ISSN 2040-3372 ; 2040-3364
    ISSN (online) 2040-3372
    ISSN 2040-3364
    DOI 10.1039/d1nr05357d
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: A nanotherapeutic approach to selectively eliminate metastatic breast cancer cells by targeting cell surface GRP78.

    Shin, Jaeho / Kim, Baksun / Lager, Tyson W / Mejia, Franklin / Guldner, Ian / Conner, Clay / Zhang, Siyuan / Panopoulos, Athanasia D / Bilgicer, Basar

    Nanoscale

    2023  Volume 15, Issue 32, Page(s) 13322–13334

    Abstract: Here, rational engineering of doxorubicin prodrug loaded peptide-targeted liposomal nanoparticles to selectively target metastatic breast cancer ... ...

    Abstract Here, rational engineering of doxorubicin prodrug loaded peptide-targeted liposomal nanoparticles to selectively target metastatic breast cancer cells
    MeSH term(s) Animals ; Mice ; Endoplasmic Reticulum Chaperone BiP ; Membrane Proteins ; Cell Line, Tumor ; Prodrugs ; Glucose ; Peptides ; Doxorubicin/pharmacology ; Neoplasms
    Chemical Substances Endoplasmic Reticulum Chaperone BiP ; Membrane Proteins ; Prodrugs ; Glucose (IY9XDZ35W2) ; Peptides ; Doxorubicin (80168379AG)
    Language English
    Publishing date 2023-08-17
    Publishing country England
    Document type Journal Article
    ZDB-ID 2515664-0
    ISSN 2040-3372 ; 2040-3364
    ISSN (online) 2040-3372
    ISSN 2040-3364
    DOI 10.1039/d3nr00800b
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  5. Article ; Online: Supramolecular Assemblies for Macrophage Activation in Cancer Therapy.

    Mejia, Franklin / Kiziltepe, Tanyel / Bilgicer, Basar

    Trends in cancer

    2018  Volume 4, Issue 11, Page(s) 713–714

    Abstract: Recently, immunotherapy has emerged as a potential, possibly safer, alternative to more traditional chemotherapeutic treatments. Nevertheless, combating the tumor microenvironment (TME) and reactivating the immune system is not without complications. A ... ...

    Abstract Recently, immunotherapy has emerged as a potential, possibly safer, alternative to more traditional chemotherapeutic treatments. Nevertheless, combating the tumor microenvironment (TME) and reactivating the immune system is not without complications. A recent report suggests a rationally designed supramolecular assembly to offer a solution to this problem.
    MeSH term(s) Animals ; Immunotherapy ; Macrophage Activation ; Neoplasms/immunology ; Neoplasms/therapy
    Language English
    Publishing date 2018-10-05
    Publishing country United States
    Document type Journal Article
    ZDB-ID 2852626-0
    ISSN 2405-8025 ; 2405-8033 ; 2405-8033
    ISSN (online) 2405-8025 ; 2405-8033
    ISSN 2405-8033
    DOI 10.1016/j.trecan.2018.09.008
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  6. Article ; Online: Disease-driven engineering of peptide-targeted DM1 loaded liposomal nanoparticles for enhanced efficacy in treating multiple myeloma by exploring DM1 prodrug chemistry.

    Khan, Sabrina / Mejia, Franklin / Shin, Jaeho / Hwang, Gyoyeon / Omstead, David T / Wu, Junmin / Cole, Sara L / Littlepage, Laurie E / Bilgicer, Basar

    Biomaterials

    2022  Volume 292, Page(s) 121913

    Abstract: Here, we report a CD138 receptor targeting liposomal formulation (TNP[Prodrug-4]) that achieved efficacious tumor growth inhibition in treating multiple myeloma by overcoming the dose limiting severe toxicity issues of a highly potent drug, Mertansine ( ... ...

    Abstract Here, we report a CD138 receptor targeting liposomal formulation (TNP[Prodrug-4]) that achieved efficacious tumor growth inhibition in treating multiple myeloma by overcoming the dose limiting severe toxicity issues of a highly potent drug, Mertansine (DM1). Despite the promising potential to treat various cancers, due to poor solubility and pharmacokinetic profile, DM1's translation to the clinic has been unsatisfactory. We hypothesized that the optimal prodrug chemistry would promote efficient loading of the prodrug into targeted nanoparticles and achieve controlled release following endocytosis by the cancer cells, consequently, accomplish the most potent tumor growth inhibition. We evaluated four functional linker chemistries for synthesizing DM1-Prodrug molecules and evaluated their stability and cancer cell toxicity in vitro. It was determined that the phosphodiester moiety, as part of nanoparticle formulations, demonstrated most favorable characteristics with an IC
    MeSH term(s) Humans ; Prodrugs/chemistry ; Multiple Myeloma/drug therapy ; Maytansine/therapeutic use ; Maytansine/pharmacology ; Nanoparticles/chemistry ; Liposomes ; Peptides ; Cell Line, Tumor
    Chemical Substances Prodrugs ; Maytansine (14083FR882) ; Liposomes ; Peptides
    Language English
    Publishing date 2022-11-18
    Publishing country Netherlands
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 603079-8
    ISSN 1878-5905 ; 0142-9612
    ISSN (online) 1878-5905
    ISSN 0142-9612
    DOI 10.1016/j.biomaterials.2022.121913
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    Zs.B 2371: Show issues Location:
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  7. Article ; Online: In vivo evaluation of CD38 and CD138 as targets for nanoparticle-based drug delivery in multiple myeloma.

    Omstead, David T / Mejia, Franklin / Sjoerdsma, Jenna / Kim, Baksun / Shin, Jaeho / Khan, Sabrina / Wu, Junmin / Kiziltepe, Tanyel / Littlepage, Laurie E / Bilgicer, Basar

    Journal of hematology & oncology

    2020  Volume 13, Issue 1, Page(s) 145

    Abstract: Background: Drug-loaded nanoparticles have established their benefits in the fight against multiple myeloma; however, ligand-targeted nanomedicine has yet to successfully translate to the clinic due to insufficient efficacies reported in preclinical ... ...

    Abstract Background: Drug-loaded nanoparticles have established their benefits in the fight against multiple myeloma; however, ligand-targeted nanomedicine has yet to successfully translate to the clinic due to insufficient efficacies reported in preclinical studies.
    Methods: In this study, liposomal nanoparticles targeting multiple myeloma via CD38 or CD138 receptors are prepared from pre-synthesized, purified constituents to ensure increased consistency over standard synthetic methods. These nanoparticles are then tested both in vitro for uptake to cancer cells and in vivo for accumulation at the tumor site and uptake to tumor cells. Finally, drug-loaded nanoparticles are tested for long-term efficacy in a month-long in vivo study by tracking tumor size and mouse health.
    Results: The targeted nanoparticles are first optimized in vitro and show increased uptake and cytotoxicity over nontargeted nanoparticles, with CD138-targeting showing superior enhancement over CD38-targeted nanoparticles. However, biodistribution and tumor suppression studies established CD38-targeted nanoparticles to have significantly increased in vivo tumor accumulation, tumor cell uptake, and tumor suppression over both nontargeted and CD138-targeted nanoparticles due to the latter's poor selectivity.
    Conclusion: These results both highlight a promising cancer treatment option in CD38-targeted nanoparticles and emphasize that targeting success in vitro does not necessarily translate to success in vivo.
    MeSH term(s) ADP-ribosyl Cyclase 1/chemistry ; ADP-ribosyl Cyclase 1/metabolism ; Animals ; Antibiotics, Antineoplastic/administration & dosage ; Antibiotics, Antineoplastic/pharmacokinetics ; Cell Line, Tumor ; Doxorubicin/administration & dosage ; Doxorubicin/pharmacokinetics ; Drug Delivery Systems ; Humans ; Liposomes/chemistry ; Liposomes/metabolism ; Male ; Mice ; Mice, Inbred NOD ; Mice, SCID ; Molecular Docking Simulation ; Multiple Myeloma/drug therapy ; Multiple Myeloma/metabolism ; Peptides/chemistry ; Peptides/metabolism ; Syndecan-1/chemistry ; Syndecan-1/metabolism ; Tissue Distribution
    Chemical Substances Antibiotics, Antineoplastic ; Liposomes ; Peptides ; Syndecan-1 ; Doxorubicin (80168379AG) ; ADP-ribosyl Cyclase 1 (EC 3.2.2.6)
    Language English
    Publishing date 2020-11-02
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2429631-4
    ISSN 1756-8722 ; 1756-8722
    ISSN (online) 1756-8722
    ISSN 1756-8722
    DOI 10.1186/s13045-020-00965-4
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