{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T13:40:54Z","timestamp":1790948454806,"version":"4.1.0"},"reference-count":64,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2023,8,26]],"date-time":"2023-08-26T00:00:00Z","timestamp":1693008000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Texas Tech University Health Sciences Center (TTUHSC) Office of Research","award":["RP170003"],"award-info":[{"award-number":["RP170003"]}]},{"name":"Texas Tech University Health Sciences Center (TTUHSC) Office of Research","award":["CA190209"],"award-info":[{"award-number":["CA190209"]}]},{"DOI":"10.13039\/100004917","name":"Cancer Prevention Research Institute of Texas Core","doi-asserted-by":"publisher","award":["RP170003"],"award-info":[{"award-number":["RP170003"]}],"id":[{"id":"10.13039\/100004917","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100004917","name":"Cancer Prevention Research Institute of Texas Core","doi-asserted-by":"publisher","award":["CA190209"],"award-info":[{"award-number":["CA190209"]}],"id":[{"id":"10.13039\/100004917","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000054","name":"National Institute of Health","doi-asserted-by":"publisher","award":["RP170003"],"award-info":[{"award-number":["RP170003"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000054","name":"National Institute of Health","doi-asserted-by":"publisher","award":["CA190209"],"award-info":[{"award-number":["CA190209"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>While tumor-associated macrophages (TAM) have pro-tumoral activity, the ablation of macrophages in cancer may be undesirable since they also have anti-tumoral functions, including T cell priming and activation against tumor antigens. Alendronate is a potent amino-bisphosphonate that modulates the function of macrophages in vitro, with potential as an immunotherapy if its low systemic bioavailability can be addressed. We repurposed alendronate in a non-leaky and long-circulating liposomal carrier similar to that of the clinically approved pegylated liposomal doxorubicin to facilitate rapid clinical translation. Here, we tested liposomal alendronate (PLA) as an immunotherapeutic agent for cancer in comparison with a standard of care immunotherapy, a PD-1 immune checkpoint inhibitor. We showed that the PLA induced bone marrow-derived murine non-activated macrophages and M2-macrophages to polarize towards an M1-functionality, as evidenced by gene expression, cytokine secretion, and lipidomic profiles. Free alendronate had negligible effects, indicating that liposome encapsulation is necessary for the modulation of macrophage activity. In vivo, the PLA showed significant accumulation in tumor and tumor-draining lymph nodes, sites of tumor immunosuppression that are targets of immunotherapy. The PLA remodeled the tumor microenvironment towards a less immunosuppressive milieu, as indicated by a decrease in TAM and helper T cells, and inhibited the growth of established tumors in the B16-OVA melanoma model. The improved bioavailability and the beneficial effects of PLA on macrophages suggest its potential application as immunotherapy that could synergize with T-cell-targeted therapies and chemotherapies to induce immunogenic cell death. PLA warrants further clinical development, and these clinical trials should incorporate tumor and blood biomarkers or immunophenotyping studies to verify the anti-immunosuppressive effect of PLA in humans.<\/jats:p>","DOI":"10.3390\/biom13091309","type":"journal-article","created":{"date-parts":[[2023,8,28]],"date-time":"2023-08-28T01:56:57Z","timestamp":1693187817000},"page":"1309","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Pegylated Liposomal Alendronate Biodistribution, Immune Modulation, and Tumor Growth Inhibition in a Murine Melanoma Model"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2226-3333","authenticated-orcid":false,"given":"Md. Rakibul","family":"Islam","sequence":"first","affiliation":[{"name":"Department of Immunotherapeutics and Biotechnology, Jerry H. Hodge School of Pharmacy, Texas Tech University Health Sciences Center, Abilene, TX 79601, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jalpa","family":"Patel","sequence":"additional","affiliation":[{"name":"Department of Immunotherapeutics and Biotechnology, Jerry H. Hodge School of Pharmacy, Texas Tech University Health Sciences Center, Abilene, TX 79601, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0137-1976","authenticated-orcid":false,"given":"Patricia Ines","family":"Back","sequence":"additional","affiliation":[{"name":"Department of Immunotherapeutics and Biotechnology, Jerry H. Hodge School of Pharmacy, Texas Tech University Health Sciences Center, Abilene, TX 79601, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hilary","family":"Shmeeda","sequence":"additional","affiliation":[{"name":"Nano-Oncology Research Center, Oncology Institute, Shaare Zedek Medical Center, Jerusalem 9103102, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raja Reddy","family":"Kallem","sequence":"additional","affiliation":[{"name":"Department of Pharmacy Practice, Jerry H. Hodge School of Pharmacy, Texas Tech University Health Sciences Center, Abilene, TX 79601, USA"},{"name":"Clinical Pharmacology and Experimental Therapeutics Center, Jerry H. Hodge School of Pharmacy, Texas Tech University Health Sciences Center, Dallas, TX 75235, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2099-0131","authenticated-orcid":false,"given":"Claire","family":"Shudde","sequence":"additional","affiliation":[{"name":"Department of Immunotherapeutics and Biotechnology, Jerry H. Hodge School of Pharmacy, Texas Tech University Health Sciences Center, Abilene, TX 79601, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maciej","family":"Markiewski","sequence":"additional","affiliation":[{"name":"Department of Immunotherapeutics and Biotechnology, Jerry H. Hodge School of Pharmacy, Texas Tech University Health Sciences Center, Abilene, TX 79601, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William C.","family":"Putnam","sequence":"additional","affiliation":[{"name":"Department of Pharmacy Practice, Jerry H. Hodge School of Pharmacy, Texas Tech University Health Sciences Center, Abilene, TX 79601, USA"},{"name":"Clinical Pharmacology and Experimental Therapeutics Center, Jerry H. Hodge School of Pharmacy, Texas Tech University Health Sciences Center, Dallas, TX 75235, USA"},{"name":"Department of Pharmaceutical Science, Jerry H. Hodge School of Pharmacy, Texas Tech University Health Sciences Center, Dallas, TX 75235, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1332-1164","authenticated-orcid":false,"given":"Alberto A.","family":"Gabizon","sequence":"additional","affiliation":[{"name":"Nano-Oncology Research Center, Oncology Institute, Shaare Zedek Medical Center, Jerusalem 9103102, Israel"},{"name":"Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem 9112102, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ninh M.","family":"La-Beck","sequence":"additional","affiliation":[{"name":"Department of Immunotherapeutics and Biotechnology, Jerry H. Hodge School of Pharmacy, Texas Tech University Health Sciences Center, Abilene, TX 79601, USA"},{"name":"Department of Pharmacy Practice, Jerry H. Hodge School of Pharmacy, Texas Tech University Health Sciences Center, Abilene, TX 79601, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,8,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2095","DOI":"10.1172\/JCI115539","article-title":"Bisphosphonate action. Alendronate localization in rat bone and effects on osteoclast ultrastructure","volume":"88","author":"Sato","year":"1991","journal-title":"J. Clin. Investig."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"2692","DOI":"10.1172\/JCI118722","article-title":"Bisphosphonates: Mechanisms of action","volume":"97","author":"Rodan","year":"1996","journal-title":"J. Clin. 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