Drug Delivery Mechanisms Research Articles

Sublingual spray: a new technology oriented formulation with multiple benefits

Sublingual drug delivery system was a well-established platform for delivering the drug that need to exhibit quick action without any first-pass metabolic effect, but various pitfall in the regular sublingual drug delivery systems such as a tablet, capsule etc., that can be overcome by novel sublingual drug delivery technology such as particulate sublingual spray. Sublingual spray for drug administration has gained attention in the market since it proved its propensity to by-pass the first-pass metabolism and to initiate a rapid onset of action due to its atomized micro particulate nature, which is significantly higher than the other sublingual formulations. The approval of sublingual spray by the regulatory agencies may commence further research in this field by subsuming various essential drugs for indications such as cancer pain, cardiovascular issue etc. This article comprises a detailed study on the drawback of conventional sublingual drug delivery system and the approach by which these drawbacks can be overruled by spray technology in the sublingual area and the, in-depth mechanism of drug delivery through sublingual with the help of atomization followed by the entire formulation strategy along with evaluation and industrial perspective of the sublingual spray dosage form as a future tool of patient-friendly drug delivery.

Evaluation of Lipophilic Properties of Thermoplastic Granule in Formulation of Sustained Release Matrix in Solid Dosage Forms

This study was aimed at developing a new, technically simple method for the preparation of a once-daily sustained release matrix formulations, which would enable reproducible release of the active ingredient. Thermoplastic granulation is a new technique in pharmaceutical formulation. Coated particles of an active pharmaceutical ingredient (API) in sustained release matrix are prepared by thermoplastic granulation technique via heating (50 – 75°C) in fluid-bed dryer (FBD) granulator. The FBD creates ideal conditions for the most intense heat and mass transfer by spraying melted liquids onto the granular API. A variety of innovative processes such as granulation, agglomeration, coating and microencapsulation can be realized. Melted mixture of cetyl alcohol, glyceryl monostearate, and polyethylene glycol 4000 (PEG 4000) was used for fluid-bed coating. The present article deals with assessing the influence of rheological properties and hydrophile-lipophile balance (HLB) parameter of thermoplastic granules on the mechanism of drug delivery from sustained release matrix in solid dosage forms. The drug release kinetics model is affected by rheology, HLB of cetyl alcohol, and physicochemical properties of API granules.

Precision Printing of Customized Cylindrical Capsules with Multifunctional Layers for Oral Drug Delivery.

Advances in personalized medicine will require custom drug formulations and delivery mechanisms. Herein, we demonstrate a new type of personalized capsule comprising of printed concentric cylindrical layers with each layer having a distinctive functional drug component. Poly ε-caprolactone (PCL) with paracetamol (APAP) and chlorpheniramine maleate (CM), synergistic drugs commonly used to alleviate influenza symptoms, are printed as an inner layer and outer layer, respectively, via microscaled electrohydrodynamic (EHD) printing. Polyvinylpyrrolidone (PVP) nanofibers are embedded as interlayers between the two printed PCL-drug layers using electrospinning (ES) techniques. The complete concentric cylindrical capsule with a 6 mm inner diameter and 15 mm length can be swallowed for oral drug delivery. After dissolution of the PVP interlayer, the capsule separates in two, with inner and outer capsules for continuous drug dosing and targeting. Imaging was achieved using a 3T MRI system which allowed temporal observations of the targeted release through the incorporation of nanoparticles (Fe3O4). The morphology and structure, chemical composition, mechanical properties, and biocompatibility of the capsules were studied in vitro. In summary, this new type of custom printed and electrospun capsule that enabled component separation, targeted drug release may advance personalized medicine via multidrug oral delivery.

Innovations in Oral Therapies for Inflammatory Bowel Disease.

Prior to the biologic era, the medical management of patients with inflammatory bowel disease (IBD) was dominated by the use of aminosalicylates, corticosteroids, and immunosuppressants. In the past two decades, the advent of biologic agents that target specific components of the immune response has greatly improved the care of patients with Crohn's disease and ulcerative colitis (UC). However, not all patients respond or maintain response to biologic therapy and some patients develop adverse events that necessitate treatment discontinuation. Furthermore, sensitization with formation of anti-drug antibodies is an inherent limitation to administration of monoclonal antibodies. This circumstance has generated renewed interest in the development of novel oral small-molecule drugs (SMDs) that are effective and well tolerated. Several classes of SMDs are currently progressing through the pipeline and offer the promise of oral delivery and high potency. In this review, we summarize different mechanisms of oral drug delivery to the gastrointestinal tract, highlight key findings from phase II and III randomized trials of novel oral SMDs, and discuss how oral SMDs are likely to be integrated into future IBD treatment paradigms. The most advanced development programs currently involve evaluation of compounds blocking Janus kinase (JAK) receptors or modulating sphingosine-1-phosphate (S1P) receptors. Tofacitinib, an oral JAK inhibitor, was recently approved for the treatment of moderate-to-severe UC. Several more selective JAK-1 inhibitors, including filgotinib and upadacitinib, have also shown positive results in phase II studies and are currently enrolling in phase III development programs. Similarly, ozanimod, an S1P1 and S1P5 receptor agonist, has shown early favorable results and is enrolling in phase III trials. As these and other novel oral SMDs come to market, several questions will need to be answered. The cost effectiveness, comparative treatment efficacy, predictors of response, and relative safety of oral SMDs compared to existing therapies will need to be evaluated. Given the modest efficacy rates observed with both biologic therapies and novel SMDs to date, the potential for combination therapy based on a non-sensitizing oral option is promising and may be facilitated by development of organ-specific therapies with pharmacodynamic activity restricted to the gut to minimize systemic toxicity.

Abstract 2672: Effect of conjugating gemcitabine with novel temperature responsive polymer in improving drug targeting, retention, and release in the KPC mouse model of pancreatic cancer

Abstract Introduction: Pancreatic cancer remains a devastating disease where most chemotherapies are modestly effective in part because of limited drug penetration into the stroma rich hypovascular tumors. Our goal was to develop a drug delivery mechanism that allows cancer specific release of cytotoxic agents and minimizes off-target effects. We have developed a gemcitabine-polyacetal drug conjugate that has a highly selective drug release profile via temperature response, pH-degradation, and ability for tuning reverse temperature transitions. The gemcitabine-polyacetal conjugates release drug selectively in acidic environments but remain inert in others. Objective: Here, we present in vitro and in vivo data on the efficacy of gemcitabine-polyacetal drug conjugates in pancreatic cancer cell lines and KPC (KrasG12D/+;Trp53R172H/+;Pdx1-Cre) derived allografts. Methods: The drug release of polyacetal-drug conjugates were previously characterized using Gel Permeation Chromatography and Nuclear Magnetic Resonance. In the current study, drug release is characterized using viability of KPC-derived cell lines and BxPC3 cells. We assessed the drug efficacy of solo-gemcitabine and gemcitabine-polyacetal drug conjugates at 24, 48, and 72-hour time points at two pHs: physiological pH using HEPES media, and PDAC tumor pH by phosphate buffer set at pH 6.8. Drug free polyacetal was used as a negative control. Results: In the two KPC and one BxPC3 cell lines tested, statistically significant differences in cell viability were observed. Gemcitabine-polyacetal conjugate at pH 6.8 showed 3-6% cell viability at drug concentrations less than 5μmol within 24 hours, while the conjugate in HEPES media (at pH ~8.0) showed more than 90% cell viability up to 72 hours. In contrast, solo-gemcitabine showed 5-8% cell viability in both pH’s. Percutaneous injection of 25μM dose of gemcitabine-polyacetal drug conjugate into allograft tumors showed a significant decrease in % of Ki67+ cells (p=0.0.009) compared to controls injected with PBS. Conclusions: The gemcitabine-polyacetal conjugate serves as a drug deactivator in its conjugated form. In acidic pH, the drug is activated and released with high selectivity. This site-specific drug release could significantly reduce off-target effects that are reported with gemcitabine. Here, we showed significant effect on direct tumor injection of the conjugated gemcitabine. As previously shown, polyacetal-drug conjugates can be synthesized using dozens of chemotherapeutic drugs without chemical modification, making polyacetal conjugation a versatile approach to minimize off-target effects and ultimately systemic cytotoxicity in a variety of chemotherapeutic treatments. These results support further development of this delivery strategy in treatment of pancreatic cancer. Citation Format: Jarwei Fang, Porakrit Leophairatana, Jeffrey Koberstein, Tamas Gonda, Chathuranga De Silva. Effect of conjugating gemcitabine with novel temperature responsive polymer in improving drug targeting, retention, and release in the KPC mouse model of pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2672.

Fractal evolution of dual pH- and temperature-responsive P(NIPAM-co-AA)@BMMs with bimodal mesoporous silica core and coated-copolymer shell during drug delivery procedure via SAXS characterization

The dual (pH- and temperature-) responsive core-shell structured mesoporous nanomaterial P@BMMs were prepared using bimodal mesoporous silica as a core and poly(N-isopropylacrylamide-co-acrylic acid) P(NIPAM-co-AA) copolymer as a shell. Ibuprofen (IBU) was used as a model drug, and the effects of copolymer-coated shell thickness on drug loading and controlled release behavior were investigated by means of N2 sorption isotherms, dynamic light scattering measurements, X-ray diffraction patterns, Fourier transform infrared spectra, scanning electron and transmission electron microscopy, thermogravimetric profiles, and elemental analysis techniques. Particularly, their fractal evolutions in the drug delivery durations were explored via small angle X-ray scattering methods, demonstrating that the resultant P@BMMs before IBU-loading and after releasing possess the typical fractal features with spherical morphology. Meanwhile, the estimation for shell thickness of P@BMMs coating in different time intervals indicated that the drug-loaded capacity was improved with the increasing shell thickness, but drug-released rate varies, strongly depending on both shell thickness and release conditions. The drug delivery mechanism was preliminarily explored, following the Korsmeyer-Peppas model. Finally, cytotoxicity in cell and pharmacokinetic of released-IBU from hybrid nanocomposite in mice via intravenously injection were preliminarily explored.

Synthetic Gene Circuits Enable Systems-Level Biosensor Trigger Discovery at the Host-Microbe Interface.

Engineering synthetic circuits into intestinal bacteria to sense, record, and respond to in vivo signals is a promising new approach for the diagnosis, treatment, and prevention of disease. However, because the design of disease-responsive circuits is limited by a relatively small pool of known biosensors, there is a need for expanding the capacity of engineered bacteria to sense and respond to the host environment. Here, we apply a robust genetic memory circuit in Escherichia coli to identify new bacterial biosensor triggers responding in the healthy and diseased mammalian gut, which may be used to construct diagnostic or therapeutic circuits. We developed a pipeline for rapid systems-level library construction and screening, using next-generation sequencing and computational analysis, which demonstrates remarkably reliable identification of responsive biosensor triggers from pooled libraries. By testing libraries of potential triggers-each consisting of a promoter and ribosome binding site (RBS)-and using RBS variation to augment the range of trigger sensitivity, we identify and validate triggers that selectively activate our synthetic memory circuit during transit through the gut. We further identify biosensor triggers with increased response in the inflamed gut through comparative screening of one of our libraries in healthy mice and those with intestinal inflammation. Our results demonstrate the power of systems-level screening for the identification of novel biosensor triggers in the gut and provide a platform for disease-specific screening that is capable of contributing to both the understanding and clinical management of intestinal illness.IMPORTANCE The gut is a largely obscure and inaccessible environment. The use of live, engineered probiotics to detect and respond to disease signals in vivo represents a new frontier in the management of gut diseases. Engineered probiotics have also shown promise as a novel mechanism for drug delivery. However, the design and construction of effective strains that respond to the in vivo environment is hindered by our limited understanding of bacterial behavior in the gut. Our work expands the pool of environmentally responsive synthetic circuits for the healthy and diseased gut, providing insight into host-microbe interactions and enabling future development of increasingly complex biosensors. This method also provides a framework for rapid prototyping of engineered systems and for application across bacterial strains and disease models, representing a practical step toward the construction of clinically useful synthetic tools.

The production of a novel poly(vinyl alcohol) hydrogel cryogenic spheres for immediate release using a droplet system

Although freeze-thaw mechanism for producing crosslinked hydrogels is relatively easy and simple, it lacks sufficient integrity and support leading to modifications on its three-dimensional polymeric network arrangement during water removal—drying. Therefore, a strengthening method for obtaining cryogenic spheres of polyvinyl alcohol hydrogels is purposed by dispensing it as liquid droplets into a low temperature solution followed by a modification on its freeze-thaw cycles to confer a good geometry without aggregation. Various materials were incorporated into this hydrogel structure, including poly(acrylic acid) to impart pH sensitivity; hydroxyapatite to improve biocompatibility; and ciprofloxacin as an antimicrobial agent relevant for the treatment of osteomyelitis. The overall network presented a porous structure with a fibrous-like pattern which varied in size and volume, with presence of Ca and P when hydroxyapatite is incorporated. These materials varied the crystalline melting point of the poly(vinyl alcohol) and a linear pH sensitivity function was obtained by the addition of the materials. These hydrogels were found to release ciprofloxacin within 60 min and were able to dissolve at the same time intervals. Therefore, the hydrogel synthesised in this work can be used as an immediate release drug delivery mechanism for the in situ delivery of active pharmaceutical such as ciprofloxacin for a treatment of osteomyelitis.

Chitosan-Based Nanocarriers for Nose to Brain Delivery

In the treatment of brain diseases, most potent drugs that have been developed exhibit poor therapeutic outcomes resulting from the inability of a therapeutic amount of the drug to reach the brain. These drugs do not exhibit targeted drug delivery mechanisms, resulting in a high concentration of the drugs in vital organs leading to drug toxicity. Chitosan (CS) is a natural-based polymer. It has unique properties such as good biodegradability, biocompatibility, mucoadhesive properties, and it has been approved for biomedical applications. It has been used to develop nanocarriers for brain targeting via intranasal administration. Nanocarriers such as nanoparticles, in situ gels, nanoemulsions, and liposomes have been developed. In vitro and in vivo studies revealed that these nanocarriers exhibited enhanced drug uptake to the brain with reduced side effects resulting from the prolonged contact time of the nanocarriers with the nasal mucosa, the surface charge of the nanocarriers, the nano size of the nanocarriers, and their capability to stretch the tight junctions within the nasal mucosa. The aforementioned unique properties make chitosan a potential material for the development of nanocarriers for targeted drug delivery to the brain. This review will focus on chitosan-based carriers for brain targeting.

Peptide-Loaded Cubosomes Functioning as an Antimicrobial Unit against Escherichia coli.

Dispersions of cubic liquid crystalline phases, also known as cubosomes, have shown great promise as delivery vehicles for a wide range of medicines. Due to their ordered structure, comprising alternating hydrophilic and hydrophobic domains, cubosomes possess unique delivery properties and compatibility with both water-soluble and -insoluble drugs. However, the drug delivery mechanism and cubosome interaction with human cells and bacteria are still poorly understood. Herein, we reveal how cubosomes loaded with the human cathelicidin antimicrobial peptide LL-37, a system with high bacteria-killing effect, interact with the bacterial membrane and provide new insights into the eradication mechanism. Combining the advanced experimental techniques neutron reflectivity and quartz crystal microbalance with dissipation monitoring, a mechanistic drug delivery model for LL-37-loaded cubosomes on bacterial mimicking bilayers was constructed. Moreover, the cubosome interaction with Escherichia coli was directly visualized using super-resolution laser scanning microscopy and cryogenic electron tomography. We could conclude that cubosomes loaded with LL-37 adsorbed and distorted bacterial membranes, providing evidence that the peptide-loaded cubosomes function as an antimicrobial unit.

A patent review of bisphosphonates in treating bone disease

ABSTRACTIntroduction: Bisphosphonates (BPs) are widely used to manage a variety of bone disorders, including osteoporosis, metastatic bone disease and myeloma bone disease. The nitrogen-containing BPs (NBPs) target osteoclast activity by disrupting protein prenylation via inhibition of farnesyl diphosphate synthase (FDPS).Areas covered: This review summarizes the recent advances in BPs with a focus on the latest patents (2015–2018). Patents involving novel BPs, new modes of BP delivery, as well as use of BPs to deliver other drugs to bone are discussed. A review of phosphonate-based drugs targeting geranylgeranyl diphosphate synthase (GGDPS) or geranylgeranyl transferase II (GGTase II) as alternative strategies to disrupt protein geranylgeranylation is provided.Expert opinion: While the NBPs remain the mainstay of treatment for most bone disorders, further understanding of their pharmacological properties could lead to further refinement of their chemical structures and optimization of efficacy and safety profiles. In addition, the development of NBP analogs or drug delivery mechanisms that allow for nonbone tissue exposure could allow for the use of these drugs as direct anticancer agents. The development of GGDPS and GGTase II inhibitors represents alternative heterocycle phosphonate-based strategies to disrupt protein geranylgeranylation and may have potential as anticancer agents and/or as bone-targeted therapies.

Drug therapies and delivery mechanisms to treat perturbed skin wound healing.

Acute wound healing is an orderly process of four overlapping events: haemostasis, inflammation, proliferation and remodelling. A drug delivery system with a temporal control of release could promote each of these events sequentially. However, acute wound healing normally proceeds very well in healthy individuals and there is little need to promote it. In the elderly and diabetics however, healing is often slow and wounds can become chronic and we need to promote their healing. Targeting the events of acute wound healing would not be appropriate for a chronic wound, which have stalled in the proinflammatory phase. They also have many additional problems such as poor circulation, low oxygen, high levels of leukocytes, high reactive oxygen species, high levels of proteolytic enzymes, high levels of proinflammatory cytokines, bacterial infection and high pH. The future challenge will be to tackle each of these negative factors to create a wound environment conducive to healing.

Rectal Endoscopic Ultrasound in Clinical Practice.

Endoscopic ultrasound (EUS) is routinely utilized for evaluation of disorders of the lower gastrointestinal tract. In this review, we summarize the current status of rectal EUS in clinical practice and describe recent developments in diagnostic and therapeutic rectal EUS. Recent guidelines recommend rectal EUS for rectal cancer staging as a second line modality in cases where MRI is contraindicated. Forward-viewing echoendoscopes and through the scope EUS miniprobes allow for EUS imaging of lesions through the entire colon and for evaluation beyond stenoses or luminal narrowings. EUS can be used to assess perianal disease and drain pelvic abscess associated with IBD, along with newer applications currently under investigation. For rectal varices, EUS can confirm the diagnosis, assess the optimal site for banding, guide therapy placement with sclerotherapy and/or coils, and assess response to treatment by confirming absence of flow. Therapeutic rectal EUS is emerging as a promising modality for drainage of pelvic fluid collection drainage and fiducial placement for rectal or prostatic cancer. Drug delivery mechanisms and substances that may increase the scope of therapy with rectal EUS are in varying stages of development. Rectal EUS continues to be an important modality for evaluation of benign and malignant disorders of the lower gastrointestinal tract, although its use as a cancer staging modality has declined due to improvements in MRI technology. Various technologies to enhance ultrasound imaging and for therapeutics have been developed that have or may contribute to expanded indications for rectal EUS.

Fatty Acids of Enteromorpha intestinalis Emulsified Drug Delivery Nanoemulsion: Evaluation of Loading Mechanism and Release Kinetics for Drug Delivery

The selection of bio-surfactants in consonance with the pharmaceutical drug in the preparation of nanoemulsion for the controlled release of drugs and bio-compatibility is still a scientific moot. We have investigated the possible mechanism of drug-surfactant interaction in this research that can iron out the surfactant identification complication. The bio-surfactants 9-Octadecenoic acid, 9-Octadeceamide and Isopropyl Myristate isolated from a marine weed Enteromorpha intestinalis were used together to stabilize the nanoemulsion. The encapsulation efficiency and release kinetics of Aspirin in nanoemulsion under different pH conditions from the nanoemulsion was studied. Nanoemulsion was prepared by the ultrasonication method and characterized by centrifugation, capillary viscometer, freeze–thaw cycle assays, dynamic light scattering analysis (DLS) and HR-TEM. The mechanism of drug surfactant interaction deduced using Spectrophotometric and ATR-FTIR analysis revealed the possible bond formations. In-vitro drug release profiles of aspirin (model drug) were evaluated by dialysis in different pH (1.2, 6.8 and 7.4) using by UV-spectrophotometry and the effective release of aspirin was observed in pH 6.8. The release kinetics was studied to identify the mode of release. The bio-surfactant based nanoemulsion of 15:6:9 composition exhibited ideal stability and controlled release in all pH conditions with linearity and time-dependent paradigm.

Mathematical Modeling and Simulation to Investigate the CNS Transport Characteristics of Nanoemulsion-Based Drug Delivery Following Intranasal Administration.

Despite encouraging preclinical results, mechanisms of CNS drug delivery following intranasal dosing of nanoemulsions remain incompletely understood. Herein, the transport characteristics of intranasally administered nanoemulsions are investigated using mathematical modeling and simulation. A compartmental model was developed to describe systemic and brain pharmacokinetics of drug solutions following intranasal dosing in rodents. The association between transport processes and CNS drug delivery was predicted using sensitivity analysis. Published pharmacokinetic data for four drugs; dosed as a nanoemulsion and aqueous solution were modeled to characterize differences in transport processes across formulations. The intranasal model structure performed in a drug agnostic fashion. Sensitivity analysis suggested that though the extent of CNS drug delivery depends on nasal bioavailability, the CNS targeting efficiency is only sensitive to changes in drug permeability across the nasal epithelium. Modeling results indicated that nanoemulsions primarily improve nasal bioavailability and drug permeability across the olfactory epithelium, with minimal effect on drug permeability across the non-olfactory epithelium. Using mathematical modeling we outlined dominant transport pathways following intranasal dosing, predicted the association between transport pathways and CNS drug delivery, predicted human CNS delivery after accounting for inter-species differences in nasal anatomy, and quantified the CNS delivery potential of different formulations in rodents.

An ingenious non-spherical mesoporous silica nanoparticle cargo with curcumin induces mitochondria-mediated apoptosis in breast cancer (MCF-7) cells.

Curcumin delivery to cancer cells is challenging due to its hydrophobic nature, low bio distribution and low availability. Many nano vehicles suffer from low stability and toxicity, and hence the prerequisite of a non-toxic nano vehicle with effective drug delivery is still being delved. The present study investigates the delivery efficiency of curcumin with non-spherical mesoporous silica nanoparticles (MSNAs). Their mechanism of drug delivery and signalling proteins activated to induce apoptosis was further explored in MCF-7 cells. A non-spherical MSN was synthesised, functionalised with PEI (MSNAP) and analysed its intracellular behaviour. Our result indicates that MSNAP was non-toxic until 20 µg/mL and likely localizes in cytoplasmic vesicles. On contrast, well-known MCM-41P induced autophagosome formation, indicating cellular toxicity. Curcumin was loaded on MSNAP and its effectiveness in inducing cell death was studied in MCF-7 and in MCF-7R cells. Curcumin loading on MSNAP induces better cell death with 30 µM curcumin, better than unbounded curcumin. Western blot analysis suggest, curcumin induce apoptosis through the activation of caspase 9, 6, 12, PARP, CHOP and PTEN. The cell survival protein Akt1 was downregulated by curcumin with and without the nanostructure. Interestingly, cleaved caspase 9 was activated in higher amount in nano-conjugated curcumin compared to the free curcumin. But other ER resident protein like IRE1α, PERK and GRP78 were downregulated indicating curcumin disturbs ER homeostasis. Further, electron microscopic analysis reveled that nanocurcumin induced apoptosis by disrupting mitochondria and nucleus. Our results with doxorubicin resistant MCF-7 cell lines confirm nanodelivery of doxorubicin and curcumin sensitised cells effectively at lesser concentration. Further docking studies of curcumin indicate it interacts with the apoptotic proteins through hydrogen bonding formation and with higher binding energy.

Multifunctional Nanobiohybrid Material Composed of Ag@Bi2Se3/RNA Three-Way Junction/miRNA/Retinoic Acid for Neuroblastoma Differentiation.

Nanoparticle-based cell differentiation therapy has attracted increasing research interest as it is a promising substitute for conventional cancer treatment methods. Here, the topological insulator bismuth selenide nanoparticle (Bi2Se3 NP) was core-shelled with silver (Ag@Bi2Se3) to represent remarkable biocompatibility and plasmonic features (ca. 2.3 times higher than those of Ag nanoparticle). Moreover, a newly developed RNA three-way junction (3WJ) structure was designed for the quad-functionalization of any type of nanoparticle and surface. One leg of the 3WJ was attached to the Ag@Bi2Se3, and the other leg harbored a cell-penetrating RNA and a florescence tag. The third leg was designed to inhibit micro-RNA-17 (miR-17) and to further release retinoic acid (RA). A new drug delivery mechanism was developed for the slow release of RA inside the cytosol based on the prerequisite inhibition of miR-17 using a strand displacement strategy. In this paper, we report a simple methodology for resolving the hydrophobicity challenges of RA by its conjugation with a RNA strand (RA/R) through a stimulus-responsive cross-linker. The developed nanobiohybrid material could fully differentiate SH-SY5Y cancer cells into neurons and stop their growth in 6 days without requiring sequential treatments which has not been reported yet. Using a surface-enhanced Raman spectroscopy technique, the RA delivery and the cell differentiation process were monitored nondestructively in real time. The fabricated nanobiohybrid material could open the new horizons in the fabrication of different diagnostic/therapeutic agents.

The Treatment of MDA-MB-231 Breast Cancer Cells with Biocompatible Manganese Iron Oxide Nanoparticles as Drug Carriers

Targeting cancer cells and killing them without affecting normal healthy cells is one of the primary objective in cancer treatment. Thus, developing better targeted drug delivery mechanisms, will enhance the efficacy of the use of already used chemotherapeutic drugs significantly by decreasing its harmful side effects. Our earlier studies have demonstrated that polymer coated Magnetic Nanoparticles (MNP) together with a chemotherapeutic drug, are 50% more- efficient drug delivery agent compared to the intrinsic drug itself. We have also observed that the interaction of the applied DC magnetic field with the MNP is primarily decided by its Curie temperature. In the current paper we report the results by expanding the scope of this study. This was achieved by changing three parameters, a different MNP (MnFe2O4) having a lower Curie temperature but a stronger magnetic susceptibility, a different cell-line (MBA-MD-231 breast cancer cells) which has been reported to show difference in similar studies, and finally including Electro-magnetic field as the coupling agent in place of DC magnetic field. Manganese iron oxide (MnFe2O4) nanoparticles were coated with PEG (Polyethylene glycol) and Sodium Oleate and their biocompatibility were tested on cells compared to treated cells with naked nanoparticles. The MNP were subsequently coupled with doxorubicin and magnetically delivered to MDA-MB-231 breast cancer cells. Furthermore the in vitro viability of the cells were studied both on coupling the MNPs with DC and AC electromagnetic field. The results of this study show that the Mn-MNPs are more biocompatible than other MNPs on this particular cell line. Also it is observed that AC electromagnetic field have more efficient drug delivery mechanism than DC magnetic field.

ATP Aptamer-Modified Quantum Dots with Reduced Glutathione/Adenosine Triphosphate Dual Response Features as a Potential Probe for Intracellular Drug Delivery Monitoring of Vesicular Nanocarriers.

Nanoparticles have great promise in drug delivery, but their functional mechanisms are very complicated. Monitoring the payloads or carriers by conventional labeling strategies may result in an inaccurate perception of the effectiveness of nano drug delivery systems (NDDSs). A GSH/ATP dual-responsive fluorescence enhancement probe was developed by manipulating the electron transfer pathways of surface-modified quantum dots (QDs). Because the intracellular concentrations of GSH and ATP are one hundred times greater than those in the extracellular environment, the intracellular drug release process could be observed by the fluorescence signal of this probe after it is loaded into NDDSs as drug simulants. As a proof-of-concept investigation, the intracellular drug release behaviors of classical liposomes were studied by loading this probe, and the observed results strongly support the known drug delivery mechanism of these systems. Although more studies are needed to investigate the in vivo performance of the probe, this study may encourage further investigations of other intracellular environment-responsive smart probes for deciphering the in vivo fate of NDDSs.

A mathematical model of sonoporation using a liquid-crystalline shelled microbubble

In recent years there has been a great deal of interest in using thin shelled microbubbles as a transportation mechanism for localised drug delivery, particularly for the treatment of various types of cancer. The technique used for such site-specific drug delivery is sonoporation. Despite there being numerous experimental studies on sonoporation, the mathematical modelling of this technique has still not been extensively researched. Presently there exists a very small body of work that models both hemispherical and spherical shelled microbubbles sonoporating due to acoustic microstreaming. Acoustic microstreaming is believed to be the dominant mechanism for sonoporation via shelled microbubbles. Rather than considering the shell of the microbubble to be composed of a thin protein, which is typical in the literature, in this paper we consider the shell to be a liquid-crystalline material. Up until now there have been no studies reported in the literature pertaining to sonoporation of a liquid-crystalline shelled microbubble. A mathematical expression is derived for the maximum wall shear stress, illustrating its dependency on the shell’s various material parameters. A sensitivity analysis is performed for the wall shear stress considering the shell’s thickness; its local density; the elastic constant of the liquid-crystalline material; the interfacial surface tension and; the shell’s viscoelastic properties. In some cases, our results indicate that a liquid-crystalline shelled microbubble may yield a maximum wall shear stress that is two orders of magnitude greater than the stress generated by commercial shelled microbubbles that are currently in use within the scientific community. In conclusion, our preliminary analysis suggests that using liquid-crystalline shelled microbubbles may significantly enhance the efficiency of site-specific drug delivery.