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Role of Immunosuppressive Microenvironment in Acquiring Immunotolerance Post-Photothermal Therapy
Kondareddy Cherukula,박명숙,Adonijah Graham Sontyana,Ansuja Pulickal Mathew,Veena Vijayan,배우균,박인규 대한의학회 2019 Journal of Korean medical science Vol.34 No.44
Background: Nanoparticle-mediated photothermal therapy (PTT) has been well studied as a treatment for cancer. However, the therapeutic outcome of PTT is often hindered by the penetration depth of laser light. In the tumor margin beyond the laser penetration limit, tumor recurrence often occurs, bypassing the immune response of the host. Accumulating evidence suggests the prominent role of tumor microenvironment (TME) and its interactions with the immune components contribute to an immunosuppressive milieu during the post- therapy period. Here, we explored the immunosuppressive cascade generated after PTT, which is responsible for tumor recurrence, and identified the potential targets to achieve an effective PTT period. Methods: Here, we investigated the immunosuppressive cascade generated after PTT in a CT26 tumor bearing mouse. The liposomal system loaded with the indocyanine green (ICG) was utilized for the generation of PTT with high efficiency. Immunological factors such as cytokines and protein expressions post-therapy were investigated through enzyme-linked immunosorbent assay, flow cytometry and western blot analysis. Results: Our results suggested that PTT with ICG-loaded liposomes (Lipo-ICG) was effective for the first 5 days after treatment, resulting in tumor suppression. However, an immunosuppressive and pro-inflammatory environment developed thereafter, causing the recruitment and upregulation of the immune evasion factors of heat shock protein 70, programmed death ligand 1, indoleamine-dioxygenase, interleukin-6, transforming growth factor-β, regulatory T-cells, and myeloid-derived suppressor cells, to develop immunotolerance. Conclusion: Collectively, these findings have determined potential therapeutic targets to modulate the TME during PTT and achieve tumor ablation without remission.
Cherukula, Kondareddy,Bae, Woo Kyun,Lee, Jae Hyuk,Park, In-Kyu Elsevier 2018 Biomaterials Vol.169 No.-
<P><B>Abstract</B></P> <P>Peritoneal carcinomatosis (PC) is a fatal condition arising in the gastrointestinal tract. PC patients administered drugs locally in the tumor region, such as in intraperitoneal chemotherapy (IPCh), suffer from low drug retention time and tumor penetration. Herein, we synthesized a lithocholic acid (LCA)-conjugated disulfide-linked polyethyleneimine (ssPEI) micelle (LAPMi) nanoconstruct by covalently conjugating ssPEI and LCA, thereby forming positive charged nanomicellar structures loaded with paclitaxel (PTX) (LAPMi-PTX) for IPCh. The incorporation of a positive surface charge aided in prolonging the peritoneal retention time, presumably via ascites-induced protein corona formation, and the subsequent size expansion caused resistance against undesired clearance through lymphatic openings. Furthermore, preferential tumor penetration by LAPMi-PTX is attributable to the permeation-enhancing properties of LCA, and the subsequent tumor activatable drug release was induced by the presence of disulfide linkages. By integrating these properties, LAPMi exhibited prolonged peritoneal residence time, enhanced tumor permeation and chemotherapeutic effect evidenced by <I>in vitro,</I> tumor spheroid and <I>in vivo</I> studies. Importantly, our strategy enabled significant PC inhibition and increased the overall survival rate of tumor-bearing mice. In conclusion, we provided a new paradigm of intractable PC treatment by enabling the prolonged residence time of the nanoconstruct, thereby enhancing tumor penetration and anti-tumor therapy.</P>
Cherukula, Kondareddy,Nurunnabi, Md.,Jeong, Yong Yeon,Lee, Yong-Kyu,Park, In-Kyu Informa UK (TaylorFrancis) 2018 Journal of Biomaterials Science. Polymer Edition Vol. No.
<P>Despite the introduction of many efficient post-consolidation therapies for complete relapse in leukemia patients, many patients suffer from relapse. Reactive oxygen species (ROS) are considered an important parameter in the immunosuppression of acute myeloid leukemia, where they suppress the cytotoxic action of immune cells such as NK cells and T cells. This study demonstrates a way to achieve effective inhibition of immunosuppression by loading the drug histamine dihydrochloride (HDC) onto graphene quantum dots (GQDs) using hyaluronic acid as a targeting moiety for K-562 cells. The prepared GQD-based nanoplatform was stable and achieved high drug loading on the surface, which resulted in a sustained drug release profile over a period of time. Additionally, the drug-loaded graphene nanoplatform proved to be non-toxic at higher concentrations to K-562 cells and could be effectively taken up into cells due to the targeting moiety. In vitro ROS detection assays proved that the HDC loaded graphene nanoplatform could effectively inhibit ROS and thus prevent the immunosuppression caused by leukemic cells.</P>