Molecular targets in arthritis and recent trends in nanotherapy

Due to its severity and increasing epidemiology, arthritis needs no description. There are various forms of arthritis most of which are disabling, very painful, and common. In spite of breakthroughs in the field of drug discovery, there is no cure for arthritis that can eliminate the disease permanently and ease the pain. The present review focuses on some of the most successful drugs in arthritis therapy and their side effects. Potential new targets in arthritis therapy such as interleukin-1β, interleukin-17A, tumor necrosis factor alpha, osteopontin, and several others have been discussed here, which can lead to refinement of current therapeutic modalities. Mechanisms for different forms of arthritis have been discussed along with the molecules that act as potential biomarkers for arthritis. Due to the difficulty in monitoring the disease progression to detect the advanced manifestations of the diseases, drug-induced cytotoxicity, and problems with drug delivery; nanoparticle therapy has gained the attention of the researchers. The unique properties of nanoparticles make them highly attractive for the design of novel therapeutics or diagnostic agents for arthritis. The review also focuses on the recent trends in nanoformulation development used for arthritis therapy. This review is, therefore, important because it describes the relevance and need for more arthritis research, it brings forth a critical discussion of successful drugs in arthritis and analyses the key molecular targets. The review also identifies several knowledge gaps in the published research so far along with the proposal of new ideas and future directions in arthritis therapy

Oral administration of iron-saturated bovine lactoferrin-loaded ceramic nanocapsules for breast cancer therapy and influence on iron and calcium metabolism

We determined the anticancer efficacy and internalization mechanism of our polymeric-ceramic nanoparticle system (calcium phosphate nanocores, enclosed in biodegradable polymers chitosan and alginate nanocapsules/nanocarriers [ACSC NCs]) loaded with iron-saturated bovine lactoferrin (Fe-bLf) in a breast cancer xenograft model. ACSC-Fe-bLf NCs with an overall size of 322±27.2 nm were synthesized. In vitro internalization and anticancer efficacy were evaluated in the MDA-MB-231 cells using multicellular tumor spheroids, CyQUANT and MTT assays. These NCs were orally delivered in a breast cancer xenograft mice model, and their internalization, cytotoxicity, biodistribution, and anticancer efficacy were evaluated. Chitosan-coated calcium phosphate Fe-bLf NCs effectively (59%, P≤0.005) internalized in a 1-hour period using clathrin-mediated endocytosis (P≤0.05) and energy-mediated pathways (P≤0.05) for internalization; 3.3 mg/mL of ACSC-Fe-bLf NCs completely disintegrated (~130-fold reduction, P≤0.0005) the tumor spheroids in 72 hours and 96 hours. The IC50 values determined for ACSC-Fe-bLf NCs were 1.69 mg/mL at 10 hours and 1.62 mg/mL after 20 hours. We found that Fe-bLf-NCs effectively (P≤0.05) decreased the tumor size (4.8-fold) compared to the void NCs diet and prevented tumor recurrence when compared to intraperitoneal injection of Taxol and Doxorubicin. Receptor gene expression and micro-RNA analysis confirmed upregulation of low-density lipoprotein receptor and transferrin receptor (liver, intestine, and brain). Several micro-RNAs responsible for iron metabolism upregulated with NCs were identified. Taken together, orally delivered Fe-bLf NCs offer enhanced antitumor activity in breast cancer by internalizing via low-density lipoprotein receptor and transferrin receptor and regulating the micro-RNA expression. These NCs also restored the body iron and calcium levels and increased the hematologic counts

Biodegradable Eri silk nanoparticles as a delivery vehicle for bovine lactoferrin against MDA-MB-231 and MCF-7 breast cancer cells

This study used the Eri silk nanoparticles (NPs) for delivering apo-bovine lactoferrin (Apo-bLf) (~2% iron saturated) and Fe-bLf (100% iron saturated) in MDA-MB-231 and MCF-7 breast cancer cell lines. Apo-bLf and Fe-bLf-loaded Eri silk NPs with sizes between 200 and 300 nm (±10 nm) showed a significant internalization within 4 hours in MDA-MB-231 cells when compared to MCF-7 cells. The ex vivo loop assay with chitosan-coated Fe-bLf-loaded silk NPs was able to substantiate its future use in oral administration and showed the maximum absorption within 24 hours by ileum. Both Apo-bLf and Fe-bLf induced increase in expression of low-density lipoprotein receptor-related protein 1 and lactoferrin receptor in epidermal growth factor (EGFR)-positive MDA-MB-231 cells, while transferrin receptor (TfR) and TfR2 in MCF-7 cells facilitated the receptor-mediated endocytosis of NPs. Controlled and sustained release of both bLf from silk NPs was shown to induce more cancer-specific cytotoxicity in MDA-MB-231 and MCF-7 cells compared to normal MCF-10A cells. Due to higher degree of internalization, the extent of cytotoxicity and apoptosis was significantly higher in MDA-MB-231 (EGFR+) cells when compared to MCF-7 (EGFR-) cells. The expression of a prominent anticancer target, survivin, was found to be downregulated at both gene and protein levels. Taken together, all the observations suggest the potential use of Eri silk NPs as a delivery vehicle for an anti-cancer milk protein, and indicate bLf for the treatment of breast cancer

Ophthalmic combination of SurR9-C84A and trichostatin-A targeting molecular pathogenesis of alkali burn

Background: Alkali burn is a frequently occurring ocular injury that resembles ocular inflammation caused by eye allergies, infection, and refractive surgeries.Methods: We investigated the synergistic regenerative potential of dominant negative survivin mutant (SurR9-C84A) and histone deacetylase (HDAC) inhibitor trichostatin-A (TSA) against alkali burn and corneal haze using human keratocytes and rabbit alkali burn model (Female New Zealand white rabbits).Results: Combination of SurR9-C84A and TSA suppressed levels of transforming growth factor (TGF)-β, alpha smooth-muscle actin (α-SMA), fibronectin and HDAC1, leading to apoptosis in myofibroblast cells and, showed the potential to clear the corneal haze. An insult with 0.5 N NaOH for 1 min led to neutrophils infiltration and formation of large vacuoles in the stroma. Treatments with TSA and SurR9-C84A for 40 min led to improvement in the conjunctival and corneal tissue integrity, marked by an increase in clathrin, and claudin expressions. An increase in TGF-β and endogenous survivin confirmed wound healing and cell proliferation in rabbit cornea. The blood analysis revealed a substantial decrease in the RBC, WBC, platelets, or the hemoglobin content post alkali burn. The cytokine array analysis revealed that NaOH induced expressions of IL-1α and MMP-9, which were found to be significantly downregulated (1.8 and 11.5 fold respectively) by the combinatorial treatment of SurR9-C84A and TSA.Conclusion: Our results confirmed that combination of SurR9-C84A with TSA worked in synergy to heal ocular injury and inflammations due to alkali burn and led to the regeneration of ocular tissue by increasing clathrin, claudin, survivin, and TGF-β and reversal of alkali burn by suppressing IL-1α and MMP-9 without inducing haze

Engineered atherosclerosis-specific zinc ferrite nanocomplex-based MRI contrast agents

BACKGROUND: Cardiovascular diseases are the most prevalent cause of morbidity and mortality affecting millions of people globally. The most effective way to counter cardiovascular complications is early diagnosis and the safest non-invasive diagnostic approach is magnetic resonance imaging (MRI). In this study, superparamagnetic ferrite nanoparticles doped with zinc, exhibiting highly enhanced saturation magnetization and T2 and computed tomography (CT) contrast were synthesized. These nanoparticles have been strategically engineered using bovine lactoferrin (Lf), polyethylene glycol (PEG), and heat shock protein (Hsp)-70 antibody specifically targeting atherosclerosis with potential therapeutic value. The nanocomplexes were further validated in vitro to assess their cytotoxicity, internalization efficiency, effects on cellular proliferation and were assessed for MRI as well as X-ray CT in ex vivo Psammomys obesus rat model. RESULTS: Optimized zinc doped ferrite nanoparticles (Zn0.4Fe2.6O4) with enhanced value of maximum saturation magnetization value on 108.4 emu/g and an average diameter of 24 ± 2 nm were successfully synthesized. Successfully incorporation with bovine lactoferrin, PEG and Hsp-70 (70 kDa) antibody led to synthesis of spherical nanocomplexes (size 224.8 nm, PDI 0.398). A significantly higher enhancement in T2 (p < 0.05, 1.22-fold) and slightly higher T1 (1.09-fold) and CT (1.08-fold) contrast compared to commercial ferrite nanoparticles was observed. The nanocomplexes exhibited effective cellular internalization within 2 h in both THP-1 and Jurkat cells. MRI scans of contrast agent injected animal revealed significant arterial narrowing and a significantly higher T2 (p < 0.05, 1.71-fold) contrast in adult animals when compared to juvenile and control animals. The excised heart and aorta agar phantoms exhibited weak MRI contrast enhancement in juvenile animal but significant contrast enhancement in adult animal specifically at the aortic arch, descending thoracic aorta and iliac bifurcation region with X-ray CT scan. Histological investigation of the contrast agent injected aorta and heart confirmed site target-specific accumulation at the atherosclerotic aortic arch and descending thoracic aorta of the adult animal with severely damaged intima full of ruptured microatheromas. CONCLUSION: Overall, the study demonstrates the strategic development of nanocomplex based bimodal MRI and CT contrast agents and its validation on Psammomys obesus for atherosclerosis diagnostics

Theranostic multimodular potential of zinc-doped ferrite-saturated metal-binding protein-loaded novel nanocapsules in cancers

The present study successfully developed orally deliverable multimodular zinc (Zn) iron oxide (Fe3O4)-saturated bovine lactoferrin (bLf)-loaded polymeric nanocapsules (NCs), and evaluated their theranostic potential (antitumor efficacy, magnetophotothermal efficacy and imaging capability) in an in vivo human xenograft CpG-island methylator phenotype (CIMP)-1(+)/CIMP2(-)/chromosome instability-positive colonic adenocarcinoma (Caco2) and claudin-low, triple-negative (ER(-)/PR(-)/HER2(-); MDA-MB-231) breast cancer model. Mice fed orally on the Zn-Fe-bLf NC diet showed downregulation in tumor volume and complete regression in tumor volume after 45 days of feeding. In human xenograft colon cancer, vehicle-control NC diet-group (n=5) mice showed a tumor volume of 52.28±11.55 mm(3), and Zn-Fe-bLf NC diet (n=5)-treated mice had a tumor-volume of 0.10±0.073 mm(3). In the human xenograft breast cancer model, Zn-Fe-bLf NC diet (n=5)-treated mice showed a tumor volume of 0.051±0.062 mm(3) within 40 days of feeding. Live mouse imaging conducted by near-infrared fluorescence imaging of Zn-Fe-bLf NCs showed tumor site-specific localization and regression of colon and breast tumor volume. Ex vivo fluorescence-imaging analysis of the vital organs of mice exhibited sparse localization patterns of Zn-Fe-bLf NCs and also confirmed tumor-specific selective localization patterns of Zn-Fe-bLf NCs. Dual imaging using magnetic resonance imaging and computerized tomography scans revealed an unprecedented theranostic ability of the Zn-Fe-bLf NCs. These observations warrant consideration of multimodular Zn-Fe-bLf NCs for real-time cancer imaging and simultaneous cancer-targeted therapy