Innovative Delivery Approaches Research Articles

An Innovative Delivery System of Oxygen-Releasing Nanospheres and Self-Healing Hydrogels Enhances the Therapeutic Effectiveness of Bone Marrow Mesenchymal Stem Cells for Chronic Limb-Threatening Ischemia.

Bone marrow mesenchymal stem cells (BMSCs) have emerged as promising candidate for postoperative therapeutics in chronic limb-threatening ischemia (CLTI). Nevertheless, their effectiveness is limited by their low survival rate and impaired functionality in the ischemic microenvironment. To overcome these challenges, we have devised an innovative delivery approach to support the utilization of BMSCs in CLTI therapy. We synthesized oxygen-releasing nanospheres and self-healing hydrogels. The in vivo functionality of the hydrogel-nanosphere delivery system was evaluated via a multimodality animal live imaging system. A unilateral lower limb ischemia model was established in mice, and a delivery system loaded with BMSCs was administered. The experimental groups included normal mice, ischemic mice, ischemic mice treated with BMSCs in PBS, and ischemic mice treated with BMSCs in the delivery system. Blood perfusion was quantitatively measured via a laser doppler flowmeter (LDF). Immunofluorescence, Masson's trichrome staining, immunohistochemistry and enzyme-linked immunosorbent assay (ELISA) were also used. For cell viability analysis 80 μg.mL-1 was considered the optimal concentration for cell survival. In vivo, 18 days after injection, the cell membrane fluorescence signal in the delivery system was significantly greater (5.65510±8.2268) p/s/cm²/sr than that in the other groups (p=0.043). Ischemic mice treated with BMSCs in the delivery system presented an improved limb salvage rate (0.926±0.12)% compared with that of ischemic mice treated with BMSCs in PBS (0.841±0.029)% at the 5th week after ischemia establishment (p=0.0033). Our findings suggest that the survival time of BMSCs is prolonged in this innovative delivery system. The combination of nanospheres and hydrogels effectively restored vascular blood perfusion while exerting minimal toxicity on BMSCs. This novel approach combining oxygen-releasing nanospheres and self-healing hydrogels as a delivery system represents an advancement in enhancing the functionality of BMSCs to treat CLTI.

Unraveling School Adolescent Depression: Insights into Cognitive Behavioral Therapy

Adolescent depression presents a significant global mental health concern, exerting profound impacts on various facets of young people's lives. Cognitive Behavioral Therapy (CBT) has emerged as a leading intervention for tackling adolescent depression, grounded in principles derived from cognitive theory. This review delves into the effectiveness, mechanisms, and outcomes of CBT in addressing adolescent depression, synthesizing findings from a range of empirical studies including randomized controlled trials, meta-analyses, and systematic reviews. The review underscores the consistent efficacy of CBT in diminishing depressive symptoms among adolescents, elucidating mechanisms such as cognitive restructuring and behavioral activation that underpin its therapeutic effects. Additionally, CBT yields favorable outcomes beyond mere symptom reduction, encompassing enhancements in social connections and academic performance. Nonetheless, challenges such as limited accessibility and hurdles in engaging adolescents persist in CBT implementation. To surmount these obstacles, forthcoming research ought to concentrate on devising innovative delivery approaches, such as internet-based interventions and school-centered programs. In essence, CBT stands as a pivotal component in the treatment of adolescent depression, furnishing a holistic framework to address the intricate interplay of cognitive, emotional, and behavioral elements, thereby fostering the mental well-being of adolescents on a global scale.

Development and characterization of ferulic acid-loaded chitosan nanoparticle embedded- hydrogel for diabetic wound delivery

Diabetic wounds present a significant global health challenge exacerbated by chronic hyperglycemia-induced oxidative stress, impeding the natural healing process. Despite various treatment strategies, diabetic foot ulceration lacks standardized therapy. Ferulic acid (FA), known for its potent antidiabetic and antioxidant properties, holds promise for diabetic wound management. However, oral administration of FA faces limitations due to rapid oxidation, stability issues, and low bioavailability. The topical application of FA-loaded chitosan nanoparticles (FA-CSNPs) has emerged as a promising approach to overcome these challenges. Here, we report the development of a sustained-release formulation of FA-CSNPs within a hydrogel matrix composed of Chitosan and gelatin. The FA-CSNPs were synthesized using the ionic gelation method andoptimized through a Central Composite Design (CCD) approach. Characterization of the optimized nanoparticles revealed spherical morphology, a particle size of 56.9 ± 2.5 nm, and an impressive entrapment efficiency of 90.3 ± 2.4 %. Subsequently, an FA-CSNPs-loaded hydrogel was formulated, incorporating chitosan as a gelling agent, gelatin to enhance mechanical properties and cell permeation, and glutaraldehyde as a cross-linker. Comprehensive characterization of the hydrogel included pH, moisture loss, porosity, swelling index, rheology, water vapor transmission rate (WVTR), SEM, TEM, invitro drug release studies, antioxidant activity, antibacterial efficacy, cell cytotoxicity, cell migration studies on L929 fibroblast cell line, and stability studies. The stability study demonstrated negligible variations in particle size, zeta potential, and entrapment efficiency over 60 days, ensuring the stable nature of nanoparticles and hydrogel. This innovative delivery approach embedded within a hydrogel matrix holds significant promise for enhancing the therapeutic efficacy of FA-CSNPs-hydrogel in diabetic wound healing applications.

Enhancing transmucosal delivery of CBD through nanoemulsion: in vitro and in vivo studies.

Cannabidiol (CBD) has gained significant attention as a complementary and alternative medicine due to its promising therapeutic properties. However, CBD faces obstacles when administered orally due to its poor solubility in water, leading to limited absorption into the bloodstream and low and variable bioavailability. Therefore, the development of innovative delivery approaches that can enhance CBD's bioavailability, facilitate administration, and promote patient adherence is crucial. We propose a new approach for buccal delivery of CBD based on a self-assembling nanoemulsion (NE) made of a mixture of surfactants (Tween 80 and Labrasol) and medium chain triglycerides (MCTs). The NE formulation showed properties suitable for buccal administration, including appropriate size, CBD content, and surface properties, and, if compared to a CBD-MCT solution, it exhibited better control of administered doses, faster dissolution in buccal medium, and enhanced stability. The CBD-NE effectively released its active load within 5h, remained stable even when diluted in simulated buccal fluids, and could be easily administered through a commercially available spray, providing consistent and reproducible doses of NE with optimized properties. In vitro permeation studies demonstrated that the CBD-NE facilitated swift and consistent permeation through the buccal mucosa, resulting in a higher concentration in the acceptor compartment compared to CBD-MCT. Furthermore, the in vivo study in mice showed that a single buccal administration of CBD-NE led to a quicker onset of action than a CBD solution in MCT, while maintaining the same plasma levels over time and leading to typically higher plasma concentrations compared to those usually achieved through oral administration. In conclusion, our CBD-NE represents a promising alternative formulation strategy for buccal CBD administration, overcoming the challenges associated with conventional formulations such as variable bioavailability and low control of administered doses.

Innovative Phospholipid Carriers: A Viable Strategy to Counteract Antimicrobial Resistance.

The overuse and misuse of antibiotics have led to the emergence and spread of multidrug-resistant (MDR), extensively drug-resistant (XDR), and pan-drug-resistant (PDR) bacteria strains, usually associated with poorer patient outcomes and higher costs. In order to preserve the usefulness of these life-saving drugs, it is crucial to use them appropriately, as also recommended by the WHO. Moreover, innovative, safe, and more effective approaches are being investigated, aiming to revise drug treatments to improve their pharmacokinetics and distribution and to reduce the onset of drug resistance. Globally, to reduce the burden of antimicrobial resistance (AMR), guidelines and indications have been developed over time, aimed at narrowing the use and diminishing the environmental spread of these life-saving molecules by optimizing prescriptions, dosage, and times of use, as well as investing resources into obtaining innovative formulations with better pharmacokinetics, pharmacodynamics, and therapeutic results. This has led to the development of new nano-formulations as drug delivery vehicles, characterized by unique structural properties, biocompatible natures, and targeted activities such as state-of-the-art phospholipid particles generally grouped as liposomes, virosomes, and functionalized exosomes, which represent an attractive and innovative delivery approach. Liposomes and virosomes are chemically synthesized carriers that utilize phospholipids whose nature is predetermined based on their use, with a long track record as drug delivery systems. Exosomes are vesicles naturally released by cells, which utilize the lipids present in their cellular membranes only, and therefore, are highly biocompatible, with investigations as a delivery system having a more recent origin. This review will summarize the state of the art on microvesicle research, liposomes, virosomes, and exosomes, as useful and effective tools to tackle the threat of antibiotic resistance.

Pediatric Diffuse Midline Gliomas: An Unfinished Puzzle.

Diffuse midline glioma (DMG) is a heterogeneous group of aggressive pediatric brain tumors with a fatal prognosis. The biological hallmark in the major part of the cases is H3K27 alteration. Prognosis remains poor, with median survival ranging from 9 to 12 months from diagnosis. Clinical and radiological prognostic factors only partially change the progression-free survival but they do not improve the overall survival. Despite efforts, there is currently no curative therapy for DMG. Radiotherapy remains the standard treatment with only transitory benefits. No chemotherapeutic regimens were found to significantly improve the prognosis. In the new era of a deeper integration between histological and molecular findings, potential new approaches are currently under investigation. The entire international scientific community is trying to target DMG on different aspects. The therapeutic strategies involve targeting epigenetic alterations, such as methylation and acetylation status, as well as identifying new molecular pathways that regulate oncogenic proliferation; immunotherapy approaches too are an interesting point of research in the oncology field, and the possibility of driving the immune system against tumor cells has currently been evaluated in several clinical trials, with promising preliminary results. Moreover, thanks to nanotechnology amelioration, the development of innovative delivery approaches to overcross a hostile tumor microenvironment and an almost intact blood–brain barrier could potentially change tumor responses to different treatments. In this review, we provide a comprehensive overview of available and potential new treatments that are worldwide under investigation, with the intent that patient- and tumor-specific treatment could change the biological inauspicious history of this disease.

The Challenges and Opportunities in the Development of MicroRNA Therapeutics: A Multidisciplinary Viewpoint.

microRNAs (miRs) are emerging as attractive therapeutic targets because of their small size, specific targetability, and critical role in disease pathogenesis. However, <20 miR targeting molecules have entered clinical trials, and none progressed to phase III. The difficulties in miR target identification, the moderate efficacy of miR inhibitors, cell type-specific delivery, and adverse outcomes have impeded the development of miR therapeutics. These hurdles are rooted in the functional complexity of miR’s role in disease and sequence complementarity-dependent/-independent effects in nontarget tissues. The advances in understanding miR’s role in disease, the development of efficient miR inhibitors, and innovative delivery approaches have helped resolve some of these hurdles. In this review, we provide a multidisciplinary viewpoint on the challenges and opportunities in the development of miR therapeutics.

Peptide Functionalised Nanocarriers for Bone Specific Delivery of PTH (1-34) in Osteoporosis

: Osteoporosis represents a major public health burden especially considering the aging population worldwide. Treatment modalities for osteoporosis are classified into two categories based on the effect on bone remodelling: anabolic drugs and antiresorptive drugs. Anabolic drugs are preferred as it stimulates new bone formation. Currently, PTH (1-34) is the only peptide-based drug approved as an anabolic agent for the treatment of osteoporosis by both USFDA as well as EMA. However, its non-specific delivery results in prolonged kidney exposure, causing hypercalcemia. Nanotechnology-based drug delivery systems functionalized by conjugating it with homing moieties, such as peptides, offer an advantage of targeted delivery with reduced off-target effects. Here, we propose an innovative and targeted nanovesicle approach to efficiently deliver PTH (1-34) to the bone surface using peptides as a homing moiety. The proposed innovative delivery approach will augment the specific interaction between the drug and bone surface without producing side effects. This will reduce the off-target effects of PTH (1-34), and at the same time, it will also improve the outcome of anabolic therapy. Therefore, we postulate that the proposed innovative drug delivery approach for PTH (1-34) will establish as a promising therapy for osteoporotic patients, specifically in postmenopausal women who are at greater risk of bone fracture.

Genome editing reagent delivery in plants.

Genome editing holds the potential for rapid crop improvement to meet the challenge of feeding the planet in a changing climate. The delivery of gene editing reagents into the plant cells has been dominated by plasmid vectors delivered using agrobacterium or particle bombardment. This approach involves the production of genetically engineered plants, which need to undergo regulatory approvals. There are various reagent delivery approaches available that have enabled the delivery of DNA-freeediting reagents. They invariably involve the use of ribonucleoproteins (RNPs), especially in the case of CRISPR/Cas9-mediated gene editing. The explant of choice for most of the non-DNA approaches utilizes protoplasts as the recipient explant. While the editing efficiency is high in protoplasts, the ability to regenerate individual plants from edited protoplasts remains a challenge. There are various innovative delivery approaches being utilized to perform in planta edits that can be incorporated in the germline cells or inherited via seed. With the modification and adoption of various novel approaches currently being used in animal systems, it seems likely that non-transgenic genome editing will become routine in higher plants.

Abortion care pathways and service provision for adolescents in high-income countries: A qualitative synthesis of the evidence.

Limited research in high-income countries (HICs) examines adolescent abortion care-seeking pathways. This review aims to examine the pathways and experiences of adolescents when seeking abortion care, and service delivery processes in provision of such care. We undertook a systematic search of the literature to identify relevant studies in HICs (2000–2020). A directed content analysis of qualitative and quantitative studies was conducted. Findings were organised to one or more of three domains of an a priori conceptual framework: context, components of abortion care and access pathway. Thirty-five studies were included. Themes classified to the Context domain included adolescent-specific and restrictive abortion legislation, mostly focused on the United States. Components of abortion care themes included confidentiality, comprehensive care, and abortion procedure. Access pathway themes included delays to access, abortion procedure information, decision-making, clinic operation and environments, and financial and transportation barriers. This review highlights issues affecting access to abortion that are particularly salient for adolescents, including additional legal barriers and challenges receiving care due to their age. Opportunities to enhance abortion access include removing legal barriers, provision of comprehensive care, enhancing the quality of information, and harnessing innovative delivery approaches offered by medical abortion.

Pre-Exposure Prophylaxis Integration Into Family Planning Services at Title X Clinics in the Southeastern United States: Protocol for a Mixed Methods Hybrid Type I Effectiveness Implementation Study (Phase 2 ATN 155).

BackgroundAdolescent and young adult women (AYAW), particularly racial and ethnic minorities, in the Southern United States are disproportionately affected by HIV. Pre-exposure prophylaxis (PrEP) is an effective, scalable, individual-controlled HIV prevention strategy that is grossly underutilized among women of all ages and requires innovative delivery approaches to optimize its benefit. Anchoring PrEP delivery to family planning (FP) services that AYAW already trust, access routinely, and deem useful for their sexual health may offer an ideal opportunity to reach women at risk for HIV and to enhance their PrEP uptake and adherence. However, PrEP has not been widely integrated into FP services, including Title X–funded FP clinics that provide safety net sources of care for AYAW. To overcome potential implementation challenges for AYAW, Title X clinics in the Southern United States are uniquely positioned to be focal sites for conceptually informed and thoroughly evaluated PrEP implementation science studies.ObjectiveThe objective of this study is two-fold: to evaluate multilevel factors associated with the level of PrEP adoption and implementation (eg, PrEP screening, counseling, and prescription) within and across 3 FP clinics and to evaluate PrEP uptake, persistence, and adherence among female patients in these clinics over a 6-month follow-up period.MethodsPhase 2 of Planning4PrEP (Adolescent Medicine Trials Network for HIV/AIDS Interventions 155) is a mixed methods hybrid type 1 effectiveness implementation study to be conducted in three clinics in Metro Atlanta, Georgia, United States. Guided by the Exploration, Preparation, Implementation, and Sustainment framework, this study will prepare clinics for PrEP integration via clinic-wide trainings and technical assistance and will develop clinic-specific PrEP implementation plans. We will monitor and evaluate PrEP implementation as well as female patient PrEP uptake, persistence, and adherence over a 6-month follow-up period.ResultsPhase 2 of Planning4PrEP research activities began in February 2018 and are ongoing. Qualitative data analysis is scheduled to begin in Fall 2020.ConclusionsThis study seeks to evaluate factors associated with the level of PrEP adoption and implementation (eg, PrEP screening, counseling, and prescription) within and across 3 FP clinics following training and implementation planning and to evaluate PrEP uptake, persistence, and adherence among female patients over a 6-month follow-up period. This will guide future strategies to support PrEP integration in Title X–funded clinics across the Southern United States.Trial RegistrationClinicalTrials.gov NCT04097834; https://clinicaltrials.gov/ct2/show/NCT04097834International Registered Report Identifier (IRRID)DERR1-10.2196/18784

Pre-Exposure Prophylaxis Integration into Family Planning Services at Title X Clinics in the Southeastern United States: A Geographically-Targeted Mixed Methods Study (Phase 1 ATN 155).

BackgroundBlack adolescent and young adult women (AYAW) in the Southern United States are disproportionately affected by HIV. Pre-exposure prophylaxis (PrEP) is an effective, scalable, individual-controlled HIV prevention strategy that is grossly underutilized among women of all ages and requires innovative delivery approaches to optimize its benefit. Anchoring PrEP delivery to health services that AYAW already trust, access routinely, and deem useful for their sexual health may offer an ideal opportunity to reach women at risk for HIV and to enhance their PrEP uptake and adherence. These services include those of family planning (FP) providers in high HIV incidence settings. However, PrEP has not been widely integrated into FP services, including Title X-funded FP clinics that provide safety net sources of care for AYAW. To overcome potential implementation challenges for AYAW, Title X clinics in the Southern United States are uniquely positioned to be focal sites for conceptually informed and thoroughly evaluated PrEP implementation science studies.ObjectiveThe aim of this study is to assess inner and outer context factors (barriers and facilitators) that may influence the adoption of PrEP prescription and treatment services in Title X clinics serving AYAW in the Southern United States.MethodsPhase 1 of Planning4PrEP is an explanatory sequential, mixed methods study consisting of a geographically-targeted Web-based survey of Title X clinic administrators and providers in the Southern United States, followed by key informant interviews among a purposively selected subset of responders to more comprehensively assess inner and outer context factors that may influence adoption and implementation of PrEP in Title X FP clinics in the South.ResultsPhase 1 of Planning4PrEP research activities began in October 2017 and are ongoing. To date, survey and key informant interview administration is near completion, with quantitative and qualitative data analysis scheduled to begin soon after data collection completion.ConclusionsThis study seeks to assess inner and outer contextual factors (barriers and facilitators) that may influence the adoption and integration of PrEP prescription and treatment services in Title X clinics serving AYAW in the Southern United States. Data gained from this study will inform a type 1 hybrid effectiveness implementation study, which will evaluate the multilevel factors associated with successful PrEP implementation while evaluating the degree of PrEP uptake, continuation, and adherence among women seen in Title X clinics.International Registered Report Identifier (IRRID)DERR1-10.2196/12774

An Innovative Approach for Delivery of Nanosized Duloxetine Via External Acoustic Meatus (EAM) Platform

Objective: Depression is a common but serious mood disorder. The treatment cost is very high. The external auditory canal is used as a delivery platform and has overcome the dose dumping problem in the case of oral system. The current research work was to explore a novelistic route for targeting to the brain through ear by formulating nanosuspension using duloxetine as a model drug permitting better control over depression. Method: The concept was proved by preparing a nano-sized formulation of API i.e duloxetine and observed its pharmacological actions by sonication bath method. Bio-nano suspension was prepared by using a biopolymer which was isolated from berries of Piper nigrum. Eight formulations were prepared viz 1:0.5, 1:1, 1:2, 1:3, 1:4, 1:5, 1:7, and 1:10. Results: The formulations were subjected to various evaluations, including pH, % transmittance, content uniformity, ex-vivo stability, release for over 36 hours. Different formulations of duloxetine out of which F1 (1:0.5) was found to be the best formulation having the r2 value of 0.9905 tT80: 22 hrs and the best fit model was found to be Higuchi matrix, and mechanism of transport was anomalous transport which was calculated by bits software. Conclusion: On the basis of the in-vitro results obtained it can be concluded that significant amount of drug reaches the brain via external acoustic meatus and so it is feasible to deliver Duloxetine by this novelistic route.

Good Things in Small Packages: an Innovative Delivery Approach for Inhaled Insulin.

The design development of a small, hand held, battery operated, breath actuated inhaler as a drug/device platform for inhaled insulin posed a number of technical challenges. Our goal was to optimize lung deposition and distribution with aerosol generators producing 3-6μm particle size distribution. In silico modeling with computational fluid dynamics (CFD) and in vitro testing of device components were assessed using an Alberta idealized adult airway (Copley, UK) to optimize mouthpiece and aerosol path design for dose delivered distal to the trachea. Human factors use testing was designed to determine the ability to perform inspiratory manuevers with LED guidance within target flow limits. In vivo testing with healthy normal subjects of radiolabeled aerosol compared 2 breathing patterns for lung deposition efficiency, distribution, and subject preference. CFD demonstrated that flows ≤5L/min and ≥15L/min reduced the delivery efficiencg. Prototypes tested with inspiratory flow of 10L/min provided up to 70% of dose delivered distal to the model throat with aerosols of 3 to 6μm. Users guided by LED were able to inhale for 8-24s with 5s breath hold. Lung dose >70% with peripheral to central ratios >2.0 were achieved, with subject preference for the longer inspiratory time with breath hold. The device design phase integration led to a novel design and inspiratory pattern with greater levels of peripheral deposition than previously reported with commercial inhalers. The rationale and process of the application of these methods are described with implications for use in future device development.

Getting Growers to Go Digital: The Power of a Positive User Experience

Using web-based applications is an innovative approach for delivery of Extension resources. For example, myFields.info is a mobile-friendly application focused on directing stakeholders to information at the field level. Acceptance and diffusion of such applications depends on initial experiences resulting from traditional face-to-face interactions with Extension personnel. We found that crop school participants involved in an Extension training event for a web-based sampling plan showed increased willingness after the training to incorporate sampling plans in their management decisions and share relevant data with others. Specifically, our study demonstrated the value of providing hands-on experience when attempting to encourage stakeholders to accept technologies.

Parent-based adolescent sexual health interventions and effect on communication outcomes: a systematic review and meta-analyses.

Parent-based adolescent sexual health interventions aim to reduce sexual risk behaviors by bolstering parental protective behaviors. Few studies of theory use, methods, applications, delivery and outcomes of parent-based interventions have been conducted. A systematic search of databases for the period 1998-2013 identified 28 published trials of U.S. parent-based interventions to examine theory use, setting, reach, delivery mode, dose and effects on parent-child communication. Established coding schemes were used to assess use of theory and describe methods employed to achieve behavioral change; intervention effects were explored in meta-analyses. Most interventions were conducted with minority parents in group sessions or via self-paced activities; interventions averaged seven hours, and most used theory extensively. Meta-analyses found improvements in sexual health communication: Analysis of 11 controlled trials indicated a medium effect on increasing communication (Cohen's d, 0.5), and analysis of nine trials found a large effect on increasing parental comfort with communication (0.7); effects were positive regardless of delivery mode or intervention dose. Intervention participants were 68% more likely than controls to report increased communication and 75% more likely to report increased comfort. These findings point to gaps in the range of programs examined in published trials-for example, interventions for parents of sexual minority youth, programs for custodial grandparents and faith-based services. Yet they provide support for the effectiveness of parent-based interventions in improving communication. Innovative delivery approaches could extend programs' reach, and further research on sexual health outcomes would facilitate the meta-analysis of intervention effectiveness in improving adolescent sexual health behaviors.

Developing the eCPP: adapting an evidence-based parent training program for digital delivery in primary care settings.

Developing innovative delivery methods is needed to overcome time and logistic barriers to in-person participation in evidence-based parent training (PT) programs. The purpose of this paper is to (a) describe the systematic process for adapting an evidence-based group PT program (the Chicago Parent Program) to a tablet-based delivery format, (b) present the adapted program, and (c) discuss opportunities and challenges of adapting evidence-based programs for alternative delivery methods. To ensure consistency with the original program and relevance to the intended program recipients, three groups-parents (n = 10), CPP developers (n = 3), and digital delivery experts- were engaged throughout the systematic steps of the delivery adaptation of the Chicago Parent Program (eCPP). Group meetings were used to identify the program's core components, develop the adaptation program model, assess potential mismatches for the new delivery context, and adapt the original program model and materials. The final eCPP is a six-module Internet-based intervention that includes: interactive activities, video examples and explanations of parenting strategies, reflection questions, assessment of parent knowledge with feedback, and module practice assignments. Developing innovative delivery approaches for evidenced-based interventions are promising to increase intervention sustainability and participant access and engagement. It is critical that these adaptations are systematic and developed with expert consultation and community input.

Dermal administration of manganese porphyrin by iontophoresis

The present study describes a technique for dermal administration of cationic manganese porphyrin (Mn-porphyrin), an antioxidant with superoxide dismutase (SOD) activity, in hairless mouse. In general, the stratum corneum on the surface of the skin represents a barrier to passive diffusion of therapeutic agents by standard dermal administration. The present study investigated whether, dermal administration of Mn-porphyrin solution using iontophoresis, the electrical dermal administration technique, could overcome this barrier. We visually confirmed that Mn-porphyrin had penetrated to the reverse side of the hairless mouse skin after iontophoresis for a short period. With prolonged iontophoresis, the ratio of detectable Mn-porphyrin solution on the reverse side of the hairless mouse skin increased.In the future, this technique could provide an innovative approach for delivery of this antioxidant in intractable disease.

Abstract 5644: Targeted nanocarriers of siRNA for the treatment of cancer

Abstract RNAi technology has brought a new category of treatments for cancer. NFκB is a transcription factor which can inhibit apoptosis and promote cell proliferation. Activation of NFκB is linked to the progression of various cancers. Inhibition of NFκB and its downstream targets using NFκB-siRNA (NS) for cancer therapy has been investigated. However, for successful siRNA delivery, it has to be delivered into the cytoplasm of cancer cells. Naked siRNA is prone to degradation and has a plasma half-life of less than five minutes. In addition, the relatively small size of the siRNA leads to rapid renal clearance. These facts, together with the negatively charged siRNA which limits permeability across cell membrane, mean that successful delivery of naked siRNA is unlikely. Cationic lipid based systems have emerged as the most attractive siRNA delivery, however the use is limited due to poor transfection efficiency and toxicity. The use of polymers (polyethyleneimines and polyesteramines) has been hampered due to substantial toxicity. Natural polymer based delivery systems (chitosan, gelatin, albumin) are biocompatible and biodegradable with high physiological tolerance and low immunogenicity. The purpose of this study was to develop NS loaded into gelatin nanocarriers (NS-GNCs) that enables effective delivery in a targeted fashion to tumors. The NS-GNCs were prepared using cationic gelatin by desolvation method. The NS-GNCs were characterized for size, charge, entrapment, release and in vitro efficacy against lung and breast cancer cells. The size and zeta potential was found to be 180 ± 4 nm and 16 ± 2 mV respectively. Entrapment efficiency was found to be 81 ± 1.4 % and the release of siRNA was in a controlled manner up to 48 h. The dose dependent in vitro efficacy of NS-GNCs was studied using A549 lung cancer and MDA-MB-231 breast cancer cells compared to naked NS using untreated cells as a control. NS-GNCs showed significantly (p&amp;lt;0.05) higher cytotoxicity against lung and breast cancer cells in a dose dependant manner compared to naked NS. At 30ng/ml, NS-GNCs treated A549 cells showed 46% cytotoxicity compared to 16% in naked NS treated A549 cells. At 60ng/ml, NS-GNCs treated MDA-MB-231 cells showed 54% cytotoxicity compared to 21% in naked NS treated cells. The increased cytotoxicity with NS-GNCs can be attributed to the tumor specific accumulation of positively charged GNCs by uptake through electrochemical diffusion. Moreover, NS-GNCs showed comparable cytotoxicity as compared to lipofectamine (tranfecting agent) in both the cancer cells. The developed targeted NS-GNCs showed enhanced activity compared to naked NS against cancer cells. This innovative delivery approach will help to overcome the limitations and adverse side effects associated with current delivery approaches. We are currently investigating NS-GNC conjugation with RGD peptide to enhance the tumor specific delivery via receptor mediated endocytosis. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5644. doi:1538-7445.AM2012-5644

Magnetic Carriers: A Promising Device for Targeting Drugs Into the Human Body

Suboptimal disposition behavior of drugs requires innovative delivery approaches. Magnetic drug targeting seems to be a promising one. Magnetic particles develop magnetic polarization and magnetophoretic mobility, and because of such unique properties, these carriers may be eligible candidates for delivering drugs to specific locations within the body. Their special properties also allow other uses, such as those in magnetic separation, hyperthermia, and magnetic resonance imaging. This review focuses on a brief discussion of magnetic drug targeting, the properties and fate of magnetic carriers, the methods used to produce and characterize them, and their other uses in biotechnology.