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Rational combination immunotherapeutic approaches for effective cancer treatment
Phung, Cao Dai,Nguyen, Hanh Thuy,Tran, Tuan Hiep,Choi, Han-Gon,Yong, Chul Soon,Kim, Jong Oh Elsevier Science Publishers 2019 Journal of controlled release Vol.294 No.-
<P><B>Abstract</B></P> <P>Immunotherapy is an important mode of cancer treatment. Over the past decades, immunotherapy has improved the clinical outcome for cancer patients. However, in many cases, mutations in cancer cells, lack of selectivity, insufficiency of tumor-reactive T cells, and host immunosuppression limit the clinical benefit of immunotherapy. Combination approaches in immunotherapy may overcome these obstacles. Accumulating evidence demonstrates that combination immunotherapy is the future of cancer treatment. However, designing safe and rational combinations of immunotherapy with other treatment modalities is critical. This review will discuss the optimal immunotherapy-based combinations mainly with respect to the mechanisms of action of individual therapeutic agents that target multiple steps in evasion and progression of tumor.</P> <P><B>Graphical abstract</B></P> <P>[DISPLAY OMISSION]</P>
Cao Dai Phung,Tuan Hiep Tran,Jong Oh Kim 대한약학회 2020 Archives of Pharmacal Research Vol.43 No.1
Natural killer (NK) cells have emerged as apotent alternative immunotherapeutic approach to T celltherapy for cancer. Despite promising results from preclinicaland clinical studies, numerous challenges have limitedthe application of NK cell-based therapy, including poorexpansion of NK cells in vitro, their short in vivo life span,time-intensiveness, treatment complexities, and the costburden of the treatment. Recent advancements in the developmentof immune cell-delivering nanosystems have ledto promising strategies to overcome these limitations andenhance NK cell toxicity towards cancer cells. This reviewfi rst summarizes the biological roles of NK cells and theirtumoricidal mechanisms. NK cells, in the context of theimmune system and the tumor microenvironment, havereportedly provided novel insights into specifi c therapeutictargets. Eventually, various strategies targeting NK cellsusing nanoplatforms to modulate the NK cell responses foreff ective cancer immunotherapy are described herein. Altogether,this review discusses the potential of nanotechnologyin advancements in NK cell-based onco-immunotherapy .
Phung, Cao Dai,Nguyen, Hanh Thuy,Choi, Ju Yeon,Pham, Thanh Tung,Acharya, Suman,Timilshina, Maheshwor,Chang, Jae-Hoon,Kim, Ju-Hyun,Jeong, Jee-Heon,Ku, Sae Kwang,Choi, Han-Gon,Yong, Chul Soon,Kim, Jong Elsevier 2019 Journal of controlled release Vol.315 No.-
<P><B>Abstract</B></P> <P>In this study, dual drug-loaded nanoparticles were constructed to co-deliver low-dose doxorubicin (DOX) and miR-200c (DOX/miR-NPs) to inhibit programmed death-1 receptor (PD-L1) expression and trigger immunogenic cell death (ICD) in cancer cells. Two block copolymers, folic acid (FA)-conjugated PLGA-PEG (PLGA-PEG-FA) and PLGA-PEI, were formulated as folate-targeted NPs and loaded with DOX and miR-200c. The NPs, which were formed as nanosize objects (110.4 ± 2.1) with narrow size distribution (0.19 ± 0.02), effectively protected the miR-200c from degradation in serum. Modifying the NPs with FA increased not only their uptake by cancer cells <I>in vitro</I> but also their accumulation in tumor microenvironments <I>in vivo</I>, as compared with those properties of non-FA-modified NPs. The DOX/miR-NPs also exhibited efficacious inhibition of PD-L1 expression and robust induction of ICD in cancer cells <I>in vitro</I> and <I>in vivo</I>, resulting in increased dendritic cell maturation and CD8<SUP>+</SUP> T cell response towards cancer cells. Furthermore, tumor growth was significantly inhibited by folate-targeted NPs loaded with the low-dose DOX/miR-200c combination, but not by treatments with free DOX, miR-NPs or DOX-NPs. Thus, our results suggest that simultaneous PD-L1 inhibition via microRNAs and the induction of an immunogenic tumor microenvironment via low-dose cytotoxic drugs may improve cancer therapy efficacy.</P> <P><B>Highlights</B></P> <P> <UL> <LI> A folate receptor-targeted nanoparticle was prepared for co-delivery of doxorubicin and miR-200c (DOX/miR-NPs). </LI> <LI> The DOX/miR-NPs inhibited PD-L1 expression and robustly induced immunogenic cell death in cancer cells <I>in vitro</I> and <I>in vivo</I>. </LI> <LI> The treatment with DOX/miR-NPs significantly increased tumor-infiltrated dendritic cells and cytotoxic T cells. </LI> <LI> The tumor growth was remarkably inhibited by DOX/miR-NPs. </LI> </UL> </P> <P><B>Graphical abstract</B></P> <P>[DISPLAY OMISSION]</P>
Nguyen, Hanh Thuy,Phung, Cao Dai,Thapa, Raj Kumar,Pham, Tung Thanh,Tran, Tuan Hiep,Jeong, Jee-Heon,Ku, Sae Kwang,Choi, Han-Gon,Yong, Chul Soon,Kim, Jong Oh Elsevier 2018 ACTA BIOMATERIALIA Vol.68 No.-
<P><B>Abstract</B></P> <P>Lanreotide (LT), a synthetic analog of somatostatin, has been demonstrated to specifically bind to somatostatin receptors (SSTRs), which are widely overexpressed in several types of cancer cells. In this study, we incorporated a chemotherapeutic agent, methotrexate (MTX), and a photosensitizer material, polyaniline (PANI), into hybrid polymer nanoparticles (NPs), which could target cancer cells after conjugation with LT (LT-MTX/PANI NPs). The successful preparation of LT–MTX/PANI NPs was confirmed by a small particle size (187.9 ± 3.2 nm), a polydispersity index of 0.232 ± 0.011, and a negative ζ potential of −14.6 ± 1.0 mV. Notably, LT-MTX/PANI NPs showed a greater uptake into SSTR-positive cancer cells and thereby better inhibited cell viability and induced higher levels of apoptosis than MTX, PANI NP, and MTX/PANI NP treatments did. In addition, the heat associated with the burst drug release induced by near-infrared (NIR) irradiation resulted in remarkably enhanced cell apoptosis, which was confirmed by an increase in the expression levels of apoptotic marker proteins. In agreement with the <I>in vitro</I> results, the administration of the SSTR-targeting NPs, followed by NIR exposure, to xenograft tumor-bearing mice resulted in an improved suppression of tumor development compared to that shown by MTX, PANI NPs, and MTX/PANI NPs, as well as by LT-MTX/PANI NPs without photothermal therapy. Thus, the SSTR-targeting NPs could be a promising delivery system for the effective treatment of SSTR-positive cancers.</P> <P><B>Statement of significance</B></P> <P>Somatostatin receptors are widely overexpressed in several types of cancer cells. In this study, we designed nanoparticles for targeted delivery of chemotherapeutic agents to tumor sites by conjugating hybrid polymers with a synthetic analog of somatostatin, specifically binding to somatostatin receptors. In addition, a photosensitizer material, polyaniline, was incorporated into the nanoparticles for combined chemo–photothermal therapy. The results demonstrated clear advantages of the newly designed targeted nanoparticles over their non-targeted counterparts or a free chemotherapeutic drug in inhibiting the viability of cancer cells <I>in vitro</I> and targeting/suppressing the tumor growth in an animal xenograft model. The study suggests that the designed nanoparticles are a promising delivery system for the effective treatment of somatostatin receptor-positive cancers.</P> <P><B>Graphical abstract</B></P> <P>[DISPLAY OMISSION]</P>
Pham, Tung Thanh,Nguyen, Hanh Thuy,Phung, Cao Dai,Pathak, Shiva,Regmi, Shobha,Ha, Dong-Ho,Kim, Jong Oh,Yong, Chul Soon,Kim, Sang Kyoon,Choi, Ji-Eun,Yook, Simmyung,Park, Jun-Beom,Jeong, Jee-Heon Elsevier 2019 Journal of industrial and engineering chemistry Vol.76 No.-
<P><B>Abstract</B></P> <P>Selective delivery of anti-cancer drugs to bone tumors remains an on-going developmental issue due to problems of drug availability and the physiological nature of bone. This study was undertaken to enhance accumulation of doxorubicin (DOX) in bone metastasis microenvironments using alendronate-functionalized graphene oxide nanosheets (NGO-ALs). In vivo biodistribution study showed NGO-ALs were retained for longer and at higher concentrations in bone tumor areas than non-functionalized NGOs. Our findings suggest that NGO-ALs could be used as a promising carrier to enhance antitumor effects and diminish the off-target effects of DOX for the treatment of bone metastasis.</P> <P><B>Graphical abstract</B></P> <P>[DISPLAY OMISSION]</P>
Tung Thanh Pham,Hanh Thuy Nguyen,Cao Dai Phung,Shiva Pathak,Shobha Regmi,하동호,김종오,용철순,김상균,최지은,육심명,박준범,정지헌 한국공업화학회 2019 Journal of Industrial and Engineering Chemistry Vol.76 No.-
Selective delivery of anti-cancer drugs to bone tumors remains an on-going developmental issue due toproblems of drug availability and the physiological nature of bone. This study was undertaken to enhanceaccumulation of doxorubicin (DOX) in bone metastasis microenvironments using alendronate-functionalized graphene oxide nanosheets (NGO-ALs). In vivo biodistribution study showed NGO-ALswere retained for longer and at higher concentrations in bone tumor areas than non-functionalizedNGOs. Ourfindings suggest that NGO-ALs could be used as a promising carrier to enhance antitumoreffects and diminish the off-target effects of DOX for the treatment of bone metastasis.
Nguyen, Hanh Thuy,Byeon, Jeong Hoon,Phung, Cao Dai,Pham, Le Minh,Ku, Sae Kwang,Yong, Chul Soon,Kim, Jong Oh American Chemical Society 2019 ACS APPLIED MATERIALS & INTERFACES Vol.11 No.28
<P>Inorganic nanomaterial (INM)-based combination cancer therapies have been extensively employed over the past two decades because of their benefits over traditional chemo- and radiotherapies. However, issues regarding the toxicity and accumulation of INMs in the body have arisen. This problem may be improved through the use of biodegradable or disintegrable nanosystems such as black phosphorus (BP). Challenges to the manufacture of fully nanodimensional BP remain. In addition, improvements in recently developed cancer immunotherapies require their incorporation with drugs, targeting agents, and delivery vehicles. With these needs in mind, this study develops a method for instant in-flight manufacture of nanodimensional BP using plug-and-play devices for subsequent assembly of photoimmunotherapeutic core@shell composites containing mutated B-raf inhibitors (dabrafenib), immune checkpoint inhibitors (PD-L1), and cancer-targeting antibodies (CXCR4). The resulting nanocomposites exhibited cancer targetability and regulatability of PD-L1 expression both in vitro and in vivo. These activities were further increased upon near-infrared irradiation due to the incorporation of a phototherapeutic component. These results suggest that these nanocomposites are promising as a new class of advanced cancer therapeutic agents.</P> [FIG OMISSION]</BR>
Combined hyperthermia and chemotherapy as a synergistic anticancer treatment
Jong Oh Kim,Duy Hieu Truong,Tuan Hiep Tran,Dai Cao Phung,Hanh Thuy Nguyen,Thi Thu Phuong Tran,Sung Giu Jin,Chul Soon Yong 한국약제학회 2019 Journal of Pharmaceutical Investigation Vol.49 No.5
To date, hyperthermia and chemotherapy have been widely investigated in the field of anticancer nanomedicine. However, in many cases, the efficacy of monotherapies have been limited owing to the heterogeneity of cancers and the acquired drug resistance. Noteworthy, hyperthermia has been demonstrated to offer numerous advantages when integrated with chemotherapy in nanoplatforms, namely increased accumulation of drugs in tumor site, enhanced cellular uptake, inhibition of DNA repair, and accelerated drug cytotoxicity against cancer cells. These evidences suggest a promising anticancer synergistic effect of hyperthermia and chemotherapy. This review will discuss the underlying mechanisms of action of chemohyperthermia combination therapy, and especially the strategies of design of advanced nanocarriers to effectively co-deliver hyperthermia and chemotherapeutic agents to the tumor based on various types of materials.
Nanoparticles for dendritic cell-based immunotherapy
Tran, Tuan Hiep,Tran, Thi Thu Phuong,Nguyen, Hanh Thuy,Phung, Cao Dai,Jeong, Jee-Heon,Stenzel, Martina H.,Jin, Sung Giu,Yong, Chul Soon,Truong, Duy Hieu,Kim, Jong Oh Elsevier 2018 International journal of pharmaceutics Vol.542 No.1
<P><B>Abstract</B></P> <P>Crosstalk among immune cells has attracted considerable attention with the advent of immunotherapy as a novel therapeutic approach for challenging diseases, especially cancer, which is the leading cause of mortality worldwide. Dendritic cells—the key antigen-presenting cells—play a pivotal role in immunological response by presenting exogenous epitopes to T cells, which induces the self-defense mechanisms of the body. Furthermore, nanotechnology has provided promising ways for diagnosing and treating cancer in the last decade. The progress in nanoparticle drug carrier development, combined with enhanced understanding of the immune system, has enabled harnessing of anti-tumor immunity. This review focuses on the recent advances in nanotechnology that have improved the therapeutic efficacy of immunotherapies, with emphasis on dendritic cell physiology and its role in presenting antigens and eliciting therapeutic T cell response.</P> <P><B>Graphical abstract</B></P> <P>[DISPLAY OMISSION]</P>