Dendritic nanoconjugates for intracellular delivery of neutral oligonucleotides

Conjugation of neutral oligonucleotides (ONs) with PAMAM dendrimers resulted in ultra-small nanoconjugates that combine superior ON delivery and reduced cytotoxicity

Clinical Translation of Nanomedicine

[Image: see text

Folate-targeted pH-responsive calcium zoledronate nanoscale metal-organic frameworks: Turning a bone antiresorptive agent into an anticancer therapeutic

Zoledronate (Zol) is a third-generation bisphosphonate that is widely used as an anti-resorptive agent for the treatment of cancer bone metastasis. While there is preclinical data indicating that bisphosphonates such as Zol have direct cytotoxic effects on cancer cells, such effect has not been firmly established in the clinical setting. This is likely due to the rapid absorption of bisphosphonates by the skeleton after intravenous (i.v.) administration. Herein, we report the reformulation of Zol using nanotechnology and evaluation of this novel nanoscale metal-organic frameworks (nMOFs) formulation of Zol as an anticancer agent. The nMOF formulation is comprised of a calcium zoledronate (CaZol) core and a polyethylene glycol (PEG) surface. To preferentially deliver CaZol nMOFs to tumors as well as facilitate cellular uptake of Zol, we incorporated folate (Fol)-targeted ligands on the nMOFs. The folate receptor (FR) is known to be overexpressed in several tumor types, including head-and-neck, prostate, and non-small cell lung cancers. We demonstrated that these targeted CaZol nMOFs possess excellent chemical and colloidal stability in physiological conditions. The release of encapsulated Zol from the nMOFs occurs in the mid-endosomes during nMOF endocytosis. In vitro toxicity studies demonstrated that Fol-targeted CaZol nMOFs are more efficient than small molecule Zol in inhibiting cell proliferation and inducing apoptosis in FR-overexpressing H460 non-small cell lung and PC3 prostate cancer cells. Our findings were further validated in vivo using mouse xenograft models of H460 and PC3. We demonstrated that Fol-targeted CaZol nMOFs are effective anticancer agents and increase the direct antitumor activity of Zol by 80-85% in vivo through inhibition of tumor neovasculature, and inhibiting cell proliferation and inducing apoptosis

Direct Observation of Early-Stage High-Dose Radiotherapy-Induced Vascular Injury via Basement Membrane-Targeting Nanoparticles

Collagen IV-targeting peptide-conjugated basement membrane-targeting nanoparticles are successfully engineered to identify early-stage blood vessel injury induced by high-dose radiotherapy

Author Correction: Antigen-capturing nanoparticles improve the abscopal effect and cancer immunotherapy

A Correction to this paper has been published: https://doi.org/10.1038/s41565-021-00864-w

Antigen-capturing nanoparticles improve the abscopal effect and cancer immunotherapy

Immunotherapy holds tremendous promise for improving cancer treatment1. Administering radiotherapy with immunotherapy has been shown to improve immune responses and can elicit an “abscopal effect”2. Unfortunately, response rates for this strategy remain low3. Herein, we report an improved cancer immunotherapy approach that utilizes antigen-capturing nanoparticles (AC-NPs). We engineered several AC-NPs formulations and demonstrated that the set of protein antigens captured by each AC-NP formulation is dependent upon NP surface properties. We showed that AC-NPs deliver tumor specific proteins to antigen-presenting cells and significantly improve the efficacy of αPD-1 treatment using the B16F10 melanoma model, generating up to 20% cure rate as compared to 0% without AC-NPs. Mechanistic studies revealed that AC-NPs induced an expansion of CD8+ cytotoxic T cells and increased both CD4+/Treg and CD8+/Treg ratios. Our work presents a novel strategy for improving cancer immunotherapy with nanotechnology

Nanoparticle formulations of histone deacetylase inhibitors for effective chemoradiotherapy in solid tumors

Histone deacetylase inhibitors (HDACIs) represent a class of promising agents that can improve radiotherapy in cancer treatment. However, the full therapeutic potential of HDACIs as radiosensitizers has been restricted by limited efficacy in solid malignancies. In this study, we report the development of nanoparticle (NP) formulations of HDACIs that overcome these limitations, illustrating their utility to improve the therapeutic ratio of the clinically established first generation HDACI vorinostat and a novel second generation HDACI quisinostat. We demonstrate that NP HDACIs are potent radiosensitizers in vitro and are more effective as radiosensitizers than small molecule HDACIs in vivo using mouse xenograft models of colorectal and prostate carcinomas. We found that NP HDACIs enhance the response of tumor cells to radiation through the prolongation of γ-H2AX foci. Our work illustrates an effective method for improving cancer radiotherapy treatment

Abstract 3685: Antigen-capturing nanoparticles improve the abscopal effect and cancer immunotherapy

Abstract Introduction Cancer immunotherapy, the utilization of patients’ own immune system to treat cancer, has emerged as a powerful new strategy in cancer treatment. The main limitation of this strategy is the low long-term durable response rate. Therefore, there has been high interest in developing strategies to further improve cancer immunotherapy. We hypothesized that antigen-capturing nanoparticles (AC-NPs) could improve immune responses to checkpoint inhibitor. The NPs can induce the abscopal effect by capturing tumor antigens released during radiotherapy and improve the presentation of antigens to professional antigen presenting cells (APCs). Methods We developed several types of antigen-capturing NPs (AC-NPs) using poly (lactic-co-glycolic acid) (PLGA), a biocompatible and biodegradable polymer. The surfaces of nanoparticles were modified to enable capturing tumor antigens released after radiotherapy. Unmodified PLGA NPs absorb antigens via hydrophobic-hydrophobic interactions. AC-NPs with positive charged bind antigens through ionic interactions. AC-NPs having maleimide group on the surface (Mal AC-NP) bind to antigens by reaction to thiol groups of antigens. The B16-F10 tumor, a syngeneic mouse melanoma model on C57BL/6 mice was employed to evaluate the efficacy of AC-NPs to improve immune responses of checkpoint inhibitor combining radiotherapy. Results The in vivo efficacy study showed that AC-NPs can significantly improve the efficacy of αPD-1 treatment in the B10F10 melanoma model, which generates up to 20% cure rate as compared to 0% without AC-NP. Mechanistic studies demonstrated that the AC-NPs can drain to lymph node and be took up by APCs, which indicate that they are able to deliver captured antigens during radiotherapy to APCs. In the meantime, it was found that there are significant increases in CD4+ and CD8+ T cell to Treg ratios, which indicate an expansion of the T-helper cells and cytotoxic T cells. We also found that AC-NPs can induce increased level of antitumor cytokine interferon-γ (IFN-γ) following stimulation ex vivo, which implied that AC-NPs were able to elicit systemic T cell activation. Therefore, a novel strategy for improving cancer immunotherapy with nanotechnology was presented by our work. Acknowledgements The authors would also like to thank our funding sources. A.Z.W., J.E.T., S.T., and J.M.D are supported by funding from the National Institutes of Health/National Cancer Institute (U54CA198999, Carolina Center of Cancer Nanotechnology Excellence (CCNE)-Nano Approaches to Modulate Host Cell Response for Cancer Therapy). B.V. is supported by funding from UNC University Cancer Research Fund, Paul Calabresi Oncology K12 Award and UNC CCNE Pilot Grant. A.Z.W. is also supported by funding from the NIH/NCI (U54 CA151652 and R01 CA178748) for this work. A.Z.W. was also supported by funding from the NIH/NCI (R21 CA182322). Citation Format: Yuanzeng Min. Antigen-capturing nanoparticles improve the abscopal effect and cancer immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3685. doi:10.1158/1538-7445.AM2017-3685</jats:p

Advances in Nanotechnology Development to Overcome Current Roadblocks in CAR-T Therapy for Solid Tumors

Chimeric antigen receptor T cell (CAR-T) therapy for the treatment of hematologic tumors has achieved remarkable success, with five CAR-T therapies approved by the United States Food and Drug Administration. However, the efficacy of CAR-T therapy against solid tumors is not satisfactory. There are three existing hurdles in CAR-T cells for solid tumors. First, the lack of a universal CAR to recognize antigens at the site of solid tumors and the compact tumor structure make it difficult for CAR-T cells to locate in solid tumors. Second, soluble inhibitors and suppressive immune cells in the tumor microenvironment can inhibit or even inactivate T cells. Third, low survival and proliferation rates of CAR-T cells in vivo significantly influence the therapeutic effect. As an emerging method, nanotechnology has a great potential to enhance cell proliferation, activate T cells, and restarting the immune response. In this review, we discuss how nanotechnology can modify CAR-T cells through variable methods to improve the therapeutic effect of solid tumors.</jats:p