Pharmacological and toxicological evaluation of methyl 4-hydroxy-2H-1,2-benzothiazine-3-carboxylate 1,1-dioxoide against haloperidol induced Parkinson like symptoms in animal model: In-vitro and in-vivo studies.

In Parkinson's disease (PD), degradation of dopaminergic neurons in substantia nigra causes striatal deficiency of dopamine, which results in tremors, bradykinesia with instability in posture, rigidity and shuffled gait. Prevalence of PD increases with age as from 65 to 85 years. In an attempt to devise targeted safe therapy, nanoparticles of methyl 4-hydroxy-2H-1,2-benzothiazine-3-carboxylate 1,1-dioxide (MBD) (MBDN), were prepared and their acute toxicity and safety was evaluated. Thirty-six healthy albino mice were randomly divided into six groups (n = 6): normal control, diseased control, standard (levodopa/carbidopa (100/25 mg/kg) and the remaining three groups were administered 1.25, 2.5 and 5 mg/kg MBDN during 21 days study. Except control, all mice, were injected haloperidol (1 mg/ kg i.p.) 1-h prior to treatment to induce PD. Acute toxicity test showed, no effect of MBDN on lipid profile, brain, renal and liver function and histoarchitecture of kidney, liver and heart, except decreased (p < 0.05) platelet count. Behavioral studies showed significant improvement (p < 0.001) in motor function and reduction of oxidation status in a MBDN in a dose dependent manner. Thus, the study findings revealed significance of MBDN as a selective MAO-B inhibitor for the improvement of Parkinson's symptoms in animal model.

Performance of two egg parasitoids of brown marmorated stink bug before and after cold storage.

Introduction: The genus Trissolcus includes a number of egg parasitoids that are known to contribute to the control of Halyomorpha halys. The number of progenies, particularly females, is important for the efficient mass rearing of species used in augmentative biological control programs. Cold storage is an important technique for extending the shelf life of natural enemies used in such programs. Methods: We assessed how fecundity, sex ratio, lifespan, and the number of hosts parasitized within 24 h were affected by host density for T. japonicus and T. cultratus when offered fresh H. halys eggs and how these parameters were affected if adult parasitoids were first placed in cold storage (11°C in the dark) for 19 weeks before being used for propagation. Results: The fecundity were 110.2 and 84.2 offspring emerged at 25°C, for parasitoids not placed in cold storage; among the offspring that emerged, 82.6% and 85.6% were female for T. japonicus and T. cultratus, respectively. If first placed in cold storage, T. japonicus and T. cultratus produced 35.1 and 24.6 offspring per female, respectively, although cold storage significantly extended the shelf life. The survival rates of parasitoids that were placed in cold storage were 90.3% and 81.3% for females, and 3.2% and 0.9% for males of T. japonicus and T. cultratus, respectively. The number of hosts parasitized within 24 h was not shown to be density dependent, but it was significantly lower after cold storage. Discussion: This information can be used to estimate the likely production for augmented rearing colonies for use in biological control programs.

Differences in morphology, mitochondrial genomes, and reproductive compatibility between two clades of parasitic wasps Aphelinus mali (Hymenoptera: Aphelindae) in China.

Aphelinus mali (Haldeman) (Hymenoptera: Aphelinidae) in China is comprised of two clades (termed, the Shandong and Liaoning clades). In order to clarify the genetic relationship between these two clades, we compared and analyzed the morphological characteristics and the mitochondrial genome of each, and performed a hybridization experiment. Morphological results showed that both males and females of the Liaoning clade were larger than Shandong clade, in terms of whole body, abdominal, wing and antennal lengths, however, there were no significant differences between clades for total length of the middle or hind leg of females. The length of the mitochondrial genome of the Shandong clade was 14415 bp and, for the Liaoning clade, it was 14804 bp. Each contained 31 genes, including 13 protein-encoded genes, 16 tRNA genes, and 2 rRNA genes. The highest AT level among the 13 protein-coding genes for the two clades were the same gene (ATP8) (Shandong clade, 91.52%; Liaoning clade, 90.91%). By hybridization and backcrossing, we found that there was no cross incompatibility between these two clades of A. mali. Our results indicate that the historic geographical isolation between these clades has not yet caused reproductive isolation of these populations, and they belong to the same species.

Tritrophic Interactions among Arthropod Natural Enemies, Herbivores and Plants Considering Volatile Blends at Different Scale Levels.

Herbivore-induced plant volatiles (HIPVs) are released by plants upon damaged or disturbance by phytophagous insects. Plants emit HIPV signals not merely in reaction to tissue damage, but also in response to herbivore salivary secretions, oviposition, and excrement. Although certain volatile chemicals are retained in plant tissues and released rapidly upon damaged, others are synthesized de novo in response to herbivore feeding and emitted not only from damaged tissue but also from nearby by undamaged leaves. HIPVs can be used by predators and parasitoids to locate herbivores at different spatial scales. The HIPV-emitting spatial pattern is dynamic and heterogeneous in nature and influenced by the concentration, chemical makeup, breakdown of the emitted mixes and environmental elements (e.g., turbulence, wind and vegetation) which affect the foraging of biocontrol agents. In addition, sensory capability to detect volatiles and the physical ability to move towards the source were also different between natural enemy individuals. The impacts of HIPVs on arthropod natural enemies have been partially studied at spatial scales, that is why the functions of HIPVs is still subject under much debate. In this review, we summarized the current knowledge and loopholes regarding the role of HIPVs in tritrophic interactions at multiple scale levels. Therefore, we contend that closing these loopholes will make it much easier to use HIPVs for sustainable pest management in agriculture.

Co-delivery of carbonic anhydrase IX inhibitor and doxorubicin as a promising approach to address hypoxia-induced chemoresistance.

Hypoxia, an oxygen-deprived condition of the tumor, is one of the major reasons for resistance to chemotherapy. Carbonic anhydrases are generally involved in pH homeostasis in normal conditions, but in solid tumors having a strong relation with hypoxia, the carbonic anhydrase IX (CA-IX) enzyme is overexpressed and results in an extracellular acidic environment. For most weakly basic anticancer drugs, including doxorubicin (Dox), the ionization in an acidic environment limits their cellular uptake, and consequently, the tumor exposure to the drug at sub-therapeutic concentration comes out as chemoresistance. Herein, a combined drug delivery system of liposomes and mesoporous silica nanoparticles (MSNPs) was developed for the co-delivery of the CA-IX enzyme inhibitor and Dox in hypoxic condition. The unique structure of MSNPs with higher surface area was utilized for higher drug loading and sustained release of Dox. Additionally, the biocompatible nature of liposomal coating as a second loading site for the CA-IX enzyme inhibitor has provided gatekeeping effects at pore opening to avoid premature drug release. Lipid coated MSNPs as a co-delivery system for Dox and the CA-IX inhibitor have synergistic cytotoxic effects against MDA-MB 231 breast cancer cells in hypoxic conditions. These findings assure the potential of this drug delivery system to overcome hypoxia-related chemoresistance.

Reproductive attributes and functional response of Anastatus japonicus on eggs of Antheraea pernyi, a factitious host.

BACKGROUND: Anastatus japonicus Ashmead (Hymenoptera: Eupelmidae) is a solitary egg endoparasitoid that has been studied for inundative biological control of Halyomorpha halys Stål (Hemiptera: Pentatomidae) in China. In this study, we assessed the reproductive attributes and functional response of Anastatus japonicus on a factitious host, Antheraea pernyi (Guérin-Méneville) (Lepidoptera: Anthelidae) at 25 ± 1 °C, 70 ± 5% relative humidity and 16 h:8 h light/dark photoperiod. RESULTS: The mean lifetime fecundity of Anastatus japonicus females was 404.3 progeny produced over an average oviposition period of 42.3 days. The sex ratio of adult progeny was slightly male biased (51.2%), whereas more female progeny were produced before day 20 of a female's life. Single 1-day-old mated Anastatus japonicus females exhibited a type II functional response to increasing host densities (1-50 eggs), with an inverse host density-dependent pattern of percent parasitism. The upper limit to the daily attack rate was estimated as 7.6 Antheraea pernyi eggs. Furthermore, mutual interference among Anastatus japonicus females occurred when increasing densities of parasitoids (1, 2, 4, 8, 16) were exposed to 30 host eggs. CONCLUSION: Laboratory functional response result revealed that individual Anastatus japonicus might be unable to respond effectively to increasing host density in the field, which could be compensated by releasing larger numbers of wasps. Strong mutual interference among foraging Anastatus japonicus females should be considered in any future inundative biological control programs for the sustainable management of Halyomorpha halys or other host insect pests. © 2022 The Authors. Pest Management Science published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.

Plant Volatiles and Herbivore Induced Plant Volatiles from Chili Pepper Act as Attractant of the Aphid Parasitoid Aphelinus varipes (Hymenoptera: Aphelinidae).

Plants have evolved a number of different chemical defenses, covering nearly all classes of (secondary) metabolites, that represent a major barrier to herbivory: some are constitutive; others are induced after attacks from herbivores (HIPVs) and may elicit the attraction of predators and parasitoids. Here, we studied how the female solitary endoparasitoid Aphelinus varipes responds to plant and host aphid volatiles in a series of experiments on five commercially important vegetables that were either healthy or infested with the aphid Myzus persicae: chili pepper, eggplant, crown daisy, Chinese cabbage and cabbage. The results for the olfactory responses of A. varipes showed that the presence of M. persicae increased the attraction of the endoparasitoid to the infested plants. In a second experiment, volatiles from highly attractive and repellent plants were obtained via headspace collection to investigate volatiles from healthy and aphid-damaged plants. The results for the differences in volatile profiles in response to aphid infestation in chili pepper cultivar were dominated by the volatile blends, including α-pinene, decanal and phthalic acid, while in cabbage they were dominated by isophorone. Moreover, when HIPVs with different concentrations were compared, α-pinene at a dose rate of 100 ng/µL attracted more parasitoids, and the comparison was useful to understand the mechanisms of plant secondary volatiles during aphid infestation and to provide new resources to control this insect pest. Overall our study shows how HIPVs can bolster tritrophic interactions by enhancing the attractiveness of parasitoids.

Short Neuropeptide F and Its Receptor Regulate Feeding Behavior in Pea Aphid (Acyrthosiphon pisum).

Insect short neuropeptide F (sNPF), an ortholog of prolactin-releasing peptide of invertebrates, regulates diverse biological processes, including feeding, olfaction, locomotion, and sleep homeostasis in insects. However, its function is still unclear in an important model insect and agricultural pest, the pea aphid (Acyrthosiphon pisum). Here, we investigated short neuropeptide F (ApsNPF) and its receptor (ApsNPFR) in A. pisum. The sNPF gene contains three exons and two long introns. In addition, the genome contains a single sNPF receptor with seven transmembrane domains. Stage- and tissue-specific transcript profiling by qRT-PCR revealed that ApsNPF and ApsNPFR were mainly expressed in the central nervous system. The receptor was also detected in antennae, midgut, and integument. The highest expression levels were found in first instar nymphs compared to other developmental stages. Besides, the starvation-induced pattern indicated that the sNPF network depends on the nutritional state of the insect. An electrical penetration graph showed that probing time and phloem duration of A. pisum on broad bean plants decreased in response to dssNPF and dssNPFR in RNAi assays. sNPF silencing reduced the number of nymphs per female but not aphid survival. We believe that our results advance in-depth knowledge of the sNPF/sNPFR signaling cascade and its place in regulating feeding behavior in insects. In turn, it may contribute to the potential design of new strategies to control aphids, with a focus on the sNPF system.

Enhancement of the Solubility and Bioavailability of Pitavastatin through a Self-Nanoemulsifying Drug Delivery System (SNEDDS).

The purpose of the study was to develop an SNEDDS to improve the solubility and bioavailability of pitavastatin. The solubility of pitavastatin in different oils, surfactants, and co-surfactants was determined and a pseudo-ternary phase diagram was constructed. The SNEDDS was characterized by zeta-sizer, zeta-potential, FTIR, DSC, and TGA. Release and permeation of pitavastatin from the SNEDDS was studied for 12 and 24 h, respectively. The lipolysis test, RBC lysis, effect on lipid profile, and pharmacokinetics were studied. The SPC3 formulation showed a 104 ± 1.50 nm particle size, a 0.198 polydispersity index (PDI), and a -29 zeta potential. FTIR, DSC, and TGA showed the chemical compatibility and thermal stability. The release and permeation of pitavastatin from SPC3 was 88.5 ± 2.5% and 96%, respectively. In the lipolysis test, the digestion of SPC3 yielded a high amount of pitavastatin and showed little RBC lysis. The lipid profile suggested that after 35 days of administration of the SNEDDS, there was a marked decrease in TC, LDL, and triglyceride levels. The SNEDDS of SPC3 showed an 86% viability of Caco-2 cells. Pharmacokinetics of SPC3 showed improved values of Cmax, Tmax, half-life, MRT, AUC, and AUMC compared to the reference formulation. Our study demonstrated that the SNEDDS effectively enhanced the solubility and bioavailability of a BCS class II drug.

Complete mitochondrial genomes of four species of praying mantises (Dictyoptera, Mantidae) with ribosomal second structure, evolutionary and phylogenetic analyses.

Praying mantises are distributed all over the world. Though some Mantodea mitogenomes have been reported, an evolutionary genomic and phylogenetic analysis study lacks the latest taxonomic system. In the present study, four new mitogenomes were sequenced and annotated. Deroplatys truncate, D. lobate, Amorphoscelis chinensis and Macromantis sp. belong to Deroplatyidae, Amorphoscelidae and Photinaidae family, respectively. Our results indicated that the ATP8 gene may be lost in D. truncate and D. lobata mt genome, and four tRNA genes have not been found in D. truncate, D. lobata and Macromantis sp. A dN/dS pair analysis was conducted and it was found that all genes have evolved under purifying selection. Furthermore, we tested the phylogenetic relationships between the eight families of the Mantodea, including 35 species of praying Mantis. Based on the complete mitochondrial genome data, it was also suggested as sister to Deroplatyidae + Mantidae, Metallyticus sp., the only representative of Metallyticidae, is sister to the remaining mantises. Our results support the taxonomic system of Schwarz and Roy and are consistent with previous studies.

Ultrasound-Responsive Smart Drug Delivery System of Lipid Coated Mesoporous Silica Nanoparticles.

The immediate release of chemotherapeutics at the target site, along with no premature release in circulation is always challenging. The purpose of this study was to develop a stimuli responsive drug delivery system, composed of lipid supported mesoporous silica nanoparticles (MSNPs) for triggered drug release at the target site and simultaneously avoiding the premature release. MSNPs with a higher drug loading capacity and very slow release were designed so as to enhance release by FDA approved US-irradiation. Doxorubicin, as a model drug, and perfluoropentane (PFP) as a US responsive material, were entrapped in the porous structure of MSNPs. Lipid coating enhanced the cellular uptake and in addition provided a gatekeeping effect at the pore opening to reduce premature release. The mechanical and thermal effects of US induced the conversion of liquid PFP to a gaseous form that was able to rupture the lipid layer, resulting in triggered drug release. The prolonged stability profile and non-toxic behavior made them suitable candidate for the delivery of anticancer drugs. This smart system, with the abilities of better cellular uptake and higher cytotoxic effects on US-irradiation, would be a good addition to the applied side of chemotherapeutic advanced drug delivery systems.

CCHamide2-receptor regulates feeding behavior in the pea aphid, Acyrthosiphon pisum.

Neuropeptide CCHamide-2 is a recently discovered peptide presents in many arthropods and it is the ligand of the CCHamide-2 receptor (CCHa2-R), which is playing a regulatory role in diverse physiological processes, such as feeding, insulin production, lipid metabolism, growth and reproduction, however, the function of this gene in aphids is still unknown. Here, we characterized and determined the presumed role of CCHa2-R signaling in the wingless pea aphid, Acyrthosiphon pisum. Quantitative real-time reverse transcription-PCR (qRT-PCR) revealed the expression levels of CCHa2-R transcripts in different development stages and different tissues, which indicates that the CCHa2-R expression was high in the first instar as compared to the upcoming nymphal instars and adult and was predominantly high in the brain. The CCHa2-R transcript levels were significantly up-regulated in starved aphids as compared to fed aphids. Moreover, RNAi knockdown by the injection of dsRNA-CCHa2-R significantly reduced the expression and also reduced their food intake in adult aphids, as revealed by electrical penetration graphs (EPGs) results. CCHa2-R-silencing was also shown to reduce reproduction but not survival in A. pisum. These observations suggest a role for the CCHa2-R pathway in the response of wingless parthenogenetic aphids to their nutritional status, and this role involves the regulation of the expression of CCHa2-R. Overall, the results of these experiments indicate that CCHa2-R plays a dominant role in the regulation of feeding in A. pisum.

Enhanced efficacy and drug delivery with lipid coated mesoporous silica nanoparticles in cancer therapy.

The exposure of cancer cells to subtherapeutic drug concentrations results in multidrug resistance (MDR). The uniqueness of mesoporous silica nanoparticles (MSNPs) with larger surface area for higher drug loading can solve the issue by delivering higher amounts of chemotherapeutics to the cancer cells. However, premature drug release and lower biocompatibility remain challenging. Lipid coating of MSNPs at the same time, can enhance the stability and biocompatibility of nanocarriers. Furthermore, the lipid coating can reduce the systemic drug release and deliver higher amounts to the tumor site. Herein, lipid coated MSNPs were prepared by utilizing cationic liposomes and further investigations were made. Our studies have shown the higher entrapment of doxorubicin (Dox) to MSNPs due to availability of porous structure. Lipid coating could provide a barrier to sustain the release of drug along with reduced premature leakage. In addition, the biocompatibility and enhanced interaction of cationic liposomes to cell membranes resulted in better cellular uptake. Lipid coated silica nanoparticles have shown higher cellular toxicity as compared to non-lipid coated particles. The increase in cytotoxicity with time supports the hypothesis of sustained release of drug from lipid coated MSNPs. We propose the Lip-Dox-MSNPs as an effective approach to treat cancer by delivering and maintaining effective concentration of drugs to the tumor site without systemic side effects.

Host-Plant Variations Affect the Biotic Potential, Survival, and Population Projection of Myzus persicae (Hemiptera: Aphididae).

The green peach aphid, Myzus persicae Sulzer (Hemiptera: Aphididae), a polyphagous insect pest is a major threat to a wide range of crops worldwide. Aiming to evaluate the life history traits of M. persicae, feeding on different host plants, we used five vegetables: cabbage, Brassica oleracea (Brassicaceae); chinese cabbage, B. rapa (Brassicaceae); chili pepper, Capsicum annum (Solanaceae); crown daisy, Chrysanthemum coronarium (Asteraceae); and eggplant, Solanum melongena (Solanaceae). TWOSEX-MSchart software was used for the statistical analysis about the age-stage, two-sex life table theory. The highest fecundity (69.65 individuals) rate of M. persicae, intrinsic rate of increase (r = 0.425 d-1), finite rate of increase (λ = 1.531 d-1), net reproductive rate (R0 = 69.65 offspring), and shortest mean generation time (T = 9.964 d) were recorded on the chili pepper plant. Whereas, lower fitness occurred on cabbage. The findings attained from population growth parameters indicate that chili pepper is the most susceptible plant, while cabbage is resistant to aphids. Population projection results also supported this statement, as the final total population size on cabbage was significantly lower than other plants. The reported information would be useful for devising integrated pest management programs, particularly those involving M. persicae. This information also suggests the adaptability of M. persicae causing economic damage to these vegetable cultivars.

Lipoparticles for Synergistic Chemo-Photodynamic Therapy to Ovarian Carcinoma Cells: In vitro and in vivo Assessments.

PURPOSE: Lipoparticles are the core-shell type lipid-polymer hybrid systems comprising polymeric nanoparticle core enveloped by single or multiple pegylated lipid layers (shell), thereby melding the biomimetic properties of long-circulating vesicles as well as the mechanical advantages of the nanoparticles. The present study was aimed at the development of such an integrated system, combining the photodynamic and chemotherapeutic approaches for the treatment of multidrug-resistant cancers. METHODS: For this rationale, two different sized Pirarubicin (THP) loaded poly lactic-co-glycolic acid (PLGA) nanoparticles were prepared by emulsion solvent evaporation technique, whereas liposomes containing Temoporfin (mTHPC) were prepared by lipid film hydration method. Physicochemical and morphological characterizations were done using dynamic light scattering, laser doppler anemometry, atomic force microscopy, and transmission electron microscopy. The quantitative assessment of cell damage was determined using MTT and reactive oxygen species (ROS) assay. The biocompatibility of the nanoformulations was evaluated with serum stability testing, haemocompatibility as well as acute in vivo toxicity using female albino (BALB/c) mice. RESULTS AND CONCLUSION: The mean hydrodynamic diameter of the formulations was found between 108.80 ± 2.10 to 405.70 ± 10.00 nm with the zeta (ζ) potential ranging from -12.70 ± 1.20 to 5.90 ± 1.10 mV. Based on the physicochemical evaluations, the selected THP nanoparticles were coated with mTHPC liposomes to produce lipid-coated nanoparticles (LCNPs). A significant (p< 0.001) cytotoxicity synergism was evident in LCNPs when irradiated at 652 nm, using an LED device. No incidence of genotoxicity was observed as seen with the comet assay. The LCNPs decreased the generalized in vivo toxicity as compared to the free drugs and was evident from the serum biochemical profile, visceral body index, liver function tests as well as renal function tests. The histopathological examinations of the vital organs revealed no significant evidence of toxicity suggesting the safety and efficacy of our lipid-polymer hybrid system.

Lipodendriplexes mediated enhanced gene delivery: a cellular to pre-clinical investigation.

Clinical success of effective gene therapy is mainly hampered by the insufficiency of safe and efficient internalization of a transgene to the targeted cellular site. Therefore, the development of a safe and efficient nanocarrier system is one of the fundamental challenges to transfer the therapeutic genes to the diseased cells. Polyamidoamine (PAMAM) dendrimer has been used as an efficient non-viral gene vector (dendriplexes) but the toxicity and unusual biodistribution induced by the terminal amino groups (-NH2) limit its in vivo applications. Hence, a state of the art lipid modification with PAMAM based gene carrier (lipodendriplexes) was planned to investigate theirs in vitro (2D and 3D cell culture) and in vivo behaviour. In vitro pDNA transfection, lactate dehydrogenase (LDH) release, reactive oxygen species (ROS) generation, cellular protein contents, live/dead staining and apoptosis were studied in 2D cell culture of HEK-293 cells while GFP transfection, 3D cell viability and live/dead staining of spheroids were performed in its 3D cell culture. Acute toxicity studies including organ to body index ratio, hematological parameters, serum biochemistry, histopathological profiles and in vivo transgene expression were assessed in female BALB/c mice. The results suggested that, in comparison to dendriplexes the lipodendriplexes exhibited significant improvement of pDNA transfection (p < 0.001) with lower LDH release (p < 0.01) and ROS generation (p < 0.05). A substantially higher cellular protein content (p < 0.01) and cell viability were also observed in 2D culture. A strong GFP expression with an improved cell viability profile (p < 0.05) was indicated in lipodendriplexes treated 3D spheroids. In vivo archives showed the superiority of lipid-modified nanocarrier system, depicted a significant increase in green fluorescent protein (GFP) expression in the lungs (p < 0.01), heart (p < 0.001), liver (p < 0.001) and kidneys (p < 0.001) with improved serum biochemistry and hematological profile as compared to unmodified dendriplexes. No tissue necrosis was evident in the animal groups treated with lipid-shielded molecules. Therefore, a non-covalent conjugation of lipids with PAMAM based carrier system could be considered as a promising approach for an efficient and biocompatible gene delivery system.

Downregulation of MDR 1 gene contributes to tyrosine kinase inhibitor induce apoptosis and reduction in tumor metastasis: A gravity to space investigation.

P-glycoprotein (P-gp) associated multidrug resistance (MDR) represents a major failure in cancer treatment. The overexpression of P-gp is responsible for ATP-dependent efflux of drugs that decrease their intracellular accumulation. An effective downregulation of MDR1 gene using small interfering RNA (siRNA) is one of the safe and effective tools to overcome the P-gp triggered MDR. Therefore, the development of an efficient and non-toxic carrier system for siRNA delivery is a fundamental challenge for effective cancer treatment. Polyamidoamine (PAMAM) dendrimer has been used for efficient delivery of siRNA (dendriplexes) to the tumor cells but the associated toxicity problems render its use in biological applications. A non-covalent lipid modification (lipodendriplexes) is supposed to offer a promising strategy to overcome the demerits linked to the naked dendriplexes system. In the current study, we deliver siRNA, designed against MDR1 gene (si-MDR1), in colorectal carcinoma cells (Caco-2), having overexpression of P-gp, to check the role of MDR1 gene in tumor progression and multidrug resistance using two dimensional (2D) and three dimensional (3D) environment. Imatinib mesylate (IM), a P-gp substrate, was used as model drug. Our results revealed that the effective knockdown by lipodendriplexes system can significantly reduce the tumor cell migration in 2D (p < 0.001) and 3D (p < 0.001) cell cultures as compared to unmodified dendriplexes and si-Control groups. It was also observed that lipodendriplexes aided downregulation of MDR1 gene effectively, re-sensitized the Caco-2 cells for IM uptake and showed a significantly (p < 0.001) higher apoptosis. Our findings imply that our lipodendriplexes system has a great potential for siRNA delivery, however, further in vivo application using a suitable targeted system can play a major role for better cancer therapeutics.

Wavelength dependent photo-cytotoxicity to ovarian carcinoma cells using temoporfin loaded tetraether liposomes as efficient drug delivery system.

5,10,15,20-Tetrakis(3-hydroxyphenyl)chlorin (mTHPC; temoporfin) is one of the most potent second-generation photosensitizers available today for the treatment of a variety of clinical disorders and has a unique capability of being activated at different wavelengths. However, due to its highly lipophilic nature, poor solubility in the aqueous media and poor bioavailability limits its application in anticancer therapies. To overcome these potential issues, we developed three different liposomal formulations with mTHPC encapsulated in hydrophobic milieu thus increasing the bioavailability of the drug. The prepared formulations were characterized in terms of hydrodynamic diameter, surface charge, encapsulation efficiency, and stability studies. The mean size of the liposomes was found to be in the nanoscale range (about 100 nm) with zeta potential ranging from -6.0 to -13.7 mV. mTHPC loaded liposomes were also evaluated for morphology using atomic force microscopy (AFM) and cryo-transmission electron microscopy (cryo-TEM). Data obtained from the hemocompatibility experiments showed that these formulations were compatible with blood showing less than 10% hemolysis and coagulation time lower than 40 s. The results obtained from the single-cell gel electrophoresis assay also demonstrated no incidence of genotoxicity. Photodynamic destruction of SK-OV-3 cells using mTHPC loaded liposomes showed a dose-response relationship upon irradiation with two different wavelength lights (blue λ = 457 nm & red λ = 652 nm). A 10-fold pronounced effect was produced when liposomal formulations were irradiated at 652 nm as compared to 457 nm. This was also evaluated by the quantitative assessment of reactive oxygen production (ROS) using fluorescence microscopy. The qualitative assessment of PDT pre- and post-irradiation was visualized using confocal laser scanning microscopy (CLSM) which demonstrated an intense localization of mTHPC liposomes in the perinuclear region. Chick chorioallantoic membrane assay (CAM) was used as an alternative in-ovo model to demonstrate the localized destruction of tumor microvasculature. Overall, the prepared nanoformulation is a biocompatible, efficient and well characterized delivery system for mTHPC for the safe and effective PDT.

Targeted ErbB3 cancer therapy: A synergistic approach to effectively combat cancer.

Surface modification of nanoparticles with aptamer is gaining popularity lately due to its selective targeting and low immunogenicity. In this study, sorafenib tosylate (SFB) was loaded in biodegradable PLGA nanoparticles prepared by solvent evaporation method. The surfaces of drug deprived and drug-loaded particles (PN and PNS, respectively) were coupled with aptamer to target ErbB3 using EDC/NHS chemical modification. Nanoparticles were characterized with regard to their size, shape and chemical composition by dynamic light scattering, atomic force microscopy, FTIR and elemental analysis respectively. To evaluate the particles in vitro cell culture studies were performed. Cell viability assay, pathway analysis and apoptosis assay showed cellular toxicity in the presence of aptamer in PNS-Apt (p < 0.001). Metastatic progression assay showed decreased cell migration in the presence of aptamer and SFB. Confocal laser scanning microscopy was used to visualize the receptor-mediated time-dependent intracellular uptake and distribution of the nanoparticles throughout the cytoplasm. The findings of the current study demonstrated the potential efficacy of the surface modified SFB-loaded particles against ErbB3.

Selective anti-ErbB3 aptamer modified sorafenib microparticles: In vitro and in vivo toxicity assessment.

The delivery of aptamer modified therapeutic moieties to specific tissue sites has become one of the major therapeutic choices to reduce the toxicity of inhibitory drugs. Bearing this in mind, the current study was designed using sorafenib (SFB) encapsulated microparticles (MP) prepared with biodegradable poly (D, L-lactic-co-glycolic acid) (PLGA) copolymer. The surfaces of these microparticles were modified with RNA aptamer having a binding affinity towards ErbB3 receptors. SFB-loaded MP (MPS) were prepared by o/w solvent evaporation method and the surface was coupled with the amino group of aptamer by EDC/NHS chemistry. Physiochemical investigations were done by dynamic light scattering, scanning electron microscopy and FTIR. In vitro apoptosis assay, cell viability assay and metastatic progression showed a significant decrease (p < 0.001) in vitro cell viability for MPS and MPS-Apt as compared to MP. The synergistic combination of SFB and aptamer also decreased the metastatic progression of cells for an extended period. Microparticles were also evaluated for in vivo toxicity in female BALB/c mice. It was evident that the presence of aptamer decreased the generalized toxicity of MPS-Apt, as measured by mean body weight loss and blood profiles, keeping all the blood formed elements level within acceptable limits. The histopathological investigations showed some necrotic and pyknotic bodies. In a similar fashion, liver function test and renal function tests showed pronounced effects of formulations on vital organs.