Clinicopathological association of mucormycosis in COVID 19 pandemic.

Context: Coinfection and superadded infections in patients with coronavirus disease 2019 (COVID-19) has been reported on multiple series. The emerging second wave of the pandemic has come with a lot of changes, especially in developing countries like India. One of such changes is sudden, significant rise in mucormycosis cases. Aims: To find out clinicopathological association of invasive mucormycosis with COVID-19 infection status and immunocompromised state. Settings and Design: A cross-sectional study done at a tertiary care centre. Methods and Material: All cases admitted in the dedicated mucormycosis ward between 1-06-2021 and 15-06-2021 were included in the study. The cases were admitted with suspicion of mucormycosis. The histopathological results were correlated with KOH mount and radiological reports. The clinicopathological association of occurrence of mucormycosis in post-covid and non-COVID patients along with other risk factors. Statistical Analysis Used: Odds ratio, chi square test were used to find the association using MS Excel 2010 and SPSS. Results: Thirty-six (81.82%) cases were of the post-COVID status, and 8 cases were non-COVID status. Out of 36 post-COVID patients, 33 (91.67%) showed evidence of invasive mucormycosis and of 8 non-COVIDpatients, 7 had evidence of mucormycosis (odds ratio = 1.57). Out of the total diagnosed cases of mucormycosis, 21 (52.5%) patients were known cases of diabetes mellitus (DM), and 7 (17.5%) cases of newly diagnosed hyperglycemia. Thirty (75%) patients out of 40 had some form of immunocompromised state. This shows statistically significant association of DM and immunocompromised state with the occurrence of mucormycosis in post-COVID patients (chi square value2 = 6.891, P value = 0.008). Twenty-five patients had the history of steroid use during the treatment of COVID-19. Conclusions: The infection with COVID-19 definitely increases the odds of contracting mucormycosis, but most of the cases had diabetes mellitus. So, it is possible that COVID-19 virus predisposes individuals to invasive fungal infection by precipitating DM.

Multicompartment systems: A putative carrier for combined drug delivery and targeting.

In this review, we discuss recent developments in multicompartment systems commonly referred to as vesosomes, as well as their method of preparation, surface modifications, and clinical potential. Vesosomal systems are able to entrap more than one drug moiety and can be customized for site-specific delivery. We focus in particular on the possible reticuloendothelial system (RES) - mediated accumulation of vesosomes, and their application in tumor targeting, as areas for further investigation.

Development and Characterization of Biocompatible Mannose Functionalized Mesospheres: an Effective Chemotherapeutic Approach for Lung Cancer Targeting.

The aim of the present study was to analyze the lung targeting potential of surface engineered mesospheres loaded with doxorubicin hydrochloride (DOX). Gelatin-based DOX encapsulated mesospheres were prepared using a steric stabilization process and surface modified with mannose, using the amino group present on the surface of the mesospheres. Gelatin-DOX-mesospheres (M1) and gelatin-mannosylated-DOX-mesospheres (M2) were characterized for particle size, polydispersity index, zeta potential, and % entrapment efficiency which were found respectively 8.7 ± 0.35, 0.671 ± 0.018, 1.74 ± 0.27, and 80.4 ± 1.2 for (M1) and 9.8 ± 0.41, 0.625 ± 0.010, 0.85 ± 0.11, and 75.1 ± 0.7 for (M2). Furthermore, the mesospheres were characterized by FTIR, DSC, SEM, and TEM. In vitro drug release study of optimized formulation was carried out using the dialysis tube method. The cumulative percent drug release was found to be 79.2 ± 0.1% and 69.6 ± 0.52% respectively for gelatin-DOX-mesospheres and gelatin-mannosylated-DOX-mesospheres. In vitro cytotoxicity of formulations was determined using xenograft A-549 tumor cell lines. The cytotoxicity recorded as IC50 was more in the case of M2 compared to M1. In addition, mesospheres exhibited minimal hemolytic toxicity and appear to be promising for sustained drug delivery of DOX to the lungs. Cytotoxicity assay was conducted on the A-549 cell line. The results revealed that gelatin-mannosylated-DOX-mesospheres were maximally cytotoxic as compared to free DOX as well as gelatin-DOX-mesospheres. The lung's accumulation of drug was measured and found maximum after administration of M2. It may, therefore, be inferred that gelatin-mannosylated-DOX-mesospheres are capable to carry bioactive(s) and can be used specifically to target the lung cancer with minimal side effects.

Nanobiotechnological modules as molecular target tracker for the treatment and prevention of malaria: options and opportunity.

Malaria is one of the major infectious diseases that remains a constant challenge to human being mainly due to the emergence of drug-resistant strains of parasite and also the availability of drugs, which are non-specific for their pharmacodynamic activity and known to be associated with multiple side effects. The disease has acquired endemic proportions in tropical countries where the hygienic conditions are not satisfactory while the environmental conditions favor the proliferation of parasite and its transmission, particularly through the female anopheles. It is obvious that to square up the problems, there is a need for designing and development of more effective drugs, which can combat the drug-resistant strains of the parasite. Molecular biology of the parasite and its homing into host cellular tropics provide multiple drug targets that could judiciously be considered for engineering and designing of new generation antimalarial drugs and also drug delivery systems. Though the recent reports document that against malaria parasite the vaccine could be developed, nevertheless, due to smart mutational change overs by the parasite, it is able to bypass the immune surveillance. The developed vaccine therefore failed to assure absolute protection against the malarial infection. In the conventional mode of treatment antimalarial drugs, the dose and dosage regimen that is followed at large crops up the contraindicative manifestations, and hence compromising the effective treatment. The emerging trends and new updates in contemporary biological sciences, material sciences, and drug delivery domain have enabled us with the availability of a multitude of mode and modules which could plunge upon the nanotechnology in particular to treat this challenging infection. The nanotechnology-based option may be tuned or customized as per the requirements to mark and target i.e. the infected RBCs, for targeted drug delivery. Graphical abstract.

Mannose functionalized plain and endosomolytic nanocomposite(s)-based approach for the induction of effective antitumor immune response in C57BL/6 mice melanoma model.

The goal of present study to assess the antigen specific immunopotentiation effect of mannose functionalized endosomolytic and conventional nanocomposite(s) based combination approach using C57BL/6 mice melanoma model. Endosomolytic and conventional nanocomposite(s) were prepared by double emulsification method. The optimized formulation was extensively characterized for average particle size, zeta potential and PDI of nanocomposite(s) which were measured in range of ≈200 nm, 0.111 ± 0.024, -23.4 ± 2.0 mV, respectively. pH-dependent morphological changes in the surface of MRPRPNs and PRPNs were analyzed by using surface electron microscopy at different time intervals. The cellular uptake assessment of developed formulations were followed by using RAW 264.7 macrophage cell lines. Results revealed that after immunizing B16F10 melanoma cells implanted C57BL/6 mice with combination [endosomolytic and conventional nanocomposite(s)] of nanocomposite(s), a significant increase in the interleukins level i.e. IL-2, IFN-ϒ, IL-12 and IL-6 and OVA Ag(s) specific antibody responses were recorded. Consequently, a strong immunological response was elicited with specific polarization contributing to humoral and activation of CD8+ to cellular responses. Finding of histological examination also support the potential of therapeutic outcome. The present approach based on mannose surface functionalization for targeting to antigen presenting cells and pH-dependent prompt endosomal release and escape can be a promising system for efficient cancer immunotherapy.

C-Type lectin receptor(s)-targeted nanoliposomes: an intelligent approach for effective cancer immunotherapy.

AIM: The purpose of present approach is to target C-Type lectin (CTL) receptors for preferential uptake by the macrophages/dendritic cells and improving the cross-presentation of ovalbumin. MATERIALS & METHODS: Conventional and engineered nanoliposomes (MPNLs) were fabricated and extensively characterized. The nanoliposome(s) was spherical in shape; and their ζ potential, size and ovalbumin loading efficiency were recorded to be 268 ± 4.15 nm, 23.4 ± 0.35 mV, 46.65 ± 1.84%, respectively. RESULTS: The findings demonstrate that MPNLs significantly improved the antigen uptake and its cross-presentation to evoke Th CD8+ cell-mediated cellular immunity. CONCLUSION: In a nutshell, this engineered approach mannose surface modification for active targeting to dendritic cells/macrophages and pH-dependent quick endosomal antigen release is a promising system for efficient cancer immunotherapy.

Theranostic Nanomedicine; A Next Generation Platform for Cancer Diagnosis and Therapy.

In the recent years, theranostic nanomedicine based strategies have gained much attention in the field of oncology particularly, in the development of new generation cancer diagnostic and therapeutic tools. Today, various approaches have been developed for bioactive(s) targeting to predefined pathological sites, as well as for quantification of physiological processes and visualization. Significant attempts have been made to combine therapeutic and diagnostic properties in to a single effective nanomedicine formulation. This concept, coined as "theranostics" is smart nanosystem(s), able to diagnose, bioactive(s) delivery and monitoring of therapeutic response. By combining therapeutic functionalities with molecular imaging, theranostic based strategies may be beneficial in the selection of therapy, planning of treatment, monitoring of objective response and planning of follow-up therapy based on the specific molecular characteristics of a disease. In this manuscript, we reviewed the recent development of theranostic approaches, various nanosystems as theranostic agents and applications of theranostic in cancer therapeutics and diagnostics.

Tailored polymer-lipid hybrid nanoparticles for the delivery of drug conjugate: dual strategy for brain targeting.

The object of the present study was to investigate the glioma targeting propensity of folic acid (F) decorated polymer-lipid hybrid nanoparticles (PLNs) encapsulating cyclo-[Arg-Gly-Asp-D-Phe-Lys] (cRGDfK) modified paclitaxel (PtxR-FPLNs). The prepared PLNs were supposed to bypass the blood-brain barrier (BBB) efficiently and subsequently target integrin rich glioma cells. The developed formulations were characterized for size, shape, drug entrapment efficiency, and in vitro release profile. PtxR-FPLNs demonstrated highest in vitro inhibitory effect, cell apoptosis and cell uptake. Pharmacokinetics and biodistribution studies showed efficacy of PtxR-FPLNs in vivo. In vivo anti-tumor studies clearly revealed that the median survival time for Balb/C mice treated with PtxR-FPLNs (42 days) was extended significantly as compared to PtxR-PLNs (35 days), free PtxR (18 days), Ptx-FPLNs (38 days), Ptx-PLNs (30 days), free Ptx (14 days) and control group (12 days). From the results it can be concluded that the developed dual targeted nanoformulation was able to efficiently cross the BBB and significantly deliver higher amounts of drug to brain tumor for better therapeutic outcome.

Capsaicin delivery into the skin with lipidic nanoparticles for the treatment of psoriasis.

The study aims to explore the potential of solid lipid nanoparticles (SLNs) and nanostructured lipid carriers (NLCs) in improving the topical delivery of capsaicin (CAP) by in vitro and in vivo studies. The lipidic nanoparticles were prepared by solvent diffusion method and were characterized for average particle size, zeta potential and entrapment efficiency. TEM photomicrographs revealed that the particles were nanometric in size. Higher amount of CAP can be encapsulated in the NLCs (87.4 ± 3.28) as compared with SLNs (79.7 ± 2.93%). The cumulative amounts of CAP permeated through the skin and retained in the SC were higher in the case of NLCs as compared with plain drug solution and SLNs. SLNs and NLCs exhibited minimum to no irritation. All the results concluded that NLCs and SLNs have shown a good ability to increase drug accumulation in the various skin layers but NLCs may be a more potential carrier for topical delivery of CAP for an effective therapy of psoriasis.

Polymeric nanomedicines as a promising vehicle for solid tumor therapy and targeting.

Inspite of demanding research that has been undertaken for cancer treatment, cancer is a major cause of mortality. Available conventional treatment options of solid tumor are associated with serious side effects. Nanomedicines mediated fascinating approach may be effectively utilized for efficient tumor targeting by avoiding all the problems associated with conventional chemotherapy. Polymeric nanomedicines such as polymer micelles, polymeric nanoparticles, polymersomes and polymer conjugates currently developed for solid tumor treatment have proved to be efficacious cancer therapeutics. These polymeric nanostructures are able to reach tumor tissue or angiogenic endothelial cells either passively or actively. To date, more advancement in the tumor targeting field includes stimuli sensitive polymeric nanocarriers that pass through the intracellular delivery barriers and release the bioactives in response to the microenvironmental trigger of tumor cell. This review discusses the molecular aspects of solid tumor pathophysiology and its dramatic impact on research for innovative and novel therapeutic approaches linked with tumor-targeting polymeric nanomedicines.

Multifunctional nanomedicines: potentials and prospects.

Nanotechnology is considered to be significant innovative revolution that have found wide spectrum of applications in the fields ranging from medicine, diagnostics, electronics, and communications. Currently used pharmaceutical nanocarriers, such as dendrimers, micelles, nanoparticles, polymeric nanoparticles, microspheres, and many of the nanocarriers particularly in the area of drug delivery, offer a wide variety of useful properties, such as longevity in the blood allowing for their accumulation in pathological areas particularly those with compromised vasculature; specific targeting to certain disease sites; enhanced intracellular penetration of nanomaterial with contrast properties allowing for the direct visualization of carrier in vivo, and stimuli sensitivity allowing for triggered drug release from the carriers under certain physiological conditions. Some of the pharmaceutical carriers have already made their way into clinic, while others are still under preclinical development. Moreover, the engineering of multifunctional nanocarriers with several useful properties can significantly enhance the efficacy of many therapeutic and diagnostic protocols. These novel materials operate at the nanoscale range and provide new and powerful cutting edge tools for imaging, diagnosis, and therapy. This review considers current standing and possible future directions in the emerging area of multifunctional nanocarriers with primary attention on the combination of such properties as longevity, targetability, intracellular penetration, and contrast loading.

Pharmaceutical and immunological evaluation of mucoadhesive nanoparticles based delivery system(s) administered intranasally.

Tri-methyl chitosan synthesis accompanies polymer chain scission, which may affect the carrier and adjuvant properties of the polymer. The main objective of this study was to synthesize the tri-methylated chitosan using mild (TMC-M) and conventional (TMC) method and compare their efficacy as nasal vaccine delivery vehicle. During in vitro studies TMC-M nanoparticles showed the lowest nasal clearance rate when compared with chitosan (CS) and TMC nanoparticles. The immunogenicity of nanoparticles based delivery system(s) was assessed by measuring anti-HBsAg antibody titer in mice serum and secretions after intranasal administration. The alum based HBsAg vaccine injected subcutaneously was used as positive control. Results indicated that alum based HBsAg induced strong humoral but negligible mucosal immunity. However, TMC-M nanoparticles induced stronger immune response at both of the fronts as compared to generated by CS or TMC nanoparticles. Present study demonstrates that TMC-M can be a better carrier adjuvant for nasal subunit vaccines.

Nanocrystallization of poorly water soluble drugs for parenteral administration.

Approximately 50% active substances discovered by combinatorial chemistry and high-throughput screening show poor solubility in water. Out of various available approaches "Nanoedege technology" (Combination of Precipitation and Homogenization) was selected. Amphotericin B (Amp B) was used as a model drug. Three different preparations of Amp B were produced by using three different surfactants Tween80, Pluronic F68, Soya Lecithin and assessed for their efficacy and stability. In this study the Amp B nanosuspension formulation, with the smaller particle size, can be effectively produced with the Nanoedge Method. The pharmacokinetic profiles of Amp B when given in the nanosuspension formulation were different compared to the corresponding raw drug.

Surface engineered nanoparticles for oral immunization.

A rationally designed oral vaccine should be successfully delivered to the intestinal mucosal immune cells, and induce both humoral and cellular counterparts of immunity along with the mucosal immune response. The aim of this study is to mimic these natural infections and excel the utility of a specific ligand for beta1 integrin (RGD peptide) to target M cells which seems to be the only portal for any particulate matter in GIT. The in vivo studies have shown higher antibody titre for alginate coated chitosan nanoparticles compared to plain chitosan nanoparticles. RGD peptide conjugated alginate coated chitosan nanoparticles proved to be the suitable carrier system for antigen delivery to gut associated lymphoid tissue. Based upon the release kinetics and strong systemic as well as mucosal immune response we can conclude that this cost effective carrier construct can be utilized for oral vaccination.

Nanoparticle-based immunopotentiation via tetanus toxoid-loaded gelatin and aminated gelatin nanoparticles.

Gelatin nanoparticles (GNPs) and aminated gelatin nanoparticles (AGNPs) were prepared and used as an adjuvant to improve the delivery of tetanus toxoid (TT). Nanoparticles were characterized in vitro for their size, shape, entrapment, and release. TT-FITC conjugate was used to determine entrapment and release from nanoparticles. The immune-stimulating activity was studied by measuring anti-TT IgG, IgG1, and IgG2a isotype and cytokine responses following subcutaneous (s.c) injection of nanoparticles in BALB/c mice and was compared with alum-TT vaccine. Gelatin and aminated gelatin (AG) specific IgG response was also determined. Both GNPs and AGNPs demonstrated comparable IgG response and a significantly higher (p < 0.05) cytokine response (IL-2 and IFN γ) as compared to alum-TT vaccine. Nanoparticulate formulations elicited both Th1 and Th2 responses and induced negligible undesirable immunogenicity against the carrier, as demonstrated by lower level of gelatin and AG-specific IgG response as compared to control.

Polymeric nanospheres modified with YIGSR peptide for tumor targeting.

YIGSR peptide anchored pegylated nanospheres (YIGSR-SN) loaded with 5-fluorouracil (5-FU) were investigated for selective and preferential presentation of carrier contents at angiogenic endothelial cells over-expressing laminin receptors on and around tumor tissue and thus for assessing their targetability. Pegylated nanosphere (SN) without peptide conjugate were used for comparison. The average size of all nanosphere preparations prepared was approximately 108 nm and maximum drug entrapment was 68.5 +/- 5.2%. In vitro endothelial cell binding of nanospheres exhibited 8-fold higher binding of YIGSR-SN to HUVEC in comparison to the SN. Spontaneous lung metastasis and angiogenesis assays show that YIGSR peptide anchored nanospheres are significantly (p

A novel cancer targeting approach based on estrone anchored stealth liposome for site-specific breast cancer therapy.

We here report the successful utilization of estrogen receptor (ER) for the delivery of anticancer drug doxorubicin (DOX) encapsulated within pegylated liposome for the treatment of breast cancer. Estrone (ES) was anchored as ligand on to stealth liposome (ES-SL-DOX) for targeting to ERs. In vitro cytotoxicity study was conducted on ER positive and negative breast carcinoma cells. The fluorescent microscopy studies were performed with estrone anchored stealth liposome (ES-SL) loaded with 6-carboxyfluorescein (6-CF). Pharmacokinetic, tissue distribution studies and tumor growth inhibition were carried out followed by intravenous (i.v.) administration of liposomal formulations. ES-SL-DOX demonstrated strongest cytotoxicity to the ER positive cell lines as compared to non-targeted formulations i.e. SL-DOX and plain DOX confirming that ES-SL-DOX was effectively taken up by cells expressing ERs. The half-life (t(1/2)) of SL-DOX and ES-SL-DOX was about 9 and 13 fold higher than that of the free DOX, respectively. Accumulation of ES-SL-DOX in the tumor tissue was 24.27 and 6.04 times higher as compared to free DOX and SL-DOX respectively, after 8 h. ES-SL-DOX at a dose of 5 mg DOX/kg resulted in effective retardation of tumor growth. These findings support that estrogen receptor(s) may be utilized as potential target for chemotherapy of cancers and estrone anchored stealth liposomes could be one of the promising solutions for the delivery of anticancer agent to breast tumors with reduced side-effects.

Implication of gut immunology in the design of oral vaccines.

In developing countries, oral immunization is more readily accepted than parenteral, as it accompanies the ease and safety of administration and induces the desired mucosal immune response against highly infectious pathogen transmitted through mucosal routes. Despite the obvious need and apparent merits, the success in the field of oral vaccination is limited due to factors including harsh gastric environment, enzymatic barrier, intestinal epithelium barrier and the fear of oral tolerance reported in case of mucosal vaccination. The number of strategies has been focused at conquering the mucosal barrier for maximization of the intestinal uptake and stabilization of the biological at all stages before they reach their target. Although, considerable success has been attained using these strategies but none of these have achieved commercial status. Therefore a rationally designed oral vaccine should be successfully delivered to the intestinal mucosal immune cells, and induce both humoral and cellular counterparts of immunity along with the mucosal immune response. The aim of this review article is to describe the recent development in the understanding of the molecular mechanism and implication of gastrointestinal epithelium and cytokines interplay in the induction of immunity and tolerance. The review has been elaborated to discuss the rationale of design of suitable carrier in conjunction with the peculiar necessities of gastrointestinal tract for induction of well balanced immune response.

Development and characterization of colon specific drug delivery system bearing 5-ASA and Camylofine dihydrochloride for the treatment of ulcerative colitis.

The treatment of ulcerative colitis (inflammatory bowel disease, IBD) has been achieved by using colon specific drug delivery system bearing 5-ASA and Camylofine dihydrochloride. Chitosan microspheres were prepared separately for both the drugs using emulsion method followed by enteric coating with EudragitS-100. The in vitro drug release was investigated in different simulated GIT medium. The drug release in PBS (pH7.4) and simulated gastric fluid has shown almost similar pattern and rate, whereas a significant increase in drug release (70.3 +/- 1.36 and 72.5 +/- 1.33% of 5-ASA and Camylofine, respectively) was observed in medium containing 3% rat caecal matter, after 24 h. In control study, 57.1 +/- 1.13% of 5-ASA and 59.2 +/- 1.2% of Camylofine release was observed in 24 h. For enzyme induction, rats were orally administered with 1 mL of 1% w/v dispersion of chitosan for 5 days and release rate studies were conducted in SCF with 3% w/v of caecal matter. An enhanced drug release (i.e., 92.3 +/- 3.81 and 95.5 +/- 3.52% 5-ASA and Camylofine, respectively) was observed after 24 h in dissolution medium containing 3% caecal content obtained from enzyme induced animals. In vivo data showed that microspheres delivered most of its drug load (76.55 +/- 2.13%) to the colon after 9 h, which reflects its targeting potential to the colon. It is concluded that orally administered microspheres of both drugs can be used together for the specific delivery of drug to the colon and reduce symptoms of ulcerative colitis.

Hyaluronic acid modified chitosan nanoparticles for effective management of glaucoma: development, characterization, and evaluation.

In clinical practices, solution of dorzolamide hydrochloride (DH) and timolol maléate (TM) is recommended for the treatment of glaucoma. However, low drug-contact time and poor ocular bioavailability of drugs due to drainage of solution, tear turnover and its dilution or lacrimation limits its uses. In addition, systemic absorption of TM may induce undesirable cardiovascular side effects. Chitosan (CS) is a polycationic biodegradable polymer which provides sustained and local delivery of drugs to the ocular sites. Hyaluronic acid (HA) also provides synergistic effect for mucoadhesion in association with chitosan. In the present study, hyaluronic acid modified chitosan nanoparticles (CS-HA-NPs) loaded with TM and DH were developed and characterized. The CS-HA-NPs were evaluated for size, shape, zeta potential, entrapment efficiency, and mucoadhesive strength. The in vitro release study was also performed in PBS pH 7.4. The ocular irritation potential of CS-HA-NPs was estimated using draize test on albino rabbits. A significant reduction in IOP level was obtained using CS-HA-NPs as compared to plain solution of drug and a comparable higher reduction in IOP level was observed as to CS-NPs. These results suggest that HA potentialy enhance the mucoadhesiveness and efficiency of CS-NPs and may be promising carrier for ocular drug delivery.