Experimental design approach for development of carboplatin loaded chitosan modified liposomal formulation with improved topical vaginal therapeutic potential.

One of the most prevalent cancers affecting women globally is cervical cancer. Cervical cancer is thought to cause 570 000 new cases annually, and standard treatments can have serious side effects. In this work, the main aim is to design, fabrication, and evaluation of carboplatin loaded chitosan coated liposomal formulation (CCLF-I) for vaginal delivery in the treatment of cervical cancer. The particle size and polydispersity index of the CCLF-1 were observed at 269.33 ± 1.15 and 0.40 ± 0.002 nm, respectively. The in vitro mucin binding studies showed good adhesiveness of CCLF-I as compared to plain liposomes (CPLF-I), which was found at 23.49 and 10.80%, respectively. The ex-vivo percent drug permeation from plain liposomal formulation (CPLF-I) was found to be higher in comparison to chitosan coated liposomal formulation which was 56.33% while in CCLF-I it was observed 47.32% this is due to, higher retainability of delivery system (CCLF-I) on targeted site attained by coating of mucoadhesive polymer on liposomes. Ex vivo tissue retention studies exhibited 24.2% of CCLF-I in comparison to 10.34% from plain drug formulation (CPLF-I). The in vivo vaginal retention studies exhibited 14% of drug retention after 24 h from the novel formulation in comparison to 6% from the plain formulation. The developed CCLF-I formulation would open a new avenue in the cervical treatment.

Design, Fabrication and Evaluation of Stabilized Polymeric mixed micelles for Effective Management in Cancer Therapy.

PURPOSE: Cancer is one of the most common and fatal disease, chemotherapy is the major treatment against many cancer types. The anti-apoptotic BCL-2 protein's expression was increased in many cancer types and Venetoclax (VLX; BCL-2 inhibitor) is a small molecule, which selectively inhibits this specified protein. In order to increase the clinical performance of this promising inhibitor as a repurposed drug, polymeric mixed micelles formulations approach was explored. METHODS: The Venetoclax loaded polymeric mixed micelles (VPMM) were prepared by using Pluronic® F-127 and alpha tocopherol polyethylene glycol 1000 succinate (TPGS) as excipients by thin film hydration method and characteristics. The percentage drug loading capacity, entrapment efficiency and in-vitro drug release studies were performed using HPLC method. The cytotoxicity assay, cell uptake and anticancer activities were evaluated in two different cancer cells i.e. MCF-7 (breast cancer) and A-549 (lung cancer). RESULTS: Particle size, polydispersity index and zeta potential of the VPMM was found to be 72.88 ± 0.09 nm, 0.078 ± 0.009 and -4.29 ± 0.24 mV, respectively. The entrapment efficiency and %drug loading were found to be 80.12 ± 0.23% and 2.13% ± 0.14%, respectively. The IC50 of VLX was found to be 4.78, 1.30, 0.94 µg/ml at 24, 48 and 72 h, respectively in MCF-7 cells and 1.24, 0.68, and 0.314 µg/ml at 24, 48, and 72 h, respectively in A549 cells. Whereas, IC50 of VPMM was found to be 0.42, 0.29, 0.09 µg/ml at 24, 48 and 72 h, respectively in MCF-7 cells and 0.85, 0.13, 0.008 µg/ml at 24, 48 and 72 h in A549 cells, respectively, indicating VPMM showing better anti-cancer activity compared to VLX. The VPMM showed better cytotoxicity which was further proven by other assays and explained the anti-cancer activity is shown through the generation of ROS, nuclear damage,apoptotic cell death and expression of caspase-3,7, and 9 activities in apoptotic cells. CONCLUSION: The current investigation revealed that the Venetoclax loaded polymeric mixed micelles (VPMM) revealed the enhanced therapeutic efficacy against breast and lung cancer in vitro models.

Release behavior and bioefficacy of imazethapyr formulations based on biopolymeric hydrogels.

Controlled release formulations of imazethapyr herbicide have been developed employing guar gum-g-cl-polyacrylate/bentonite clay hydrogel composite (GG-HG) and guar gum-g-cl-PNIPAm nano hydrogel (GG-NHG) as carriers, to assess the suitability of biopolymeric hydrogels as controlled herbicide release devices. The kinetics of imazethapyr release from the developed formulations was studied in water and it revealed that the developed formulations of imazethapyr behaved as slow release formulations as compared to commercial formulation. The calculated diffusion exponent (n) values showed that Fickian diffusion was the predominant mechanism of imazethapyr release from the developed formulations. Time for release of half of the loaded imazethapyr (t1/2) ranged between 0.06 and 4.8 days in case of GG-NHG and 4.4 and 12.6 days for the GG-HG formulations. Weed control index (WCI) of GG-HG and GG-NHG formulations was similar to that of the commercial formulation and the herbicidal effect was observed for relatively longer period. Guar gum-based biopolymeric hydrogels in both macro and nano particle size range can serve as potential carriers in developing slow release herbicide formulations.

Investigating the effectiveness of Difluprednate-Loaded core-shell lipid-polymeric hybrid nanoparticles for ocular delivery.

Uveitis is a sight-threatening disease that causes inflammation in the uvea; difluprednate (DFB) is the first approved drug molecule for postoperative pain, inflammation, and endogenous uveitis. Complex ocular physiology and structure make it difficult to deliver drugs to the eye. Increased permeation and retention in the layer of the eye are required to improve the bioavailability of ocular drugs. In the current research investigation, DFB-loaded lipid polymer hybrid nanoparticles (LPHNPs) were designed and fabricated to enhance the corneal permeation and sustained release of DFB. A well-established two-step approach was used to fabricate the DFB-LPHNPs, comprising of Poly-Lactic-co-Glycolic Acid (PLGA) core that entrapped the DFB and DFB loaded PLGA NPs covered by lipid shell. The manufacturing parameters were optimized for the preparation of DFB-LPHNPs; the optimal DFB-LPHNPs showed a mean particle size of 117.3 ± 2.9 nm, suitable for ocular administration and high entrapment efficiency of 92.45 ± 2.17 % with neutral pH (7.18 ± 0.02) and isotonic Osmolality (301 ± 3 mOsm/kg). Microscopic examination confirms the core-shell morphological structure of DFB-LPHNPs. The prepared DFB-LPHNPs were extensively characterized using spectroscopic techniques and physicochemical characterization, which confirms the entrapment of the drug and the formation of the DFB-LPHNPs. The confocal laser scanning microscopy studies revealed that Rhodamine B-loaded LPHNPs were penetrated into stromal layers of the cornea in ex-vivo conditions. The DFB-LPHNPs showed a sustained release pattern in simulated tear fluid and 4- folds enhanced permeation of DFB as compared to pure DFB solution. The ex-vivo histopathological studies revealed that DFB-LPHNPs didn't cause any damage or no alteration in the cellular structure of the cornea. Additionally, the results of the HET-CAM assay confirmed that the DFB-LPHNPs were not toxic for ophthalmic administration.

Colloidal therapeutics in the management of traumatic brain injury: Portray of biomarkers and drug-targets, preclinical and clinical pieces of evidence and future prospects.

Complexity associated with the aberrant physiology of traumatic brain injury (TBI) makes its therapeutic targeting vulnerable. The underlying mechanisms of pathophysiology of TBI are yet to be completely illustrated. Primary injury in TBI is associated with contusions and axonal shearing whereas excitotoxicity, mitochondrial dysfunction, free radicals generation, and neuroinflammation are considered under secondary injury. MicroRNAs, proinflammatory cytokines, and Glial fibrillary acidic protein (GFAP) recently emerged as biomarkers in TBI. In addition, several approved therapeutic entities have been explored to target existing and newly identified drug-targets in TBI. However, drug delivery in TBI is hampered due to disruption of blood-brain barrier (BBB) in secondary TBI, as well as inadequate drug-targeting and retention effect. Colloidal therapeutics appeared helpful in providing enhanced drug availability to the brain owing to definite targeting strategies. Moreover, immense efforts have been put together to achieve increased bioavailability of therapeutics to TBI by devising effective targeting strategies. The potential of colloidal therapeutics to efficiently deliver drugs at the site of injury and down-regulate the mediators of TBI are serving as novel policies in the management of TBI. Therefore, in present manuscript, we have illuminated a myriad of molecular-targets currently identified and recognized in TBI. Moreover, particular emphasis is given to frame armamentarium of repurpose drugs which could be utilized to block molecular targets in TBI in addition to drug delivery barriers. The critical role of colloidal therapeutics such as liposomes, nanoparticles, dendrimers, and exosomes in drug delivery to TBI through invasive and non-invasive routes has also been highlighted.

Multifunctional targetable liposomal drug delivery system in the management of leukemia: Potential, opportunities, and emerging strategies.

The concern impeding the success of chemotherapy in leukemia treatment is descending efficacy of drugs because of multiple drug resistance (MDR). The previous failure of traditional treatment methods is primarily responsible for the present era of innovative agents to treat leukemia effectively. The treatment option is a chemotherapeutic agent in most available treatment strategies, which unfortunately leads to high unavoidable toxicities. As a result of the recent surge in marketed products, theranostic nanoparticles, i.e., multifunctional targetable liposomes (MFTL), have been approved for improved and more successful leukemia treatment that blends therapeutic and diagnostic characteristics. Since they broadly offer the required characteristics to get past the traditional/previous limitations, such as the absence of site-specific anti-cancer therapeutic delivery and ongoing real-time surveillance of the leukemia target sites while administering therapeutic activities. To prepare MFTL, suitable targeting ligands or tumor-specific antibodies are required to attach to the surface of the liposomes. This review exhaustively covered and summarized the liposomal-based formulation in leukemia treatment, emphasizing leukemia types; regulatory considerations, patents, and clinical portfolios to overcome clinical translation hurdles have all been explored.

Polymer nanotherapeutics: A versatile platform for effective rheumatoid arthritis therapy.

Rheumatoid arthritis is an aggressive and severely debilitating disorder that is characterized by joint pain and cartilage damage. It restricts mobility in patients, leaving them unable to carry out simple tasks. RA presents itself with severe lasting pain, swelling and stiffness in the joints and may cause permanent disability in patients. Treatment regimens currently employed for rheumatoid arthritis revolve around keeping clinical symptoms like joint pain, inflammation, swelling and stiffness at bay. The current therapeutic interventions in rheumatoid arthritis involve the use of non-steroidal anti-inflammatory drugs, glucocorticoids, disease-modifying anti-rheumatic drugs and newer biological drugs that are engineered for inhibiting the expression of pro-inflammatory mediators. These conventional drugs are plagued with severe adverse effects because of their higher systemic distribution, lack of specificity and higher doses. Oral, intra-articular, and intravenous routes are routinely used for drug delivery which is associated with decreased patient compliance, high cost, poor bioavailability and rapid systemic clearance. All these drawbacks have enticed researchers to create novel strategies for drug delivery, the main approach being nanocarrier-based systems. In this article, we aim to consolidate the remarkable contributions of polymeric carrier systems including microneedle technology and smart trigger-responsive polymeric carriers in the management of rheumatoid arthritis along with its detailed pathophysiology. This review also briefly describes the safety and regulatory aspects of polymer therapeutics.

Advances in nanoparticle mediated targeting of RNA binding protein for cancer.

RNA binding proteins (RBPs) enact a very crucial part in the RNA directive processes. Atypical expression of these RBPs affects many steps of RNA metabolism, majorly altering its expression. Altered expression and dysfunction of RNA binding proteins lead to cancer progression and other diseases. We enumerate various available interventions, and recent findings focused on targeting RBPs for cancer therapy and diagnosis. The treatment, sensitization, chemoprevention, gene-mediated, and virus mediated interventions were studied to treat and diagnose cancer. The application of passively and actively targeted lipidic nanoparticles, polymeric nanoparticles, virus-based particles, and vaccine-based immunotherapy for the delivery of therapeutic agent/s against cancer are discussed. We also discuss the formulation aspect of nanoparticles for achieving delivery at the site of action and ongoing clinical trials targeting RBPs.

Multifunctional hybrid nanoparticles in diagnosis and therapy of breast cancer.

Breast cancer is the most prevalent non-cutaneous malignancy in women, with greater than a million new cases every year. In the last decennium, numerous diagnostic and treatment approaches have been enormously studied for Breast cancer. Among the different approaches, nanotechnology has appeared as a promising approach in preclinical and clinical studies for early diagnosis of primary tumors and metastases and eradicating tumor cells. Each of these nanocarriers has its particular advantages and drawbacks. Combining two or more than two constituents in a single nanocarrier system leads to the generation of novel multifunctional Hybrid Nanocarriers with improved structural and biological properties. These novel Hybrid Nanocarriers have the capability to overcome the drawbacks of individual constituents while having the advantages of those components. Various hybrid nanocarriers such as lipid polymer hybrid nanoparticles, inorganic hybrid nanoparticles, metal-organic hybrid nanoparticles, and hybrid carbon nanocarriers are utilized for the diagnosis and treatment of various cancers. Certainly, Hybrid Nanocarriers have the capability to encapsulate multiple cargos, targeting agents, enhancement in encapsulation, stability, circulation time, and structural disintegration compared to non-hybrid nanocarriers. Many studies have been conducted to investigate the utilization of Hybrid nanocarriers in breast cancer for imaging platforms, photothermal and photodynamic therapy, chemotherapy, gene therapy, and combinational therapy. In this review, we mainly discussed in detailed about of preparation techniques and toxicological considerations of hybrid nanoparticles. This review also discussed the role of hybrid nanocarriers as a diagnostic and therapeutic agent for the treatment of breast cancer along with alternative treatment approaches apart from chemotherapy including photothermal and photodynamic therapy, gene therapy, and combinational therapy.

Nanomedicine based approaches for combating viral infections.

Millions of people die each year from viral infections across the globe. There is an urgent need to overcome the existing gap and pitfalls of the current antiviral therapy which include increased dose and dosing frequency, bioavailability challenges, non-specificity, incidences of resistance and so on. These stumbling blocks could be effectively managed by the advent of nanomedicine. Current review emphasizes over an enhanced understanding of how different lipid, polymer and elemental based nanoformulations could be potentially and precisely used to bridle the said drawbacks in antiviral therapy. The dawn of nanotechnology meeting vaccine delivery, role of RNAi therapeutics in antiviral treatment regimen, various regulatory concerns towards clinical translation of nanomedicine along with current trends and implications including unexplored research avenues for advancing the current drug delivery have been discussed in detail.

Polymer-drug conjugates: recent advances and future perspectives.

Polymer-drug conjugates (PDC) have exhibited clinical and commercial success in the field of drug delivery. A polymeric backbone, linker, targeting moiety, and drug constitute the building blocks of PDCs. Current attention is focusing on natural polymeric carriers, in particular the concept of graft copolymers, such as a combination of polymers and polysaccharides, to explore dual benefits such as combined vehicles and targeting moieties. Polymer heterogeneity, synthesis of PDCs, broad molecular weight distribution, conjugate variability, immunogenicity of polymers, safety, stability, and stringent regulatory approval are the major obstacles to the successful transition of PDCs to the clinic. In this review, we discuss natural and synthetic PDCs combined with computational modeling for diverse pharmaceutical and biomedical applications.

Sequence of inoculation influences the nature of extracellular polymeric substances and biofilm formation in Azotobacter chroococcum and Trichoderma viride.

Extracellular polymeric substances (EPS) are important structural components of biofilms. In the present study, the EPS in biofilms developed using two agriculturally beneficial organisms-Azotobacter chroococcum (Az) and Trichoderma viride (Tv) were quantified and characterised. Time course experiments were undertaken to optimise the EPS yield of biofilm samples resulting from coculture and staggered inoculation. The EPS produced during biofilm formation was found to differ quantitatively and qualitatively in individual cultures (Az alone, Tv alone), and in treatments differing in the sequence of inoculation of bacterium and fungus (Az + Tv coculture, staggered inoculation of Az followed by Tv i.e. Az - Tv, or Tv followed by Az i.e. Tv - Az). Significant enhancement in terms of growth and biofilm formation, as compared to individual inoculation was recorded, with Tv - Az exhibiting higher values of these attributes. The EPS from biofilms showed significantly higher concentrations of protein, acetyl, and uronic acids, while planktonic EPS recorded higher total carbohydrates. Fourier transform infrared spectroscopy analyses illustrated the significant influence on chemical and structural aspects of EPS (planktonic and biofilm). This represents a first report correlating EPS production, cell aggregation and biofilm formation during bacterial-fungal biofilm development, which can have implications in the colonisation of soil and plants.