Nanoparticle-mediated Delivery Research Articles

Polymeric Nanoparticles with a Sera-Derived Coating for Efficient Cancer Cell Uptake and Killing.

Nanoparticle-mediated cancer drug delivery remains an inefficient process. The protein corona formed on nanoparticles (NPs) controls their biological identity and, if optimized, could enhance cancer cell uptake. In this study, a hyperbranched polyester polymer (HBPE) was synthesized from diethyl malonate and used to generate NPs that were subsequently coated with normal sera (NS) collected from mice. Cellular uptake of NS-treated HBPE-NPs was compared to PEGylated HBPE-NPs and was assessed using MDA-MB-231 triple-negative breast cancer (TNBC) cells as well as endothelial and monocytic cell lines. NS-treated HBPE-NPs were taken up by TNBC cells more efficiently than PEGylated HBPE-NPs, while evasion of monocyte uptake was comparable. NS coatings facilitated cancer cell uptake of HBPE-NPs, even after prior interaction of the particles with an endothelial layer. NS-treated HBPE-NPs were not inherently toxic, did not induce the migration of endothelial cells that could lead to angiogenesis, and could efficiently deliver cytotoxic doses of paclitaxel (taxol) to TNBC cells. These findings suggest that HBPE-NPs may adsorb select sera proteins that improve uptake by cancer cells, and such NPs could be used to advance the discovery of novel factors that improve the bioavailability and tissue distribution of drug-loaded polymeric NPs.

Designing Mesoporous Silica Nanoparticles to Overcome Biological Barriers by Incorporating Targeting and Endosomal Escape.

The several biological barriers that nanoparticles might encounter when administered to a patient constitute the major bottleneck of nanoparticle-mediated tumor drug delivery, preventing their successful translation into the clinic and reducing their therapeutic profile. In this work, mesoporous silica nanoparticles have been employed as a platform to engineer a versatile nanomedicine able to address such barriers, achieving (a) excessive premature drug release control, (b) accumulation in tumor tissues, (c) selective internalization in tumoral cells, and (d) endosomal escape. The nanoparticles have been decorated with a self-immolative redox-responsive linker to prevent excessive premature release, to which a versatile and polyvalent peptide that is able to recognize tumoral cells and induce the delivery of the nanoparticles to the cytoplasm via endosomal escape has been grafted. The excellent biological performance of the carrier has been demonstrated using 2D and 3D in vitro cell cultures and a tumor-bearing chicken embryo model, demonstrating in all cases high biocompatibility and cytotoxic effect, efficient endosomal escape and tumor penetration, and accumulation in tumors grown on the chorioallantoic membrane of chicken embryos.

Update on Nanoparticle-Based Drug Delivery System for Anti-inflammatory Treatment.

Nanobiotechnology plays an important role in drug delivery, and various kinds of nanoparticles have demonstrated new properties, which may provide opportunities in clinical treatment. Nanoparticle-mediated drug delivery systems have been used in anti-inflammatory therapies. Diseases, such as inflammatory bowel disease, rheumatoid arthritis, and osteoarthritis have been widely impacted by the pathogenesis of inflammation. Efficient delivery of anti-inflammatory drugs can reduce medical dosage and improve therapeutic effect. In this review, we discuss nanoparticles with potential anti-inflammatory activity, and we present a future perspective regarding the application of nanomedicine in inflammatory diseases.

Delivery of toll-like receptor 3 ligand poly(I:C) to the liver by calcium phosphate nanoparticles conjugated with an F4/80 antibody exerts an anti-hepatitis B virus effect in a mouse model

Hepatitis B virus (HBV) is a global health issue, but currently available anti-HBV drugs have limited success. Previously, introduction of the Toll-like receptor (TLR)-3 ligand poly(I:C) to the liver via hydrodynamic injection (HI) was shown to effectively suppress HBV replication in a chronic HBV replication mouse model. However, this method cannot be applied in human beings. To improve the liver targeting of poly(I:C) via intravenous injection, calcium phosphate nanoparticles (CPNs) carrying poly(I:C) with or without antibodies were constructed, and their anti-HBV effects were investigated. We found that significantly more anti-F4/80-conjugated and IgG2α-conjugated nanoparticles were taken up in liver cells both in vivo and in vitro. In addition, these nanoparticles produced pronounced immunostimulatory effects in vitro in primary liver cells. Importantly, treatment with nanoparticles carrying poly(I:C) increased the production of intrahepatic cytokines and chemokines and enhanced T cell responses, significantly reducing HBsAg, HBeAg and HBV DNA levels in the mice. Compared to nonconjugated and isotype-antibody-conjugated nanoparticles, the anti-F4/80-conjugated nanoparticles demonstrated the strongest anti-HBV effects. In summary, nanoparticles carrying poly(I:C) conjugated with an F4/80 antibody promoted liver targeting, and they may represent a suitable alternative to HI for future anti-HBV treatment. Statement of significanceHBV chronically infects approximately 250 million individuals worldwide but current anti-HBV drugs have limited success. Introduction of toll-like receptor 3 ligand poly(I:C) into liver by hydrodynamic injection has been proven to promote HBV clearance in mouse model. However, this technique is not clinically suitable for human patients. We have constructed calcium phosphate nanoparticles carrying poly(I:C) with specific antibody targeting liver nonparenchymal cells. The uptake into relevant liver cells and the anti-HBV effects were studied. After intravenous injection into mice, the uptake rate of anti-F4/80-conjugated nanoparticels was enhanced in liver, and these nanoparticles exert effective anti-HBV effects in vivo. This may provide important insight into future HBV immunotherapy based on nanoparticle-mediated drug delivery.

Hepatic macrophages act as a central hub for relaxin-mediated alleviation of liver fibrosis.

Relaxin is an antifibrotic peptide hormone previously assumed to directly reverse the activation of hepatic stellate cells for liver fibrosis resolution. Using nanoparticle-mediated delivery, here we show that, although relaxin gene therapy reduces liver fibrosis in vivo, in vitro treatment fails to induce quiescence of the activated hepatic stellate cells. We show that hepatic macrophages express the primary relaxin receptor, and that, on relaxin binding, they switch from the profibrogenic to the pro-resolution phenotype. The latter releases exosomes that promote the relaxin-mediated quiescence of activated hepatic stellate cells through miR-30a-5p. Building on these results, we developed lipid nanoparticles that preferentially target activated hepatic stellate cells in the fibrotic liver and encapsulate the relaxin gene and miR-30a-5p mimic. The combinatorial gene therapy achieves synergistic antifibrosis effects in models of mouse liver fibrosis. Collectively, our findings highlight the key role that macrophages play in the relaxin-primed alleviation of liver fibrosis and demonstrate a proof-of-concept approach to devise antifibrotic strategies through the complementary application of nanotechnology and basic science.

A Biomimetic Drug Delivery System by Integrating Grapefruit Extracellular Vesicles and Doxorubicin-Loaded Heparin-Based Nanoparticles for Glioma Therapy.

Existing nanoparticle-mediated drug delivery systems for glioma systemic chemotherapy remain a great challenge due to poor delivery efficiency resulting from the blood brain barrier/blood-(brain tumor) barrier (BBB/BBTB) and insufficient tumor penetration. Here, we demonstrate a distinct design by patching doxorubicin-loaded heparin-based nanoparticles (DNs) onto the surface of natural grapefruit extracellular vesicles (EVs), to fabricate biomimetic EV-DNs, achieving efficient drug delivery and thus significantly enhancing antiglioma efficacy. The patching strategy allows the unprecedented 4-fold drug loading capacity compared to traditional encapsulation for EVs. The biomimetic EV-DNs are enabled to bypass BBB/BBTB and penetrate into glioma tissues by receptor-mediated transcytosis and membrane fusion, greatly promoting cellular internalization and antiproliferation ability as well as extending circulation time. We demonstrate that a high-abundance accumulation of EV-DNs can be detected at glioma tissues, enabling the maximal brain tumor uptake of EV-DNs and great antiglioma efficacy in vivo.

Nanoparticle-Mediated Delivery of Emodin via Colonic Irrigation Attenuates Renal Injury in 5/6 Nephrectomized Rats.

Our previous study showed that emodin enema modulates gut microbiota and delays CKD progression. However, the poor solubility, limited colonic irrigation retention time, and inadequate colon adhesion of emodin hinder its clinical application. Based on the deficiencies of emodin, we prepared monomethoxy-poly (ethylene glycol)-poly (lactic acid)-chitosan-2-mercaptobenzimidazole nanoparticles with incorporated emodin (emodin-NP) and studied their efficacy in delaying CKD progression. 5/6 nephrectomized Male Sprague Dawley rats were administered via colonic irrigation with emodin-NP every two days for eight weeks. We found that treatment with emodin-NP improved the kidney function of the rats and limited the expansion of tubulointerstitial fibrosis. Treatment with emodin-NP once every two days is comparable to emodin treatment once a day. Furthermore, emodin-NP via colonic irrigation remarkably reduced IL-1β, IL-6, and LPS levels in serum, improved intestinal barrier functions, and downregulated the key proteins (TLR4, MyD88, and NF-κB) expression in intestinal TLR4 signaling pathway. 16S rDNA analyses showed that emodin-NP can regulate microbiota disturbance in CKD. Taken together, these results suggest that emodin-NP alleviates kidney dysfunction and tubulointerstitial fibrosis by mediation through the modification of gut microbiota disorders. Emodin-NP may be a new method to treat CKD.

Nanoparticle-Mediated Delivery of Pitavastatin to Monocytes/Macrophages Inhibits Angiotensin II-Induced Abdominal Aortic Aneurysm Formation in Apoe-/- Mice.

Aim: Abdominal aortic aneurysm (AAA) is a lethal and multifactorial disease. To prevent a rupture and dissection of enlarged AAA, prophylactic surgery and stenting are currently available. There are, however, no medical therapies preventing these complications of AAA. Statin is one of the candidates, but its efficacy on AAA formation/progression remains controversial. We have previously demonstrated that nanoparticles (NPs) incorporating pitavastatin (Pitava-NPs)—clinical trials using these nanoparticles have been already conducted—suppressed progression of atherosclerosis in apolipoprotein E-deficient ( Apoe −/− ) mice. Therefore, we have tested a hypothesis that monocytes/macrophages-targeting delivery of pitavastatin prevents the progression of AAA. Methods: Angiotensin II was intraperitoneally injected by osmotic mini-pumps to induce AAA formation in Apoe −/− mice. NPs consisting of poly(lactic-co-glycolic acid) were used for in vivo delivery of pitavastatin to monocytes/macrophages. Results: Intravenously administered Pitava-NPs (containing 0.012 mg/kg/week pitavastatin) inhibited AAA formation accompanied with reduction of macrophage accumulation and monocyte chemoattractant protein-1 (MCP-1) expression. Ex vivo molecular imaging revealed that Pitava-NPs not only reduced macrophage accumulation but also attenuated matrix metalloproteinase activity in the abdominal aorta, which was underpinned by attenuated elastin degradation. Conclusion: These results suggest that Pitava-NPs inhibit AAA formation associated with reduced macrophage accumulation and MCP-1 expression. This clinically feasible nanomedicine could be an innovative therapeutic strategy that prevents devastating complications of AAA.

Nanoparticle-mediated targeting of autoantigen peptide to cross-presenting liver sinusoidal endothelial cells protects from CD8 T-cell-driven autoimmune cholangitis.

SummaryAutoimmune diseases are caused by adaptive immune responses to self‐antigens. The development of antigen‐specific therapies that suppress disease‐related, but not unrelated immune responses in general, is an important goal of biomedical research. We have previously shown that delivery of myelin peptides to liver sinusoidal endothelial cells (LSECs) using LSEC‐targeting nanoparticles provides effective protection from CD4 T‐cell‐driven autoimmune encephalomyelitis. Here, we investigated whether this methodology might also serve antigen‐specific treatment of a CD8 T‐cell‐driven autoimmune disease. As a model for CD8 T‐cell‐mediated autoimmunity, we used OT‐1 T‐cell‐driven cholangitis in K14‐OVAp mice expressing the cognate MHC I‐restricted SIINFEKL peptide in cholangiocytes. To study whether peptide delivery to LSECs could modulate cholangitis, SIINFEKL peptide‐conjugated nanoparticles were administered intravenously one day before transfer of OT‐1 T cells; five days after cell transfer, liver pathology and hepatic infiltrates were analysed. SIINFEKL peptide‐conjugated nanoparticles were rapidly taken up by LSECs in vivo, which effectively cross‐presented the delivered peptide on MHC I molecules. Intriguingly, K14‐OVAp mice receiving SIINFEKL‐loaded nanoparticles manifested significantly reduced liver damage compared with vehicle‐treated K14‐OVAp mice. Mechanistically, treatment with LSEC‐targeting SIINFEKL‐loaded nanoparticles significantly reduced the number of liver‐infiltrating OT‐1 T cells, which up‐regulated expression of the co‐inhibitory receptor PD‐1 and down‐regulated cytotoxic effector function and inflammatory cytokine production. These findings show that tolerogenic LSECs can effectively internalize circulating nanoparticles and cross‐present nanoparticle‐bound peptides on MHC I molecules. Therefore, nanoparticle‐mediated autoantigen peptide delivery to LSECs might serve the antigen‐specific treatment of CD8 T‐cell‐driven autoimmune disease.

Recent Advances in Nanoparticle-Mediated Treatment of Inflammatory Bowel Diseases

There have been continuous advances in nanoscience since the beginning of the 21st century, and the emerging field of computational nanomedicine, the development of nanomaterial-based sensors or the prominent biomedical engineering applications should be mentioned. Intestinal disorders causing prolonged inflammation of the digestive tract, largely known as inflammatory bowel disease (IBD), include Crohn’s disease (CD) and ulcerative colitis (UC), have seen a significant increase in incidence rates. Nanoparticle-based approaches to locally target therapy could help regulate immune responses and act as an anti-inflammatory in individual patients diagnosed with IBD. The results of the paper emphasize the major role that nanoparticle-mediated drug delivery has in IBD treatment, giving IBD patients in remission the chance for a more effective drug therapy with a decreased medication load.

Cetuximab-siRNA Conjugate Linked Through Cationized Gelatin Knocks Down KRAS G12C Mutation in NSCLC Sensitizing the Cells Toward Gefitinib.

Delivery of small-interfering RNA (siRNA) has been of great interest in the past decade for effective gene silencing. To overcome synthetic and regulatory challenges posed by nanoparticle-mediated siRNA delivery, antibody–siRNA conjugate (ARC) platform is emerging as a potential siRNA delivery system suitable for clinical translation. Herein, we have developed a delivery technology based on the ARC platform for stable delivery of siRNA called as Gelatin-Antibody Delivery System (GADS). In GADS, positively charged gelatin acts as a linker between antibody–siRNA and enables the endosomal escape of siRNA for gene silencing postcellular internalization. For proof of concept, we synthesized a scalable GADS conjugate comprising of Cetuximab (CTB), cationized gelatin (cGel) and NSCLC KRASG12C-specific siRNA. CTB was chemically conjugated to cGel through an amide link to form the CTB–cGel complex. Thereafter, siRNA was chemically conjugated to the cGel moiety of the complex through the thioether link to form CTB–cGel–siRNA conjugate. RP-HPLC analysis was used to monitor the reaction while gel retardation assay was used to determine siRNA loading capacity. SPR analysis showed the preservation of ligand binding affinity of antibody conjugates with KD of ∼0.3 nM. Furthermore, cellular internalization study using florescent microscopy revealed receptor-mediated endocytosis. The conjugate targeted EGFR receptor of KRAS mutant NSCLC to specifically knockdown G12C mutation. The oncogene knockdown sensitized the cells toward small molecule inhibitor—Gefitinib causing ∼70% loss in cell viability. Western blot analysis revealed significant downregulation for various RAS downstream proteins postoncogene knockdown. Comparison of the efficiency of GADS vis-à-vis positive siRNA control and CRISPR–Cas9-based knockout of KRAS Exon 2 in the NCI-H23 NSCLC cell line suggests GADS as a potential technology for clinical translation of gene therapy.

H-Ferritin nanoparticle-mediated delivery of antibodies across a BBB in vitro model for treatment of brain malignancies.

Brain cancers are a group of neoplasms that can be either primary, such as glioblastoma multiforme (GBM), or metastatic, such as the HER2+ breast cancer brain metastasis. The brain represents a sanctuary for cancer cells thanks to the presence of the blood brain barrier (BBB) that controls trafficking of molecules, protecting the brain from toxic substances including drugs. Considering that GBM and HER2+ breast cancer brain metastases are characterized by EGFR and HER2 over-expression respectively, CTX- and TZ-based treatment could be effective. Several studies show that these monoclonal antibodies (mAbs) exert both a cytostatic activity interfering with the transduction pathways of EGFR family and a cytotoxic activity mainly through the immune system activation via the antibody dependent cell-mediated cytotoxicity (ADCC). Since the major limitation to therapeutic mAbs application is the presence of the BBB, here we use a recombinant form of human apoferritin (HFn) as a nanovector to promote the delivery of mAbs to the brain for the activation of the ADCC response. Using a transwell model of the BBB we proved the crossing ability of HFn-mAb. Cellular uptake of HFn-mAb by human cerebral microvascular endothelial cells (hCMEC/D3) was demonstrated by confocal microscopy. Moreover, after crossing the endothelial monolayer, HFn-conjugated mAbs retain their biological activity against targets, as assessed by MTS and ADCC assays. Our data support the use of HFn as efficient carrier to enhance the BBB crossing of mAbs, without affecting their antitumoral activity.

The Potential of Helianthin Loaded Into Magnetic Nanoparticles to Induce Cytotoxicity in Glioblastoma Cells.

The central nervous system tumors are the most common solid tumors in adults.. Unlike other types of cancers, brain cancer is much difficult to treat because of the blood-brain barrier (BBB) that prevents drug substances from crossing it and accessing the brain. Different types of methods to overcome BBB have been used in vivo and in vitro, of which the use of nanoparticle-mediated delivery of therapeutic drugs is particularly promising. In the present study, we used iron oxide magnetic nanoparticles (NPs) as carrier system for helianthin (He/NPs) to treat cancer cells derived from glioblastoma. An early passage cell cultures (GB1B), established in our laboratory from tissue obtained from a patient diagnosed with glioblastoma, was used. The cells were treated with different concentrations of NPs or HeNPs and then cell proliferation was measured at 24, 48 and 72 hours. Our results showed that the treatment with NPs was well tolerated by glioblastoma cells, the viability of the cells increased very slightly after the treatment. Furthermore, we demonstrated that helianthin loaded Fe3O4 magnetic nanoparticles induced cytotoxicity in human glioblastoma cells. The treatment with HeNPs induced dose and time dependent.

Cover 1 - Nanoparticle-mediated Delivery of 2-Deoxy-D-glucose to Liver Cancer

Cover 1 - Nanoparticle-mediated Delivery of 2-Deoxy-D-glucose to Liver Cancer

Nanoparticles as Smart Carriers for Enhanced Cancer Immunotherapy.

Cancer immunotherapy has emerged as a promising strategy for the treatment of many forms of cancer by stimulating body's own immune system. This therapy not only eradicates tumor cells by inducing strong anti-tumor immune response but also prevent their recurrence. The clinical cancer immunotherapy faces some insurmountable challenges including high immune-mediated toxicity, lack of effective and targeted delivery of cancer antigens to immune cells and off-target side effects. However, nanotechnology offers some solutions to overcome those limitations, and thus can potentiate the efficacy of immunotherapy. This review focuses on the advancement of nanoparticle-mediated delivery of immunostimulating agents for efficient cancer immunotherapy. Here we have outlined the use of the immunostimulatory nanoparticles as a smart carrier for effective delivery of cancer antigens and adjuvants, type of interactions between nanoparticles and the antigen/adjuvant as well as the factors controlling the interaction between nanoparticles and the receptors on antigen presenting cells. Besides, the role of nanoparticles in targeting/activating immune cells and modulating the immunosuppressive tumor microenvironment has also been discussed extensively. Finally, we have summarized some theranostic applications of the immunomodulatory nanomaterials in treating cancers based on the earlier published reports.

The phototherapy toward corneal neovascularization elimination: An efficient, selective and safe strategy

Corneal neovascularization (CNV) can induce severe visual impairment and even blindness. Current treatments have limited efficacy and some undesirable side effects. Phototherapy (PT) is a modern medical technique in CNV treatment and worth further improvement. Nanotechnology has various advantages and nanoparticle-mediated drug delivery also contributes to CNV elimination. Phototherapy combined with functional nanoparticles featuring photoacoustic imaging contrast properties can accomplish accurate and safe inhibition of CNV, thus is promising in clinical application.

Chitosan nanoparticle-mediated delivery of curcumin and phycocyanin for photodynamic therapy against biofilm forming bacteria

Bacteria within biofilm display resistance to host defense and conventional antimicrobial agents. The present study was aimed to reduce biofilm formation by Staphylococcus aureus and Pseudomonas aeruginosa using photodynamic therapy. Natural photosensitizers such as curcumin and phycocyanin were encapsulated within chitosan nanoparticles synthesized by ionic gelation method. It was characterized by SEM, TEM, Particle size analyzer, UV-Vis analysis, FTIR, XRD and TGA. The antibacterial activity of curcumin and phycocyanin delivered through chitosan nanoparticles against S. aureus and P. aeruginosa was investigated by well diffusion assay. Photodynamic antibiofilm activity was investigated by crystal violet assay. Generation of reactive oxygen species by photosensitizers was recorded using spectrophotometer. The chitosan nanoparticles encapsulated with photosensitizers were spherical in shape with an average size of 20 nm. Encapsulation efficiency of chitosan nanoparticles was 36.45% for phycocyanin and 44.96% for curcumin. The antibacterial and antibiofilm activity of curcumin and phycocyanin increased with concentration. Curcumin and phycocyanin reduced less than 0.5% of biofilm formed by S. aureus and P. aeruginosa in dark treatment. Illumination reduced 2.57% and 2.18% of biofilm formed by S. aureus and P. aeruginosa respectively. Photodynamic activity of curcumin and phycocyanin delivered through chitosan nanoparticles at 100 _g/mL reduced 92% and 88% of biofilm formed by S. aureus and P. aeruginosa respectively. The dose dependent photodynamic antibacterial activity was found to be mediated through the formation of reactive oxygen species. The viability of fibroblast cells was 90% in phycocyanin, 85% in curcumin, 98.5% in sham control CNPs and 88% in CNPs encapsulated with PS at 80 _g/mL. Thus, the study demonstrated the significant reduction of biofilm formed by clinical isolates through photodynamic therapy without detrimental effect to human fibroblast cells.

Collagen Nanoparticle-Mediated Brain Silymarin Delivery: An Approach for Treating Cerebral Ischemia and Reperfusion-Induced Brain Injury.

Silymarin is a bioactive constituent isolated from milk thistle (Silybum marinum). Since its discovery, silymarin has been considered a gold standard drug in treating ailments related to the liver, resulting from alcohol consumption and viral hepatitis. This hepatoprotective nature of silymarin arises out of antioxidative and tissue-regenerating properties of silymarin. However, several recent studies have established the neuroprotective link of silymarin, too. Thus, the current investigation was aimed at exploring the neuroprotective effect of nanosilymarin (silymarin encapsulated inside collagen-based polymeric nanoparticulate drug delivery system). The study aimed at bringing out the role of nanoparticles in enhancing the therapeutic effect of silymarin against neuronal injury, originating out of oxidative-stress-related brain damages in focal cerebral ischemia. Collagen-based micellar nanoparticles were prepared and stabilized using 3-ethyl carbodiimide-hydrochloride (EDC-Hcl) and malondialdehyde (MDA) as crosslinkers. Nanoparticles were characterized using dynamic light scattering (DLS), transmission electron microscopy (TEM), and Fourier transform infrared (FT-IR) spectroscopy techniques, and the size of nanoparticles was found to be around 48 nm. Male albino Wistar rats were pretreated with three different doses of nanosilymarin of 10, 100, and 1,000 μg/kg b.wt and a dose of free silymarin of 100 mg/kg b.wt intraperitoneally (i.p.) for 7 days. Focal cerebral ischemia was induced using the middle cerebral artery occlusion (MCAO) model on the eighth day for 1 h followed by 24 h reperfusion. The animals were then evaluated for neurobehavioral, infarct analysis, biochemical, histopathological, and immunohistochemical studies. All the above parameters showed remarkable improvement in nanosilymarin-treated groups in comparison to the silymarin-treated group. Nanoparticle encapsulation of drug enhanced neuroprotection by increasing drug bioavailability and targeting. Thus, the present study concluded with satisfactory results, showing the critical role played by nanoparticles in improving the neuroprotection at very low drug doses.

Nanoparticle-Mediated Delivery of 2-Deoxy-D-Glucose Induces Antitumor Immunity and Cytotoxicity in Liver Tumors in Mice.

Background & AimsImmune checkpoint inhibitors have shed light on the importance of antitumor immunity as a therapeutic strategy for hepatocellular carcinoma (HCC). The altered glucose metabolism known as the Warburg effect recently has gained attention as a cancer immune-resistance mechanism. Considering glycolysis inhibitors as therapeutic agents, their specific delivery to cancer cells is critical not to induce adverse effects. Thus, we investigated antitumor effects of a glycolysis inhibitor, consisting of 2-deoxy-D-glucose (2DG)-encapsulated poly(lactic-co-glycolic acid) (PLGA) nanoparticles (2DG-PLGA-NPs), against hepatocellular carcinoma in mice.MethodsThe antitumor effects of 2DG-PLGA-NPs were examined using hepatoma cell lines, xenograft tumors, and hepatocarcinogenic and syngeneic mouse models.ResultsThe 2DG-PLGA-NPs induced cytotoxic effects and antitumor immunity through enhanced T-cell trafficking. In addition, 2DG-PLGA-NPs induced decreased lactate production and increased interferon-γ–positive T cells in liver tumors. Human CD8+ T cells cocultured with 2DG-PLGA-NP–treated Huh7 cells showed their increased interferon-γ production and glucose uptake compared with the CD8+ T cells co-cultured with PLGA-NP–treated Huh7 cells. Chemotaxis of CD8+ T cells was suppressed by lactate and enhanced by glucose. Interferon-γ enhanced CD8+ T-cell chemotaxis in both an autocrine and paracrine manner. Notably, the 2DG-PLGA-NPs augmented chemokine (CXCL9/CXCL10) production in liver tumors via interferon-γ–Janus kinase–signal transducers and activator of transcription pathway and 5' adenosine monophosphate-activated protein kinase–mediated suppression of histone H3 lysine 27 trimethylation. These 2DG-PLGA-NPs not only amplified antitumor effects induced by sorafenib or an anti–programmed death-1 antibody, but also suppressed anti–programmed death-1–resistant tumors.ConclusionsThe newly developed 2DG-PLGA-NPs showed antitumor immunity and cytotoxicity in liver tumors in mice, suggesting the potential of 2DG-PLGA-NPs for future clinical applications.

Gold Nanoparticles Mediated Drug-Gene Combinational Therapy for Breast Cancer Treatment.

BackgroundCancer is a complex heterogeneous disease to which singular modes of treatment mostly fail to produce a desired therapeutic efficacy. Targeting different cellular pathways using combinational therapies has been gaining popularity in cancer treatment, with the added benefit of reducing dosage and side effects.MethodsA gold nanoparticle-mediated drug delivery nanoplatform was developed for co-delivery of doxorubicin and polo-like kinase 1 (PLK1) siRNA. Gold nanoparticles were coated with polyethyleneimine to facilitate assembly of PLK1 on the surface. Doxorubicin was loaded on nanoparticles through a pH-sensitive linker with a thiol group at one terminal end for controlled release.ResultsThe therapeutic efficiency of this co-delivery system was evaluated in 2D and 3D cultured systems. The reduced IC50 value clearly demonstrated the synergistic effect of combined drug and gene delivery over their individual delivery in a cancer treatment model.ConclusionThis study may provide an adaptable, facile platform to investigate drug-siRNA combinations for cancer inhibition.