The three-dimensional (3D) tumor spheroid model is a critical tool for high-throughput ovarian cancer research and anticancer drug development in vitro. However, the 3D structure prevents high-resolution imaging of the inner side of the spheroids. We aim to visualize and characterize 3D morphological and physiological information of the contact multicellular ovarian tumor spheroids growing over time. We intend to further evaluate the distinctive evolutions of the tumor spheroid and necrotic tissue volumes in different cell numbers and determine the most appropriate mathematical model for fitting the growth of tumor spheroids and necrotic tissues. A label-free and noninvasive swept-source optical coherence tomography (SS-OCT) imaging platform was applied to obtain two-dimensional (2D) and 3D morphologies of ovarian tumor spheroids over 18 days. Ovarian tumor spheroids of two different initial cell numbers (5,000- and 50,000- cells) were cultured and imaged (each day) over the time of growth in 18 days. Four mathematical models (Exponential-Linear, Gompertz, logistic, and Boltzmann) were employed to describe the growth kinetics of the tumor spheroids volume and necrotic tissues. Ovarian tumor spheroids have different growth curves with different initial cell numbers and their growths contain different stages with various growth rates over 18 days. The volumes of 50,000-cells spheroids and the corresponding necrotic tissues are larger than that of the 5,000-cells spheroids. The formation of necrotic tissue in 5,000-cells numbers is slower than that in the 50,000-cells ones. Moreover, the Boltzmann model exhibits the best fitting performance for the growth of tumor spheroids and necrotic tissues. Optical coherence tomography (OCT) can serve as a promising imaging modality to visualize and characterize morphological and physiological features of multicellular ovarian tumor spheroids. The Boltzmann model integrating with 3D OCT data of ovarian tumor spheroids provides great potential for high-throughput cancer research in vitro and aiding in drug development.
Immunotherapy has provided a new avenue to treat metastatic cancers, which result in ∼90% of cancer related deaths. However, current immunotherapies, such as immune checkpoint therapy (ICT), have met with limited success, primarily due to tumor intrinsic and extrinsic factors that inhibit antitumor immune responses. To overcome the immune suppression of the tumor microenvironment (TME) and enhance the tumoricidal activity of ICT, phototherapy, particularly photothermal therapy (PTT), combined with nanomedicine has become a viable option. PTT disrupts target tumor homeostasis, releasing tumor associated antigens (TAAs), tumor specific antigens (TSAs), danger associated molecular patterns (DAMPs), and scarce nutrients required to “feed” activated antitumor immune cells. While nanoparticles localize and specify the phototherapeutic effect, they can also be loaded with immune stimulants, TME modulators, and/or chemotherapeutic agents to greatly enhance immune stimulation and tumor killing. Combining these three technologies, which we term nano-ablative immunotherapy (NAIT), with ICT can greatly enhance their therapeutic effects. In this review, we will discuss the successes and limitations of NAIT + ICT. Specifically, we will discuss how the TME limits tumoricidal activity and what should be considered to overcome these limitations.
Mucosal vaccinations for respiratory pathogens provide superior protection as they stimulate localized cellular and humoral immunity at the site of infection. Currently, the major limitation of the intranasal vaccination is using effective adjuvants capable of withstanding the harsh environment imposed by the mucosa. Herein, we describe the efficacy of using a novel biopolymer, N-dihydrogalactochitosan (GC), as a nasal mucosal vaccine adjuvant against respiratory infections. Specifically, using COVID as an example, we mixed GC with recombinant SARS-CoV-2 trimeric spike (S) and nucleocapsid (NC) proteins to intranasally vaccinate K18-hACE2 transgenic mice, in comparison with Addavax (AV), an MF-59 equivalent. In contrast to AV, intranasal application of GC induces a robust, systemic antigen-specific antibody response and increases the number of T cells in the cervical lymph nodes. Moreover, GC+S+NC vaccinated animals were largely resistant to lethal SARS-CoV-2 challenge and experienced drastically reduced morbidity and mortality, with the animal weights and behavior returning to normal 22 days post infection. In contrast, animals intranasally vaccinated by AV+S+NC experienced severe weight loss, mortality, and respiratory distress, with none surviving beyond 6 days post infection. Our findings demonstrate that GC can serve as a potent mucosal vaccine adjuvant against SARS-CoV-2 and potentially other respiratory viruses.
N-dihydrogalactochitosan (GC) is developed for inducing immune responses. Synthesized from chitosan and galactose, GC is a new chemical entity that significantly enhances the immune-stimulating properties of its parental material, chitosan, making it a promising therapeutic agent. When used in combination with antigenic material, GC stimulates innate and adaptive antitumor and antiviral immunities. However, the mechanism of GC has not been fully investigated. Herein we demonstrate that GC drives type I IFN production and IFN responses in antigen presenting cells (APCs) and has superior potency compared to its corresponding chitosan. More importantly, GC drives alternative activation of STING leading to inflammatory cell death that enhances dendritic cell (DC) activation, which triggers a variety of nucleic acid sensing pattern recognition receptors (PRRs) and IL-1b production. In vivo, GC induced a potent response of type I IFN and upregulated genes associated with STING signaling within the tumor microenvironment (TME). Moreover, intratumoral delivery of GC reduced the numbers of M2-like macrophages residing within the TME, while subsequently increasing the number of DCs. Our findings demonstrate GC's unique ability to activate STING and stimulate a broad type I IFN response which holds therapeutic promise in generating antitumor and antiviral immunities.
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