Drug Delivery and Translational Research最新文献

Background: Empagliflozin (EMPA) is an SGLT2 inhibitor, a new class of anti-diabetic medication, indicated for treating type-2 diabetes. Its low permeability, poor solubility and bioavailability limits its use in management of diabetes. The study was aimed to formulate EMPA loaded polymeric micelles (PMs) to overcome these obstacles in oral absorption.

Methodology: In silico studies-molecular docking, molecular dynamic simulation (MDS), and quantum chemical calculation were employed to study the interaction of EMPA with different polymers. EMPA loaded TPGS polymeric micelles (EMPA-TPGS-PMs) were formulated by direct dissolution method and characterized in terms of surface morphology, entrapment, particle size, in vitro drug release, and in vitro cytotoxicity (HEK293 cells). In vivo pharmacokinetic and pharmacodynamic studies were also performed.

Results: The results suggested a good interaction between TPGS and EMPA with lowest binding energy compared to other polymers. Further MDS results and DFT calculations validated the stable binding of the complex hence TPGS was selected for further wet lab experiments. The EMPA-TPGS complex displayed lower value of Total energy (T.E.) than its individual components, indicating the overall stability of the complex while, the energy band gap (∆E) value lied between the two individual molecules, signifying the better electron transfer between HOMO and LUMO of the complex. Based on the solubility, entrapment and cytotoxicity studies, 5% TPGS was selected for formulating drug loaded micelles. EMPA-TPGS5-PMs presented a size of 9.008 ± 1.25 nm, Polydispersity index (PDI) of 0.254 ± 0.100, a controlled release behaviour upto 24 h. SEM and AFM images of the nanoformulation suggested spherical particles whereas, DSC, and PXRD studies confirmed the loss of crystallinity of EMPA. A 3.12-folds higher AUC and a greater reduction in blood glucose levels was exhibited by EMPA-TPGS5-PMs in comparison to EMPA-SUSP in mice model.

Conclusion: EMPA-TPGS-PMs has exhibited better bio absorption and therapeutic effectiveness in diabetes treatment. This improved performance would open the possibility of dose reduction, reduced dosing frequency & dose-related side effects, improving pharmaco-economics and thereby improved overall compliance to the patient. However, this translation from bench to bedside would necessitate studies in higher animals and human volunteers.

One of the advancements of the transdermal drug delivery system (TDDS) is the development of microneedles (MNs). These micron-sized needles are used for delivering various types of drugs to address the disadvantage of other transdermal techniques as well as oral drug delivery systems. MNs have high patient acceptance due to self-administration with minimally invasive and pain compared to the parenteral drug delivery. Over the years, various methods have been adopted to evolve the MNs and make them more cost-effective, accurate, and suitable for multiple applications. One such method is the 3D printing of MNs. The development of MN platforms using 3D printing has been made possible by improved features like precision, printing resolution, and the feasibility of using low-cost raw materials. In this review, we have tried to explain various types of MNs, fabrication methods, materials used in the formulation of MNs, and the recent applications that utilize 3D-printed MNs.

The objective of this study was to develop a physiologically based pharmacokinetic (PBPK) model to predict the concentrations of encapsulated and free doxorubicin in plasma and tissues in mice after intravenous injection of PEGylated liposomes (Doxil^®). The PBPK model used in this study contains liposomes and free doxorubicin disposition components. The free doxorubicin disposition component was used to simulate the disposition of free doxorubicin produced by mononuclear phagocyte system (MPS)-degrading liposomes. The liver, spleen, kidneys, and lungs contain an additional MPS subcompartment. These compartments are interconnected through blood and lymphatic circulation. The model was validated strictly by four doses of external observed plasma and tissue concentration-time profiles. The fold error (FE) values were almost all within threefold. The sensitivity analysis revealed that the MPS-related parameters greatly influenced the model. The predicted in vivo distribution characteristics of the doxorubicin liposomes and doxorubicin solution were consistent with the observed values. The PBPK model was established based on the physiological mechanism and parameters of practical significance that can be measured in vitro. Thus, it can be used to study the pharmacokinetic properties of liposomes. This study also provides a reference for the establishment of liposome PBPK model.

Drug delivery technology has advanced significantly over >50 years, and has produced remarkable innovation, countless publications and conferences, and generations of talented and creative scientists. However, a critical review of the current state-of-the-art reveals that the translation of clever and sophisticated drug delivery technologies into products, which satisfy important, unmet medical needs and have been approved by the regulatory agencies, has - given the investment made in terms of time and money - been relatively limited. Here, this point of view is illustrated using a case study of technology for drug delivery into and through the skin and aims:  to examine the historical development of this field and the current state-of-the-art;  to understand why the translation of drug delivery technologies into products that improve clinical outcomes has been quite slow and inefficient; and  to suggest how the impact of technology may be increased and the process of concept to approved product accelerated.

To improve the therapeutic activity of inhaled glucocorticoids and reduce potential side effects, we designed a formulation combining the advantages of nanoparticles, which have an enhanced uptake by alveolar cells, allow targeted delivery and sustained drug release, as well as limited drug systemic passage, with those of microparticles, which display good alveolar deposition. Herein, a polymer-drug conjugate, poly(malic acid)-budesonide (PMAB), was first synthesized with either 11, 20, 33, or 43 mol% budesonide (drug:polymer from 1:8 to 3:4), the drug creating hydrophobic domains. The obtained conjugates self-assemble into nanoconjugates in water, yielding excellent drug loading of up to 73 wt%, with 80-100 nm diameters. In vitro assays showed that budesonide could be steadily released from the nanoconjugates, and the anti-inflammatory activity was preserved, as evidenced by reduced cytokine production in LPS-activated RAW 264.7 macrophages. Nanoconjugates were then embedded into microparticles through spray-drying with L-leucine, forming nano-embedded microparticles (NEMs). NEMs were produced with an aerodynamic diameter close to 1 µm and a density below 0.1 g.cm^-3, indicative of a high alveolar deposition. NEMs spray-dried with the less hydrophobic nanoconjugates, PMAB 1:4, were readily dissolved in simulated lung fluid and were chosen for in vivo experiments to study pharmacokinetics in healthy rats. As it was released in vivo from NEMs, sustained distribution of budesonide was obtained for 48 h in lung tissue, cells, and lining fluid. With high loading rates, modulable release kinetics, and low cytotoxicity, these nanoconjugates delivered by NEMs are promising for the more efficient treatment of pulmonary inflammatory diseases.

Combination therapy with small interfering RNA (siRNA) and chemotherapeutic drug is proven to be effective in downregulating cancer resistance proteins, such as P-glycoprotein (P-gp). These proteins are involved in multidrug resistance (MDR) of tumors. A targeted formulation capable of delivering siRNA and chemotherapeutic drug will not only downregulate P-gp but also increase the concentration of the chemotherapeutic drug at the site of tumor thereby increasing the therapeutic effect and lowering the systemic exposure. In this study, monoclonal antibody 2C5-modified dendrimer-based micelles were used to co-deliver siRNA and doxorubicin (DOX) to the tumor site in both male and female xenograft mouse model. The nucleosome-specific 2C5 antibody recognizes the cancer cells via the cell-surface bound nucleosomes. The ability of ability of the 2C5-modified formulation to affect the metastasis of highly aggressive triple negative breast cancer cell migration in (MDA-MB-231) was assessed by a wound healing. Further, the therapeutic efficacy of the formulation was assessed by measuring the tumor volume progression in which the 2C5-modified nanoparticle group had a similar tumor volume to the free drug group at the end of the study, although a 50% increase in DOX concentrations in blood was observed after the last dose of nanoparticle. The free drug group on the other hand showed body weight reduction as well as the visible irritation around the injection spot. The treatment group with 2C5-modified micelles has shown to be safe at the current dose of DOX and siRNA. Furthermore, the siRNA mediated P-gp downregualtion was studied using western blotting assay. We observed a 29% reduction of P-gp levels in both males and females with respect to the control (BHG). We also conclude that the dose of DOX and siRNA should be further optimized to have a better efficacy in a metastatic tumor model, which will be the subject of our future studies.

Achieving a controlled release of several active pharmaceutical ingredients (APIs) remains a challenge for improving their therapeutic effects and reduced their side effects. In the current work, stimulable Drug Delivery Systems (DDS) based on supramolecular hydrogels were designed by combining two APIs featuring anticancer activities, namely the doxorubicin and phenazine 14. In vitro studies revealed promising physicochemical properties for all the investigated API loaded gels. Fluorinated GlycoNucleoLipid (GNF) based supramolecular gels remain stable in the presence of either doxorubicin (Doxo) or phenazine 14 (Phe) as anticancer drugs. Noteworthy, the stiffness of the GNF-based supramolecular gels was enhanced in the presence of both APIs while maintaining their thixotropic properties. We demonstrated that the storage modulus (G') of the GNF gels was increased from 1.3 kPa to 9.3 kPa upon loading of both APIs within the same gels. With a low mechanical stimulation (within the LVR), a passive diffusion out of gels was observed for Dox whereas Phe remained trapped in the GNF gels over several hours. Also, in this work we showed that mechanical stress triggered the release of both Phe and Doxo at different rates.

While long-acting injectable treatments are gaining increasing interest in managing chronic diseases, the available drug delivery systems almost exclusively rely on hydrophobic matrixes, limiting their application to either hydrophobic drugs or large and hydrophilic molecules such as peptides. To address the technological lock for long-acting delivery systems tailored to small, hydrophilic drugs such as anticancer and antiviral nucleoside/nucleotide analogues, we have synthesized and characterized an original approach with a multi-scale structure: (i) a nucleotide (adenosine triphosphate, ATP) is first incorporated in hydrophilic chitosan-Fe(III) nanogels; (ii) these nanogels are then transferred by freeze-drying and resuspension into a water-free, hydrophobic medium containing PLGA and an organic solvent, N-methyl-2-pyrrolidone. We show that this specific association allows an injectable and homogeneous dispersion, able to form in situ implants upon injection in physiological or aqueous environments. This system releases ATP in vitro without any burst effect in a two-step mechanism, first as nanogels acting as an intermediate reservoir over a week, then as free drug over several weeks. In vivo studies confirmed the potential of such nanostructured implants for sustained drug release following subcutaneous injection to mice hock, opening perspectives for sustained and targeted delivery through the lymphatic system.

Neuroblastoma is a pediatric tumor that originates during embryonic development and progresses into aggressive tumors, primarily affecting children under two years old. Many patients are diagnosed as high-risk and undergo chemotherapy, often leading to short- and long-term toxicities. Nanomedicine offers a promising solution to enhance drug efficacy and improve physical properties. In this study, lipid-based nanomedicines were developed with an average size of 140 nm, achieving a high encapsulation efficiency of over 90% for the anticancer drug etoposide. Then, cytotoxicity and apoptosis-inducing effects of these etoposide nanomedicines were assessed in vitro using human cell lines, both cancerous and non-cancerous. The results demonstrated that etoposide nanomedicines exhibited high toxicity and selectively induced apoptosis only in cancerous cells.Next, the biosafety of these nanomedicines in C. elegans, a model organism, was evaluated by measuring survival, body size, and the effect on dividing cells. The findings showed that the nanomedicines had a safer profile than the free etoposide in this model. Notably, nanomedicines exerted etoposide's antiproliferative effect only in highly proliferative germline cells. Therefore, the developed nanomedicines hold promise as safe drug delivery systems for etoposide, potentially leading to an improved therapeutic index for neuroblastoma treatment.

This study explores the efficacy of human serum albumin (HSA)-based Drug-Free Macromolecular Therapeutics (DFMT) in treating Chronic Lymphocytic Leukemia (CLL), a prevalent adult leukemia subtype. DFMT, a novel strategy, employs biomimetic crosslinking of CD20 and CD38 receptors on malignant B cells without the need for low molecular weight drugs. Apoptosis is initiated via a two-step process: i) Recognition of a bispecific engager, Fab' fragment conjugated with morpholino oligonucleotide (Fab'-MORF1), by a cell surface antigen; followed by ii) crosslinking of the MORF1-decorated cells with a multivalent effector, HSA holding multiple copies of complementary MORF2, HSA-(MORF2)x. Herein we evaluated the efficacy of HSA-based DFMT in the treatment of 56 samples isolated from patients diagnosed with CLL. Fab' fragments from Obinutuzumab (OBN) and Isatuximab (ISA) were employed in the synthesis of anti-CD20 (Fab'_OBN-MORF1) and anti-CD38 (Fab'_ISA-MORF1) bispecific engagers. The efficacy of DFMT was significantly influenced by the expression levels of CD20 and CD38 receptors. Dual-targeting DFMT strategies (CD20 + CD38) were more effective than single-target approaches, particularly in samples with elevated receptor expression. Pretreatment of patient cells with gemcitabine or ricolinostat markedly increased cell surface CD20 and CD38 expression, respectively. Apoptosis was effectively initiated in 62.5% of CD20-targeted samples and in 42.9% of CD38-targeted samples. Our findings demonstrate DFMT's potential in personalized CLL therapy. Further research is needed to validate these outcomes in a larger number of patient samples and to explore DFMT's applicability to other malignancies.