Peptide spiders are emerging as novel therapeutic interventions for nucleic acid delivery.

The FDA has approved many nucleic acid (NA)-based products. The presence of charges and biological barriers however affect stability and restrict widespread use. The electrostatic complexation of peptide with polyethylene glycol-nucleic acids (PEG-NAs) via nonreducible and reducible agents lead to three parts at one platform.. The reducible linkage made detachment of siRNA from PEG easy compared with a nonreducible linkage. A peptide spider produces a small hydrodynamic particle size, which can improve drug release and pharmacokinetics. Several examples of peptide spiders that enhance stability, protection and transfection efficiency are discussed. Moreover, this review also covers the challenges, future perspectives and unmet needs of peptide-PEG-NAs conjugates for NAs delivery.

mRNA Lipoplexes with Cationic and Ionizable α-Amino-lipophosphonates: Membrane Fusion, Transfection, mRNA Translation and Conformation.

Cationic liposomes are attractive carriers for mRNA delivery. Here, mRNA lipoplexes (LX) were prepared with the cationic lipids α-aminolipophosphonate (3b) or imidazolium lipophosphoramidate (2) associated with various α-aminolipophosphonates co-lipids comprising protonable groups (imidazole or pyridine) and DOPE. Physicochemical parameters of liposomes and their membrane fusion activity were measured. LXs comprising either 3b- or 2- allowed transfection of ~25% and 40% of dendritic cells with low cytotoxicity, respectively; the efficiency increased up to 80% when 2 was combined with the imidazole-based co-lipid 1. The transfections were high with 3b/1, 3b/DOPE, 2/1 and 2/DOPE LXs. We observed that the transfection level was not well correlated with the acid-mediated membrane fusion activity of liposomes supposed to destabilize endosomes. The mRNA release from LXs and its translation capacity after release were studied for the most efficient LXs. The results showed that the more mRNA was condensed, the poorer the translation efficiency after release was. In contrast to DNA, circular dichroism performed on mRNA complexed with 2/DOPE revealed the presence of denatured mRNA in LXs explaining this lack of translation efficiency. This is an important parameter that should be stressed for the preparation of mRNA LXs with a conserved mRNA translation activity.

Mupirocin-Loaded Chitosan Microspheres Embedded in Piper betle Extract Containing Collagen Scaffold Accelerate Wound Healing Activity.

This study reports the formulation of mupirocin-loaded chitosan microspheres embedded in Piper betle extract containing collagen scaffold as combinational drug delivery for improved wound healing. Selection of chitosan type (molecular weight and degree of deacetylation) was carried out based on their antibacterial efficacy. The low molecular weight chitosan was selected owing to the highest antibacterial action against gram-positive as well as gram-negative bacteria. Low molecular weight chitosan-microspheres showed spherical shape with largely smooth surface morphology, 11.81% of mupirocin loading, and its controlled release profile. The XRD, DSC thermograms, and FT-IR spectral analysis revealed the mupirocin loaded in molecularly dispersed or in amorphous form, and having no chemical interactions with the chitosan matrix, respectively. The in vivo study indicates potential effect of the mupirocin, Piper betle, and chitosan in the collagen scaffold in the wound healing efficiency with approximately 90% wound healing observed at the end of 15 days of study for combinational drug-loaded chitosan microspheres-collagen scaffold-treated group. The histopathology examination further revealed tissue lined by stratified squamous epithelium, collagen deposition, fibroblastic proliferation, and absence of inflammation indicating relatively efficient wound healing once treated with combinational drug-loaded chitosan microspheres containing scaffold.

Lipid/polymer-based nanocomplexes in nucleic acid delivery as cancer vaccines.

Cancer vaccines consist of nucleic acid derivatives such as plasmid DNA, small interfering RNA and mRNA, and can be customized according to the patient's needs. Nanomedicines have proven to be exceptionally good as miniaturized drug carriers, and thus they offer great advantages for delivering cancer vaccines. This review provides an overview of the literature on cancer vaccines, from their inception to current developments in the field.

Novel nanoemulsion gel containing triple natural bio-actives combination of curcumin, thymoquinone, and resveratrol improves psoriasis therapy: in vitro and in vivo studies.

Curcumin, resveratrol, and thymoquinone are the potential natural bio-actives reported with good anti-psoriatic activity. However, poor aqueous solubility and limited skin permeation of these natural bio-actives hinder their effective delivery and potential therapeutic outcome. In this regard, current research work focuses on the design and optimization of nanoemulsion (NE) gel formulation for the concurrent delivery of these three drugs. The NE system is consisting of oleic acid as oil phase, Tween 20 as surfactant, and PEG 200 as co-surfactant. The optimized formulation exhibited the droplet size 76.20 ± 1.67 nm, PDI of 0.12 ± 0.05, RI of 1.403 ± 0.007, and viscosity of 137.9 ± 4.07 mp. Carbopol 940 (0.5% w/v) was used as the gelling agent to prepare the NE gel which exhibited a good texture profile. The optimized formulation exhibited a higher % of growth inhibition on A-431 cells and demonstrated good anti-angiogenic activity in the HET-CAM test. Finally, in vivo studies in Balb/c mice model showed improved anti-psoriatic conditions which indicated that the triple natural bio-actives combination in nanoemulgel formulation is effective in the management of psoriasis.

Emerging advances in synthetic cancer nano-vaccines: opportunities and challenges.

Introduction: Cancer immunotherapy is a fast-growing field that has achieved tremendous progress in recent years. It is one of the most potent tools that can activate the immune system against cancer. Nevertheless, the development of safe and effective vaccines to overcome emerging new disease remains challenging since several emerging antigens are poorly immunogenic. Nanotechnology has provided a realistic resolution for the drawback of traditional cancer immunotherapy. Area covered: This review discusses different cancer immunotherapy approaches focusing on recent advancements in nanomedicine-based cancer immunotherapy. The literature review method includes inclusion and exclusion criteria to categorize important articles. The literature survey was carried out using PubMed, Google Scholar, Scopus, and the Saudi digital library. Expert opinion: In the last two decades, the development and application of nanoparticles incorporating antigen/adjuvant in cancer immunotherapy have experienced rapid growth. Soon, progressively multifaceted nanovaccines presenting different antigens and co-delivered with antigens will be clinically translated. Better understanding and improved knowledge of nanomedicines-based delivery approaches and immunostimulatory action, and in-vivo biodistribution would inevitably facilitate the altruistic design of cancer nanovaccine for humankind.

Progress of Cancer Nanotechnology as Diagnostics, Therapeutics, and Theranostics Nanomedicine: Preclinical Promise and Translational Challenges.

Early detection, right therapeutic intervention, and simultaneous effectiveness mapping are considered the critical factors in successful cancer therapy. Nevertheless, these factors experience the limitations of conventional cancer diagnostics and therapeutics delivery approaches. Along with providing the targeted therapeutics delivery, advances in nanomedicines have allowed the combination of therapy and diagnostics in a single system (called cancer theranostics). This paper discusses the progress in the pre-clinical and clinical development of therapeutics, diagnostics, and theranostics cancer nanomedicines. It has been well evident that compared to the overabundance of works that claimed success in pre-clinical studies, merely 15 and around 75 cancer nanomedicines are approved, and currently under clinical trials, respectively. Thus, we also brief the critical bottlenecks in the successful clinical translation of cancer nanomedicines.

Systematic development of a bioanalytical UPLC-MS/MS method for estimation of risperidone and its active metabolite in long-acting microsphere formulation in rat plasma.

A systematic approach to develop a UPLC-MS/MS method was applied for quantifying of risperidone (RISP), its active metabolite, 9-hydroxy risperidone (9-OH-RISP) and internal standard (propranolol) in rat plasma. Liquid-liquid extraction was performed using methyl tert-butyl ether for quantification of drug and its active metabolite by MS detection in the positive ion mode. Acquity UPLC system with BEH C18 (2.1 mm × 100 mm, particle size 1.7 µm) column was used along with acetonitrile (0.1% formic acid)-2 mM (milli mole) ammonium acetate in isocratic condition was used as the mobile phase. Detection was performed by multiple reactions monitoring with precursor-to-product ion transitions with m/z 411.2 â†’ 191.0 for RISP, m/z 427.2 â†’ 207.0 for 9-OH-RISP and m/z 260.1 â†’ 116.0 for IS. The method was validated as per the FDA guidance on bioanalytical method validation. Linearity (r2 = 0.999) was observed in the drug concentration ranging between 0.1 and 50 ng mL-1, while all other parameters were found to be within the acceptable ranges. Method robustness was optimized by Box-Behnken design to monitor the influential variables to achieve maximal recovery of the analytes in the rat plasma. Pharmacokinetic evaluation of the analytes from long-acting microparticles in rat plasma showed two peaks indicating an initial burst effect within 24 h of administration followed by controlled drug release pattern upto 45 days, while marketed formulation (Risperdal Consta®) showed no plasma concentration during the lag-time of 21 days followed by maximal drug absorption between 28 and 40 days.

Therapeutic Nanoemulsion: Concept to Delivery.

Nanoemulsions (NEs) or nanometric-scaled emulsions are transparent or translucent, optically isotropic and kinetically stable heterogeneous system of two different immiscible liquids namely, water and oil stabilized with an amphiphilic surfactant having droplet size ranges up to 100 nm. They offer a variety of potential interests for certain applications: improved deep-rooted stability; excellent optical clarity; and, enhanced bioavailability due to its nanoscale of particles. Though there is still comparatively narrow insight apropos design, development, and optimization of NEs, which mainly stems from the fact that conventional characteristics of emulsion development and stabilization only partly apply to NEs. The contemporary article focuses on the nanoemulsion dosage form journey from concept to key application in drug delivery. In addition, industrial scalability of the nanoemulsion, as well as its presence in commercial and clinical practice, are also addressed.

Co-encapsulation of docetaxel and thymoquinone in mPEG-DSPE-vitamin E TPGS-lipid nanocapsules for breast cancer therapy: Formulation optimization and implications on cellular and in vivo toxicity.

Rationally designed combination nano-therapy approaches have emerged as a promising strategy for resistant breast cancer treatment. This research reports the combination of Docetaxel (DTX) and Thymoquinone (THQ) co-encapsulated within long circulating sub-100 nm mPEG-DSPE-Vitamin E TPGS-Lipid nanocapsules (DxTq-LNCs). DxTq-LNCs with sufficient drug loading exhibited controlled drug release, enhanced protein binding resistance (confirming its long circulation in physiological environment and suitability for iv application) and retained the antioxidant effects of THQ. DxTq-LNCs were further subjected to cytotoxicity analysis against human breast cancer cells (MCF-7 & MDA-MB-231). The presence of multidrug resistance (MDR) reversal agents; Vitamin E TPGS and THQ, along with the nanoencapsulation, re-sensitized the resistant triple negative breast cancer (TNBC) cells to the anticancer effects of DTX. Greater inhibition of cell migration indicated improved anti-metastatic effects. Drastic changes in cellular morphology indicated by nuclear fragmentation (the hall marks of apoptosis), were observed upon DxTq-LNCs treatment to the breast cancer cells. In vivo toxicity studies indicated no substantial blood biochemical and histological changes with near normal appearance of kidney and liver tissue sections upon DxTq-LNCs treatment in contrast to free drug that showed parenchymal degeneration, areas of interstitial haemorrhage, glomerular atrophy and other histological changes, indicating hepato- and nephro-protective potential of DxTq-LNCs. Furthermore, enhanced antitumor efficacy was observed with DxTq-LNCs treatment to mice bearing ehrlich ascites carcinoma. Thus, nanocapsules presents a simple yet effective approach for successful combination chemotherapy with reduced unwanted toxicity.

Omega-3 fatty acids as adjunctive therapeutics: prospective of nanoparticles in its formulation development.

Omega-3 polyunsaturated fatty acids (ω-3-PUFAs) are dietary components that have been extensively recognized for their therapeutic value and have shown diverse therapeutic effects including anti-inflammatory, antiarrhythmic, antithrombotic, immunomodulatory and antineoplastic activities. Most of the ω-3-PUFAs are obtained through diet or supplements because the body does not synthesize them. The high instability of ω-3-PUFAs to oxidative deterioration, lower bioavailability at the target tissues and reduced bioactivity of ω-3-PUFAs is an impediment for achieving their therapeutic potential. The present review provides an overview of potential therapeutic activities of ω-3-PUFAs and different novel technical approaches based on nanotechnology, which have been emphasized to overcome instability problems as well as enhance the bioactivity of ω-3-PUFAs. Future prospects related to this area of research are also provided.

Improved chemotherapeutic efficacy against resistant human breast cancer cells with co-delivery of Docetaxel and Thymoquinone by Chitosan grafted lipid nanocapsules: Formulation optimization, in vitro and in vivo studies.

In recent years, multi-targeted chemotherapeutic combinations have received considerable attention in solid tumor chemotherapy. Here, we optimized low-molecular-weight chitosan (CS)-grafted lipid nanocapsules (LNCs, referred to as CLNCs) for the co-delivery of docetaxel (DTX) and thymoquinone (THQ) to treat drug-resistant breast cancer. We first screened size reduction techniques (homogenization vs ultrasonication), and then the 33-Box-Behnken design was employed to determine optimal conditions of the final LNCs with the desired quality attributes. Uncoated LNCs had a particle size of 141.7 ± 2.8 nm (Polydispersity index, PdI: 0.17 ± 0.02) with entrapment efficiency (%EE) of 66.1 ± 3.5 % and 85.3 ± 3.1 % for DTX and THQ, respectively. The CS functionalization of LNCs improved the uptake and endosomal escape effect, and led to a significantly higher cytotoxicity against MCF-7 and triple-negative (MDA-MB-231) breast cancer cells. Furthermore, an enhanced antiangiogenic effect was observed with DTX- and THQ-carrying CLNCs in the Chick embryo chorioallantoic membrane (CAM) assay.

Synthesis and characterization of novel carboxymethyl Assam Bora rice starch for the controlled release of cationic anticancer drug based on electrostatic interactions.

Carboxymethyl Assam Bora rice starch (CM-ABRS) was chemically synthesized in non-aqueous medium with the optimum degree of substitution (DS) of 1.23, and physicochemically characterized by FT-IR, DSC, XRD, and SEM analysis. Comparative evaluation of CM-ABRS with native starch (ABRS) for powder flow characteristics, swelling index, apparent solubility, rheological properties, textural properties, and mucoadhesive studies were carried out. The aim of the current work was to investigate the potential of CM-ABRS as a novel carrier for the water-soluble chemotherapeutic, doxorubicin hydrochloride (DOX). Formation of drug/polymer complex (DOX-CM-ABRS) via electrostatic interaction has been evaluated for the controlled release of DOX in three different pH media (phosphate-buffered saline (PBS), pH 7.4, 6.8, and 5.5). In vitro drug release studies illustrated faster release of drug in PBS at pH 5.5 as compared to pH 6.8 and pH 7.4, respectively, indicating the importance of pH-sensitive drug release from the DOX-CM-ABRS complex in malignant tissues.

3D Printing Technology in Customized Drug Delivery System: Current State of the Art, Prospective and the Challenges.

BACKGROUND: 3D printing/Additive Manufacturing seems a pragmatic approach to realize the quest for a truly customized and personalized drug delivery. 3DP technology, with innovations in pharmaceutical development and an interdisciplinary approach to finding newer Drug Delivery Systems can usher a new era of treatments to various diseases. The true potential of this is yet to be realized, and the US-FDA is focusing on the regulatory science of 3D printed medical devices to help patients access this technology safely and effectively. The approval of the first 3D printed prescription medicine by FDA is a promising step in the translation of more research in this area. METHODS: A web-search on PubMed, ScienceDirect, and Nature was performed with the keywords Customized 3D printing and Drug delivery, publications dealing with the aspects of drug delivery using 3D printing for personalized or customized delivery were further considered and analyzed and discussed. RESULTS: We present the advantages offered by 3DP over conventional methods of formulation development and discuss the current state of 3DP in pharmaceutics and how it can be used to develop a truly customized drug delivery system, various 3DP technologies including Stereolithography (SLA), Selective Laser Sintering (SLS), Fused Deposition Modelling (FDM), Pressure Assisted Microsyringe (PAM) that have been used to develop pharmaceutical products have been discussed along with their limitations and also the regulatory considerations to help formulation scientists envisaging research in this area with the necessary information. CONCLUSION: 3D printing has the potential to fabricate a customized drug delivery system. Presence of many drug formulation and the devices are already in the regulatory approval process indicating its success.

Liposome-Based Nanomedicine Therapeutics for Rheumatoid Arthritis.

Rheumatoid arthritis (RA) is a very painful severe autoimmune disease with complex pathology characterized by progressive chronic inflammation, and devastation of the synovium, cartilage, and other joint-associated structures. Significant advances in research in the area of pathophysiology, diagnosis, drug development, and targeted delivery have led to improved RA therapy and better patient compliance. Targeted drug delivery using liposomal nanomedicines significantly alleviate the challenges with conventional anti-RA medications such as off-target effects, short biological half-life, poor bioavailability, high dose-related toxicity, etc. Liposomal nanomedicines in RA drug targeting offer the opportunity for passive targeting [based on size and polyethylene glycol (PEG)-ylation-mediated enhanced permeability and retention] and active targeting (ligation with antibody or peptides, etc.) and encapsulation of lipophilic, hydrophilic drugs, and/or combinational drugs. However, it has been found recently that such injectable nanomedicines raise the concern of an adverse immune phenomenon called complement activationrelated pseudo allergy (CARPA) and failure of therapy on multiple doses due to accelerated body clearance caused many by anti-PEG immunoglobulin M. To ensure safety and efficacy of RA therapy, these need to be considered along with the common formulation quality parameters. Here, we discuss nanotherapeutic targeting in RA therapy using liposomes. Liposomal nanoparticles are investigated for individual anti-RA drug categories. CARPA issues and pathophysiology with such nanomedicines are also discussed in detail.

Nanotechnology Based Theranostic Approaches in Alzheimer's Disease Management: Current Status and Future Perspective.

BACKGROUND: Alzheimer's disease (AD), a cognitive dysfunction/dementia state amongst the elders is characterized by irreversible neurodegeneration due to varied pathophysiology. Up till now, anti-AD drugs having different pharmacology have been developed and used in clinic. Yet, these medications are not curative and only lowering the AD associated symptoms. Improvement in treatment outcome required drug targeting across the blood-brain barrier (BBB) to the central nervous system (CNS) in optimal therapeutic concentration. Nanotechnology based diagnostic tools, drug carriers and theranostics offer highly sensitive molecular detection, effective drug targeting and their combination. Over the past decade, significant works have been done in this area and we have seen very remarkable outocome in AD therapy. Various nanoparticles from organic and inorganic nanomaterial category have successfully been investigated against AD. CONCLUSION: This paper discussed the role of nanoparticles in early detection of AD, effective drug targeting to brain and theranostic (diagnosis and therapy) approaches in AD's management.

Supercritical anti-solvent technique assisted synthesis of thymoquinone liposomes for radioprotection: Formulation optimization, in-vitro and in-vivo studies.

The aim of this study was to develop Thymoquinone (TQ) loaded PEGylated liposomes using supercritical anti-solvent (SAS) process for enhanced blood circulation, and greater radioprotection. The SAS process of PEGylated liposomes synthesis was optimized by Box-Behnken design. Spherical liposomes with a particle size of 195.6±5.56nm and entrapment efficiency (%EE) of 89.4±3.69% were obtained. Optimized SAS process parameters; temperature, pressure and solution flow rate were 35°C, 140bar and 0.18mL/min, respectively, while 7.5mmol phospholipid, 0.75mmol of cholesterol, and 1mmol TQ were optimized formulation ingredients. Incorporation of MPEG-2000-DSPE (5% w/w) provided the PEGylated liposomes (FV-17B; particle size=231.3±6.74nm, %EE=91.9±3.45%, maximum TQ release >70% in 24h). Pharmacokinetics of FV-17B in mice demonstrated distinctly superior systemic circulation time for TQ in plasma. Effectiveness of radioprotection by FV-17B in mice model was demonstrated by non-significant body weight change, normal vital blood components (WBCs, RBCs, and Platelets), micronuclei and spleen index and increased survival probability in post irradiation animal group as compared to controls (plain TQ and marketed formulation). Altogether, the results anticipated that the SAS process could serve as a single step environmental friendly technique for the development of stable long circulating TQ loaded liposomes for effective radioprotection.

Emerging Advances in Nanomedicine as a Nanoscale Pharmacotherapy in Rheumatoid Arthritis: State of the Art.

There are several significant setbacks including limited bioavailability, high clearance, and further current therapies require higher and frequent dosing to gain desired therapeutic effects. Nanomedicines have been widely investigated for rheumatoid arthritis (RA). Though, higher doses also increase the incidence of dreadful adverse effects. Further, nanocarrier properties are tuned by the use of different approaches like varied methods of loading, hydrophilic polymers and targeting ligands, to change the physicochemical properties including higher encapsulation, better penetrating ability to biological barriers, thus preventing the uptake of various nanocarriers by liver and spleen. Along with these they provide longer circulation which enhances drug localization at the inflamed site and selective targeting to enhance the therapeutic index of anti-rheumatic drugs. However, the optimal properties also depend on the route of administration and nanocarrier size, thus larger size show more retention upon local injection and smaller sized ones are more optimal for passive targeting. The present review discusses the emergence of nano-carriers for anti-rheumatic drugs, which delivers drug molecule to the inflamed site by topical, intra-articular (i.a) and intra-venous (i.v) administration to achieve therapeutic efficacy by passive and active drug targeting. Advancements have been made extensively but still better investigations are needed to optimize the risk-benefit ratio for the development of safe and stable targeting nanocarriers for the effective treatment of rheumatoid arthritis (RA).