Delivery System
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Emilie Audouard ◽  
Lisa Rousselot ◽  
Marc Folcher ◽  
Nathalie Cartier ◽  
Françoise Piguet

Improving a drug delivery system is critical to treat central nervous system disorders. Here we studied an innovative approach based on implantation of a wireless-powered cell-based device in mice. This device, coupling biologic material and electronics, is the first of its kind. The advantage of this technology is its ability to control the secretion of a therapeutic molecule and to switch the classical permanent delivery to activation on demand. In diseases with relapsing-remitting phases such as multiple sclerosis, such activation could be selectively achieved in relapsing phases. However, the safety (tolerance to biomaterials and surgical procedure) of such a clinical device needs to be verified. Therefore, the development of tools to assess the biocompatibility of the system in animal models is an essential step. We present the development of this new therapeutic approach, the challenges we encountered during the different steps of its development (such as cell loading in the chamber, surgery protocol for subcutaneous implantation of the device) and the tools we used to evaluate cell viability and biocompatibility of the device.

2021 ◽  
Soohyung Park ◽  
Yeol Kyo Choi ◽  
Seonghoon Kim ◽  
Jumin Lee ◽  
Wonpil Im

A lipid nanoparticle (LNP) formulation is a state-of-the-art delivery system for genetic drugs such as DNA, mRNA, and siRNA, which is successfully applied to COVID-19 vaccines and gains tremendous interest in therapeutic applications. Despite its importance, a molecular-level understanding of the LNP structures and dynamics is still lacking, which makes a rational LNP design almost impossible. In this work, we present an extension of CHARMM-GUI Membrane Builder to model and simulate all-atom LNPs with various (ionizable) cationic lipids and PEGylated lipids (PEG-lipids). These new lipid types can be mixed with any existing lipid types with or without a biomolecule of interest, and the generated systems can be simulated using various molecular dynamics engines. As a first illustration, we considered model LNP membranes with DLin-KC2-DMA (KC2) or DLin-MC3-DMA (MC3) without PEG-lipids. The results from these model membranes are consistent with those from the two previous studies albeit with mild accumulation of neutral MC3 in the bilayer center. To demonstrate Membrane Builder's capability of building a realistic LNP patch, we generated KC2- or MC3-containing LNP membranes with high concentrations of cholesterol and ionizable cationic lipids together with 2 mol% PEG-lipids. We observe that PEG-chains are flexible, which can be more preferentially extended laterally in the presence of cationic lipids due to the attractive interactions between their head groups and PEG oxygen. The presence of PEG-lipids also relaxes the lateral packing in LNP membranes, and the area compressibility modulus (KA) of LNP membranes with cationic lipids fit into typical KA of fluid-phase membranes. Interestingly, the interactions between PEG oxygen and head group of ionizable cationic lipids induce a negative curvature. We hope that this LNP capability in Membrane Builder can be useful to better characterize various LNPs with or without genetic drugs for a rational LNP design.

2021 ◽  
Vol 13 (1) ◽  
Xu Li ◽  
Bingyang Dai ◽  
Jiaxin Guo ◽  
Lizhen Zheng ◽  
Quanyi Guo ◽  

AbstractOsteoarthritis is the most prevalent chronic and debilitating joint disease, resulting in huge medical and socioeconomic burdens. Intra-articular administration of agents is clinically used for pain management. However, the effectiveness is inapparent caused by the rapid clearance of agents. To overcome this issue, nanoparticles as delivery systems hold considerable promise for local control of the pharmacokinetics of therapeutic agents. Given the therapeutic programs are inseparable from pathological progress of osteoarthritis, an ideal delivery system should allow the release of therapeutic agents upon specific features of disorders. In this review, we firstly introduce the pathological features of osteoarthritis and the design concept for accurate localization within cartilage for sustained drug release. Then, we review the interactions of nanoparticles with cartilage microenvironment and the rational design. Furthermore, we highlight advances in the therapeutic schemes according to the pathology signals. Finally, armed with an updated understanding of the pathological mechanisms, we place an emphasis on the development of “smart” bioresponsive and multiple modality nanoparticles on the near horizon to interact with the pathological signals. We anticipate that the exploration of nanoparticles by balancing the efficacy, safety, and complexity will lay down a solid foundation tangible for clinical translation.

2021 ◽  
Vol 9 ◽  
Xia Li ◽  
Liang Zhang ◽  
Zhong Li ◽  
Wenxi Tang

Introduction: Gatekeeping mechanism of primary care institutions (PCIs) is essential in promoting tiered healthcare delivery system in China. However, patients seeking for higher-level institutions instead of gatekeepers as their first contact has persisted in the past decade. This study aims to explain patients' choice and willingness and to provide potential solutions.Methods: A survey was conducted among residents who had received medical care within the previous 14 days. Patients' choice and willingness of PCIs for first contact together with influencing factors were analyzed using binary logistic regression.Results: Of 728 sampled patients in Hubei, 55.22% chose PCIs for first contact. Patients who are older, less educated, with lower family income, not living near non-PCIs, with better self-perceived health status, only buying medicines, and living in rural instead of urban area had significantly higher probability of choosing PCIs. As of willingness, over 90% of the patients inclined to have the same choice for their first contact under similar health conditions. Service capability was the primary reason limiting patients' choice of PCIs.Conclusions: The gatekeeper system did not achieve its goal which was 70% of PCIs among all kinds of institutions for first contact. Future measures should aim to improve gate-keepers' capability.

PLoS ONE ◽  
2021 ◽  
Vol 16 (6) ◽  
pp. e0251719
Mahsa Mohseni ◽  
Cezary Kucharski ◽  
Remant Bahadur K. C. ◽  
Mohammad Nasrullah ◽  
Xiaoyan Jiang ◽  

Overexpression and persistent activation of STAT5 play an important role in the development and progression of acute lymphoblastic leukemia (ALL), the most common pediatric cancer. Small interfering RNA (siRNA)-mediated downregulation of STAT5 represents a promising therapeutic approach for ALL to overcome the limitations of current treatment modalities such as high relapse rates and poor prognosis. However, to effectively transport siRNA molecules to target cells, development of potent carriers is of utmost importance to surpass hurdles of delivery. In this study, we investigated the use of lipopolymers as non-viral delivery systems derived from low molecular weight polyethylenimines (PEI) substituted with lauric acid (Lau), linoleic acid (LA) and stearic acid (StA) to deliver siRNA molecules to ALL cell lines and primary samples. Among the lipid-substituted polymers explored, Lau- and LA-substituted PEI displayed excellent siRNA delivery to SUP-B15 and RS4;11 cells. STAT5A gene expression was downregulated (36–92%) in SUP-B15 and (32%) in RS4;11 cells using the polymeric delivery systems, which consequently reduced cell growth and inhibited the formation of colonies in ALL cells. With regard to ALL primary cells, siRNA-mediated STAT5A gene silencing was observed in four of eight patient cells using our leading polymeric delivery system, 1.2PEI-Lau8, accompanied by the significant reduction in colony formation in three of eight patients. In both BCR-ABL positive and negative groups, three of five patients demonstrated marked cell growth inhibition in both MTT and trypan blue exclusion assays using 1.2PEI-Lau8/siRNA complexes in comparison with their control siRNA groups. Three patient samples did not show any positive results with our delivery systems. Differential therapeutic responses to siRNA therapy observed in different patients could result from variable genetic profiles and patient-to-patient variability in delivery. This study supports the potential of siRNA therapy and the designed lipopolymers as a delivery system in ALL therapy.

M. S. Neeharika ◽  
B. Jeevana Jyothi

The objective of the present study was to formulate and evaluate an oral, time-controlled drug delivery system of Zafirlukast. Zafirlukast belongs to BCS class II drugs as it has poor aqueous solubility and good permeability. Hence an attempt has been made to improve its aqueous solubility by solid dispersion technique so that its dissolution, bioavailability, and therapeutic effect can be optimized. The optimized solid dispersion was then formulated into a chronotherapeutic drug delivery system by compression coating technology. FT-IR study revealed that there was no chemical interaction between the drug and polymers used. Tablets were prepared by direct compression method using different super disintegrants and then followed by compression coating using natural polymers. Pre-compression and post-compression parameters complied with the Pharmacopoeia limit for the tablets. In vitro release studies were performed and the results indicated the formulation Z9F9 to be the optimized formulation.

2021 ◽  
Vol 10 (12) ◽  
pp. 2725
Ruíz-Piñón Manuel ◽  
Gancedo-Gancedo Tania ◽  
Seoane-Prado Rafael ◽  
Pérez-Estévez Antonio ◽  
Blanco-Méndez José ◽  

This study aimed to evaluate the in vitro performance of collagen-based sponges as a drug delivery system for intracanal antimicrobial administration. Four groups of loaded collagen-based sponges (A, 0.3% w/v amoxicillin trihydrate: potassium clavulanate (4:1); B, 0.03% w/v chlorhexidine gluconate [CHX]; C, 0.3% w/v amoxicillin trihydrate: potassium clavulanate (4:1) and 0.03% w/v CHX; D, 1% w/v amoxicillin trihydrate: potassium clavulanate (4:1) and 0.03% w/v CHX) were designed. Release kinetics were tested in vitro on cultures in Petri dishes, and the effect on bacterial biofilms was studied ex vivo on 114 extracted human single-rooted teeth. Biofilm formation was tested by scanning electron microscopy (SEM). Collagen sponges containing amoxicillin and chlorhexidine showed a time-sustained antimicrobial effect in vitro and were also able to destroy mature biofilms ex vivo. This datum was validated by means of SEM-based study of E. faecalis and S. aureus biofilms.

2021 ◽  
Vol 12 ◽  
Jiayi Chen ◽  
Chenhong Qian ◽  
Peng Ren ◽  
Han Yu ◽  
Xiangjia Kong ◽  

The enhancement of tumor targeting and cellular uptake of drugs are significant factors in maximizing anticancer therapy and minimizing the side effects of chemotherapeutic drugs. A key challenge remains to explore stimulus-responsive polymeric nanoparticles to achieve efficient drug delivery. In this study, doxorubicin conjugated polymer (Poly-Dox) with light-responsiveness was synthesized, which can self-assemble to form polymeric micelles (Poly-Dox-M) in water. As an inert structure, the polyethylene glycol (PEG) can shield the adsorption of protein and avoid becoming a protein crown in the blood circulation, improving the tumor targeting of drugs and reducing the cardiotoxicity of doxorubicin (Dox). Besides, after ultraviolet irradiation, the amide bond connecting Dox with PEG can be broken, which induced the responsive detachment of PEG and enhanced cellular uptake of Dox. Notably, the results of immunohistochemistry in vivo showed that Poly-Dox-M had no significant damage to normal organs. Meanwhile, they showed efficient tumor-suppressive effects. This nano-delivery system with the light-responsive feature might hold great promises for the targeted therapy for osteosarcoma.

2021 ◽  
Vol 12 (1) ◽  
Alexander Martin Geller ◽  
Inbal Pollin ◽  
David Zlotkin ◽  
Aleks Danov ◽  
Nimrod Nachmias ◽  

AbstractThe extracellular Contractile Injection System (eCIS) is a toxin-delivery particle that evolved from a bacteriophage tail. Four eCISs have previously been shown to mediate interactions between bacteria and their invertebrate hosts. Here, we identify eCIS loci in 1,249 bacterial and archaeal genomes and reveal an enrichment of these loci in environmental microbes and their apparent absence from mammalian pathogens. We show that 13 eCIS-associated toxin genes from diverse microbes can inhibit the growth of bacteria and/or yeast. We identify immunity genes that protect bacteria from self-intoxication, further supporting an antibacterial role for some eCISs. We also identify previously undescribed eCIS core genes, including a conserved eCIS transcriptional regulator. Finally, we present our data through an extensive eCIS repository, termed eCIStem. Our findings support eCIS as a toxin-delivery system that is widespread among environmental prokaryotes and likely mediates antagonistic interactions with eukaryotes and other prokaryotes.

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