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  • Engineering personalized peptide-based cancer nanovaccines Kakwere, H., Zhang, H., Kheirolomoom, A., Ferrara, K. AMER CHEMICAL SOC. 2019
  • Tumor-specific delivery of gemcitabine with activatable liposomes. Journal of controlled release : official journal of the Controlled Release Society Tucci, S. T., Kheirolomoom, A., Ingham, E. S., Mahakian, L. M., Tam, S. M., Foiret, J., Hubbard, N. E., Borowsky, A. D., Baikoghli, M., Cheng, R. H., Ferrara, K. W. 2019

    Abstract

    Gemcitabine delivery to pancreatic ductal adenocarcinoma is limited by poor pharmacokinetics, dense fibrosis and hypo-vascularization. Activatable liposomes, with drug release resulting from local heating, enhance serum stability and circulation, and the released drug retains the ability to diffuse within the tumor. A limitation of liposomal gemcitabine has been the low loading efficiency. To address this limitation, we used the superior solubilizing potential of copper (II) gluconate to form a complex with gemcitabine at copper:gemcitabine (1:4). Thermosensitive liposomes composed of DPPC:DSPC:DSPE-PEG2k (80:15:5, mole%) then reached 12?wt% loading, 4-fold greater than previously reported values. Cryo transmission electron microscopy confirmed the presence of a liquid crystalline gemcitabine?copper mixture. The optimized gemcitabine liposomes released 60% and 80% of the gemcitabine within 1 and 5?min, respectively, at 42?C. Liposomal encapsulation resulted in a circulation half-life of ~2?h in vivo (compared to reported circulation of 16?min for free gemcitabine in mice), and free drug was not detected within the plasma. The resulting gemcitabine liposomes were efficacious against both murine breast cancer and pancreatic cancer in vitro. Three repeated treatments of activatable gemcitabine liposomes plus ultrasound hyperthermia regressed or eliminated tumors in the neu deletion model of murine breast cancer with limited toxicity, enhancing survival when compared to treatment with gemcitabine alone. With 5% of the free gemcitabine dose (5 rather than 100?mg/kg), tumor growth was suppressed to the same degree as gemcitabine. Additionally, in a more aggressive tumor model of murine pancreatic cancer, liposomal gemcitabine combined with local hyperthermia induced cell death and regions of apoptosis and necrosis.

    View details for DOI 10.1016/j.jconrel.2019.07.014

    View details for PubMedID 31301340

  • Localized nanodelivery combined with immunotherapy promotes curative anti-tumor responses in a murine breast cancer model Kheirolomoom, A., Silvestrini, M. T., Ingham, E. S., Mahakian, L. M., Tam, S. M., Tumbale, S. K., Foiret, J., Hubbard, N. E., Borowsky, A. D., Murphy, W. J., Ferrara, K. W. AMER ASSOC CANCER RESEARCH. 2019
  • Activatable nanodelivery of high payload gemcitabine augments therapeutic efficacy in murine breast and pancreatic cancer models Tucci, S. T., Kheirolomoom, A., Ingham, E. S., Mahakian, L. M., Tam, S. M., Foiret, J., Hubbard, N. E., Borowsky, A. D., Baikoghli, M., Cheng, R., Ferrara, K. W. AMER ASSOC CANCER RESEARCH. 2019
  • Combining activatable nanodelivery with immunotherapy in a murine breast cancer model JOURNAL OF CONTROLLED RELEASE Kheirolomoom, A., Silvestrini, M. T., Ingham, E. S., Mahakian, L. M., Tam, S. M., Tumbale, S. K., Foiret, J., Hubbard, N. E., Borowsky, A. D., Ferrara, K. W. 2019; 303: 42?54
  • Combining activatable nanodelivery with immunotherapy in a murine breast cancer model. Journal of controlled release : official journal of the Controlled Release Society Kheirolomoom, A., Silvestrini, M. T., Ingham, E. S., Mahakian, L. M., Tam, S. M., Tumbale, S. K., Foiret, J., Hubbard, N. E., Borowsky, A. D., Ferrara, K. W. 2019

    Abstract

    A successful chemotherapy-immunotherapy solid-tumor protocol should accomplish the following goals: debulk large tumors, release tumor antigen for cross-presentation and cross-priming, release cancer-suppressive cytokines and enhance anti-tumor immune cell populations. Thermally-activated drug delivery particles have the potential to synergize with immunotherapeutics to accomplish these goals; activation can release chemotherapy within bulky solid tumors and can enhance response when combined with immunotherapy. We set out to determine whether a single protocol, combining locally-activated chemotherapy and agonist immunotherapy, could accomplish these goals and yield a potentially translational therapy. For effective delivery of free doxorubicin to tumors with minimal toxicity, we stabilized doxorubicin with copper in temperature-sensitive liposomes that rapidly release free drug in the vasculature of cancer lesions upon exposure to ultrasound-mediated hyperthermia. We found that in vitro exposure of tumor cells to hyperthermia and doxorubicin resulted in immunogenic cell death and the local release of type I interferons across murine cancer cell lines. Following intravenous injection, local activation of the liposomes within a single tumor released doxorubicin and enhanced cross-presentation of a model antigen at distant tumor sites. While a variety of protocols achieved a complete response in >50% of treated mice, the complete response rate was greatest (90%) when 1?week of immunotherapy priming preceded a single activatable chemotherapeutic administration. While repeated chemotherapeutic delivery reduced local viable tumor, the complete response rate and a subset of tumor immune cells were also reduced. Taken together, the results suggest that activatable chemotherapy can enhance adjuvant immunotherapy; however, in a murine model the systemic adaptive immune response was greatest with a single administration of chemotherapy.

    View details for PubMedID 30978432

  • A Scalable Method for Squalenoylation and Assembly of Multifunctional 64Cu-Labeled Squalenoylated Gemcitabine Nanoparticles. Nanotheranostics Tucci, S. T., Seo, J. W., Kakwere, H., Kheirolomoom, A., Ingham, E. S., Mahakian, L. M., Tam, S., Tumbale, S., Baikoghli, M., Cheng, R. H., Ferrara, K. W. 2018; 2 (4): 387?402

    Abstract

    Squalenoylation of gemcitabine, a front-line therapy for pancreatic cancer, allows for improved cellular-level and system-wide drug delivery. The established methods to conjugate squalene to gemcitabine and to form nanoparticles (NPs) with the squalenoylated gemcitabine (SqGem) conjugate are cumbersome, time-consuming and can be difficult to reliably replicate. Further, the creation of multi-functional SqGem-based NP theranostics would facilitate characterization of in vivo pharmacokinetics and efficacy. Methods: Squalenoylation conjugation chemistry was enhanced to improve reliability and scalability using tert-butyldimethylsilyl (TBDMS) protecting groups. We then optimized a scalable microfluidic mixing platform to produce SqGem-based NPs and evaluated the stability and morphology of select NP formulations using dynamic light scattering (DLS) and transmission electron microscopy (TEM). Cytotoxicity was evaluated in both PANC-1 and KPC (KrasLSL-G12D/+; Trp53LSL-R172H/+; Pdx-Cre) pancreatic cancer cell lines. A 64Cu chelator (2-S-(4-aminobenzyl)-1,4,7-triazacyclononane-1,4,7-triacetic acid, NOTA) was squalenoylated and used with positron emission tomography (PET) imaging to monitor the in vivo fate of SqGem-based NPs. Results: Squalenoylation yields of gemcitabine increased from 15% to 63%. Cholesterol-PEG-2k inclusion was required to form SqGem-based NPs using our technique, and additional cholesterol inclusion increased particle stability at room temperature; after 1 week the PDI of SqGem NPs with cholesterol was ~ 0.2 while the PDI of SqGem NPs lacking cholesterol was ~ 0.5. Similar or superior cytotoxicity was achieved for SqGem-based NPs compared to gemcitabine or Abraxane when evaluated at a concentration of 10 M. Squalenoylation of NOTA enabled in vivo monitoring of SqGem-based NP pharmacokinetics and biodistribution. Conclusion: We present a scalable technique for fabricating efficacious squalenoylated-gemcitabine nanoparticles and confirm their pharmacokinetic profile using a novel multifunctional 64Cu-SqNOTA-SqGem NP.

    View details for PubMedID 30324084

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