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Rajendrakumar, Santhosh Kalash,Uthaman, Saji,Cho, Chong-Su,Park, In-Kyu American Chemical Society 2018 Biomacromolecules Vol.19 No.6
<P>Immune system evasion by cancer cells is one of the hallmarks of cancers, and it occurs with the support of tumor-associated immune cells (TICs) in the tumor microenvironment that increase the growth and invasiveness of tumor cells. With recent advancements in the development of novel near-infrared (NIR)-responsive nanoparticles, specifically eradicating TICs or inducing an inflammatory immune response by activating killer T cells has become possible. This review will discuss the mechanisms and applications of phototriggered immunotherapy in detail. In addition, various nanoparticles employed in phototriggered immunotherapy for cancer treatment will be covered. Furthermore, the challenges and future directions of phototriggered nanoparticle development for anticancer immunotherapy will be briefly discussed.</P> [FIG OMISSION]</BR>
Rajendrakumar, Santhosh Kalash,Revuri, Vishnu,Samidurai, Manikandan,Mohapatra, Adityanarayan,Lee, Jae Hyuk,Ganesan, Palanivel,Jo, Jihoon,Lee, Yong-Kyu,Park, In-Kyu American Chemical Society 2018 Nano letters Vol.18 No.10
<P>Oxidative stress during sepsis pathogenesis remains the most-important factor creating imbalance and dysregulation in immune-cell function, usually observed following initial infection. Hydrogen peroxide (H<SUB>2</SUB>O<SUB>2</SUB>), a potentially toxic reactive oxygen species (ROS), is excessively produced by pro-inflammatory immune cells during the initial phases of sepsis and plays a dominant role in regulating the pathways associated with systemic inflammatory immune activation. In the present study, we constructed a peroxide scavenger mannosylated polymeric albumin manganese dioxide (mSPAM) nanoassembly to catalyze the decomposition of H<SUB>2</SUB>O<SUB>2</SUB> responsible for the hyper-activation of pro-inflammatory immune cells. In a detailed manner, we investigated the role of mSPAM nanoassembly in modulating the expression and secretion of pro-inflammatory markers elevated in bacterial lipopolysaccharide (LPS)-mediated endotoxemia during sepsis. Through a facile one-step solution-phase approach, hydrophilic bovine serum albumin reduced manganese dioxide (BM) nanoparticles were synthesized and subsequently self-assembled with cationic mannosylated disulfide cross-linked polyethylenimine (mSP) to formulate mSPAM nanoassembly. In particular, we observed that the highly stable mSPAM nanoassembly suppressed HIF1α expression by scavenging H<SUB>2</SUB>O<SUB>2</SUB> in LPS-induced macrophage cells. Initial investigation revealed that a significant reduction of free radicals by the treatment of mSPAM nanoassembly has reduced the infiltration of neutrophils and other leukocytes in a local endotoxemia animal model. Furthermore, therapeutic studies in a systemic endotoxemia model demonstrated that mSPAM treatment reduced TNF-α and IL-6 inflammatory cytokines in serum, in turn circumventing organ damage done by the inflammatory macrophages. Interestingly, we also observed that the reduction of these inflammatory cytokines by mSPAM nanoassembly further prevented IBA-1 immuno-positive microglial cell activation in the brain and consequently improved the cognitive function of the animals. Altogether, the administration of mSPAM nanoassembly scavenged H<SUB>2</SUB>O<SUB>2</SUB> and suppressed HIF1α expression in LPS-stimulated macrophages and thereby inhibited the progression of local and systemic inflammation as well as neuroinflammation in an LPS-induced endotoxemia model. This mSPAM nanoassembly system could serve as a potent anti-inflammatory agent, and we further anticipate its successful application in treating various inflammation-related diseases.</P> [FIG OMISSION]</BR>
Rajendrakumar, Santhosh Kalash,Chang, Ning-Chu,Mohapatra, Adityanarayan,Uthaman, Saji,Lee, Byeong-Il,Tsai, Wei-bor,Park, In-Kyu MDPI 2018 INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES Vol.19 No.4
<P>To prolong blood circulation and avoid the triggering of immune responses, nanoparticles in the bloodstream require conjugation with polyethylene glycol (PEG). However, PEGylation hinders the interaction between the nanoparticles and the tumor cells and therefore limits the applications of PEGylated nanoparticles for therapeutic drug delivery. To overcome this limitation, zwitterionic materials can be used to enhance the systemic blood circulation and tumor-specific delivery of hydrophobic agents such as IR-780 iodide dye for photothermal therapy. Herein, we developed micellar nanoparticles using the amphiphilic homopolymer poly(12-(methacryloyloxy)dodecyl phosphorylcholine) (PCB-lipid) synthesized via reversible addition–fragmentation chain transfer (RAFT) polymerization. The PCB-lipid can self-assemble into micelles and encapsulate IR-780 dye (PCB-lipid–IR-780). Our results demonstrated that PCB-lipid–IR-780 nanoparticle (NP) exhibited low cytotoxicity and remarkable photothermal cytotoxicity to cervical cancer cells (TC-1) upon near-infrared (NIR) laser irradiation. The biodistribution of PCB-lipid–IR-780 showed higher accumulation of PCB-lipid–IR-780 than that of free IR-780 in the TC-1 tumor. Furthermore, following NIR laser irradiation of the tumor region, the PCB-lipid–IR-780 accumulated in the tumor facilitated enhanced tumor ablation and subsequent tumor regression in the TC-1 xenograft model. Hence, these zwitterionic polymer-lipid hybrid micellar nanoparticles show great potential for cancer theranostics and might be beneficial for clinical applications.</P>
Rajendrakumar, Santhosh Kalash,Venu, Akhil,Revuri, Vishnu,George Thomas, Reju,Thirunavukkarasu, Guru Karthikeyan,Zhang, Jun,Vijayan, Veena,Choi, Seok-Yong,Lee, Jae Young,Lee, Yong-Kyu,Jeong, Yong Yeon American Chemical Society 2019 MOLECULAR PHARMACEUTICS Vol.16 No.5
<P>Tailoring combinatorial therapies along with real-time monitoring strategies has been the major focus of overcoming multidrug resistance in cancer. However, attempting to develop a multifunctional nanoplatform in a single construct leads to compromising therapeutic outcomes. Herein, we developed a simple, theranostic nanoassembly containing a hyaluronic acid-stabilized redox-sensitive (HART) polyethylenimine polyplex composed of a doxorubicin (DOX) intercalated Bcl-2 shRNA encoded plasmid along with a green-synthesized hausmannite (Mn<SUB>3</SUB>O<SUB>4</SUB>) and hematite (Fe<SUB>3</SUB>O<SUB>4</SUB>) nanoparticle (GMF). The highly stable HART nanoassembly has enhanced CD44-mediated intracellular uptake along with hyaluronidase (hylase) and redox-responsive drug-gene release. With Bcl-2 gene silencing induced by the successful delivery of HART in multidrug-resistant MCF7 breast cancer cells, the synergistic cytotoxic effect of Bcl-2 silencing and DOX was achieved. In addition, the HART nanoassembly containing GMF exhibited excellent dual MRI contrast (T1/T2) by reducing artifact signals. Overall, the HART nanoassembly with its enhanced theranostic properties has the potential to improve the therapeutic efficacy in future preclinical and clinical trials.</P> [FIG OMISSION]</BR>
Rajendrakumar, Santhosh Kalash,Cherukula, Kondareddy,Park, Hyeong Ju,Uthaman, Saji,Jeong, Yong Yeon,Lee, Byeong-Il,Park, In-Kyu Elsevier 2018 Journal of controlled release Vol.276 No.-
<P><B>Abstract</B></P> <P>Stimuli-responsive polymeric nanoparticles are useful for overcoming challenges such as transfection efficiency and the specific and safe delivery of genes to cancer cells. Transfection outcomes can be improved through spatially and temporally controlled gene release. We formulated a nanoassembly comprising a disulfide-crosslinked polyethylenimine (ssPEI) conjugated with a tumor-specific cell-penetrating peptide (DS 4-3) (SPD) polyplex and bovine serum albumin (BSA)-loaded IR780 (BI) nanoparticle, thereby forming a dual-stimulus-triggered, tumor-penetrating and gene-carrying nanoassembly (BI-SPD) via electrostatic complexing. BI-SPD nanoassembly were composed of highly stable nanosized complexes with an average size of 457 ± 27.5 nm, exhibiting an up to two-fold enhanced transfection efficiency with no sign of potential cytotoxicity in breast cancer cells. Moreover, upon laser irradiation, a four-fold increase in transfection efficiency was achieved due to the rapid endosomal escape of polyplexes triggered by the local heat induced by the BI-SPD nanoassembly. Additionally, the high redox environment in tumor cells facilitated the disassembly of the SPD polyplex for efficient plasmid release in the cytosol. The BI-SPD nanoassembly also exhibited high penetration and enhanced photothermally triggered gene expression in the 4T1 spheroid model. This BI-SPD nanoassembly has the potential to enhance the expression of therapeutic genes in tumor models without causing significant toxicity to surrounding healthy tissues, since it has shown higher tumor targeting and accumulation in the 4T1 tumor in mice model.</P> <P><B>Graphical abstract</B></P> <P>Dual stimuli responsive nanoassembly was developed by forming complex between the bovine serum albumin loaded IR780 dye with DNA polyplex, which improved the transfection efficiency by photothermally endosomal escape as well as gluthione redox mediated DNA release from polyplex. Additionally, it possess the ability to penetrate the tumor spheroid.</P> <P>[DISPLAY OMISSION]</P>