Manufacture, characterization, and elucidation of drug release mechanisms of etonogestrel implants based on ethylene vinyl acetate.

In this work, etonogestrel implants were manufactured using coextrusion. The purpose of the study was to correlate changes in microstructure and transport properties that occurred in etonogestrel implants to drug release mechanisms. The implants consisted of an EVA 28 (28% vinyl acetate) core containing dispersed and dissolved etonogestrel, and an EVA 15 (15% vinyl acetate) skin. The drug release was determined to be via diffusion at a controlled rate and governed by implant dimensions. In-vitro release revealed evidence of supersaturation in the implant core and skin, likely from the intense mechanical energy input during the twin-screw manufacturing process. Subsequently during storage under ambient conditions, supersaturation resulted in recrystallization of drug crystals, preferentially in the implant core. Etonogestrel solubility and diffusivity in EVA were determined by permeation experiments and used for release modeling. Drug release from the EVA skin layer deviated from the predicted values due to 1) formation of a drug depletion zone in the core and 2) presence of a stagnant media layer adjacent to the skin. Drug release from implant ends was significantly faster than predicted. Air-filled pores were observed in the implant core using microCT which likely contributed to the faster release from implant ends.

Preparation irinotecan hydrochloride loaded PEGylated liposomes using novel method supercritical fluid and condition optimized by Box-Behnken design.

A semi-synthetic camptothecin derivative known as irinotecan hydrochloride is frequently used to treat colorectal cancer, including colorectal adenocarcinoma and lung cancers involving small cells. Irinotecan has a very short half-life; therefore, continuous infusions are required to keep the drug's blood levels at therapeutic levels, which could produce cumulative toxicities. Effective delivery techniques, including liposomes, have been developed to address these shortcomings. In this study, a continuous supercritical fluid approach dubbed Expansion Supercritical Fluid into an aqueous solution, in which the pressure decreases rapidly but remains over the critical pressure, is proposed to manufacture polyethylene glycolylated (PEGylated) liposomes carrying irinotecan hydrochloride. To accomplish this, PEGylated liposomes were created using a Box-Behnken design, and the operating parameters (flow rate, temperature, and pressure drop) were optimized. Encapsulation efficiency, mean size, and prepared liposome count were 94.6%, 55 nm, and 758 under ideal circumstances. Additionally, the stability of the PEGylated liposome was investigated during 8 weeks, and also PEGylated liposome-loaded irinotecan release profile was compared to conventional liposomes and free irinotecan, and a constant drug release was seen after the first burst release from liposomes.

The use of nanomaterials as drug delivery systems and anticancer agents in the treatment of triple-negative breast cancer: an updated review (year 2005 to date).

Triple-negative breast cancer (TNBC) is characterised by the lack or low expression of estrogen, progesterone, and human epidermal growth factor receptor 2 receptors. TNBC has a high recurrence rate, swiftly metastasizes, and has a high mortality rate. Subsequently, the increase in cases of TNBC has signaled the need for treatment strategies with improved drug delivery systems. New diagnostic approaches, chemical entities, formulations particular those in the nanometric range have emerged after extensive scientific research as alternative strategies for TNBC treatment. As compared to contemporary cancer therapy, nanoparticles offer peculiar tunable features namely small size, shape, electrical charge, magnetic and fluorescent properties. Specifically in targeted drug delivery, nanoparticles have been demonstrated to be highly efficient in encapsulating, functionalization, and conjugation. Presently, nanoparticles have ignited and transformed the approach in photodynamic therapy, bioimaging, use of theranostics and precision medicine delivery in breast cancer. Correspondingly, recent years have witnessed a drastic rise in literature pertaining to treatment of TNBC using nanomaterials. Subsequently, this manuscript aims to present a state-of-the-art of nanomaterials advance on TNBC treatment; the ubiquitous utility use of nanomaterials such as liposomes, dendrimers, solid lipid nanomaterials, gold nanomaterials and quantum dots as anticancer agents and drug delivery systems in TNBC.

The Many Faces of Cyclodextrins within Self-Assembling Polymer Nanovehicles: From Inclusion Complexes to Valuable Structural and Functional Elements.

Most chemotherapeutic agents are poorly soluble in water, have low selectivity, and cannot reach the tumor in the desired therapeutic concentration. On the other hand, sensitive hydrophilic therapeutics like nucleic acids and proteins suffer from poor bioavailability and cell internalization. To solve this problem, new types of controlled release systems based on nano-sized self-assemblies of cyclodextrins able to control the speed, timing, and location of therapeutic release are being developed. Cyclodextrins are macrocyclic oligosaccharides characterized by a high synthetic plasticity and potential for derivatization. Introduction of new hydrophobic and/or hydrophilic domains and/or formation of nano-assemblies with therapeutic load extends the use of CDs beyond the tried-and-tested CD-drug host-guest inclusion complexes. The recent advances in nano drug delivery have indicated the benefits of the hybrid amphiphilic CD nanosystems over individual CD and polymer components. This review provides a comprehensive overview of the most recent advances in the design of CDs self-assemblies and their use for delivery of a wide range of therapeutic molecules. It aims to offer a valuable insight into the many roles of CDs within this class of drug nanocarriers as well as current challenges and future perspectives.

Nanomedicines as Guardians of the Heart: Unleashing the Power of Antioxidants to Alleviate Myocardial Ischemic Injury.

Ischemic heart disease (IHD) is increasingly recognized as a significant cardiovascular disease with a growing global incidence. Interventions targeting the oxidative microenvironment have long been pivotal in therapeutic strategies. However, many antioxidant drugs face limitations due to pharmacokinetic and delivery challenges, such as short half-life, poor stability, low bioavailability, and significant side effects. Fortunately, nanotherapies exhibit considerable potential in addressing IHD. Nanomedicines offer advantages such as passive/active targeting, prolonged circulation time, enhanced bioavailability, and diverse carrier options. This comprehensive review explores the advancements in nanomedicines for mitigating IHD through oxidative stress regulation, providing an extensive overview for researchers in the field of antioxidant nanomedicines. By inspiring further research, this study aims to accelerate the development of novel therapies for myocardial injury.

3D printed personalized therapies for pediatric patients affected by adrenal insufficiency.

BACKGROUND: Adrenal insufficiency is usually diagnosed in children who will need lifelong hydrocortisone therapy. However, medicines for pediatrics, in terms of dosage and acceptability, are currently unavailable. RESEARCH DESIGN AND METHODS: Semi-solid extrusion (SSE) 3D printing (3DP) was utilized for manufacturing of personalized and chewable hydrocortisone formulations (printlets) for an upcoming clinical study in children in Vall d'Hebron University Hospital in Barcelona, Spain. The 3DP process was validated using a specific software for dynamic dose modulation. RESULTS: The printlets contained doses ranging from one to six mg hydrocortisone in three different flavor and color combinations to aid adherence among the pediatric patients. The pharma-ink (mixture of drug and excipients) was assessed for its rheological behavior to ensure reproducibility of printlets through repeated printing cycles. The printlets showed immediate hydrocortisone release, and were stable for one month of storage, the duration of the clinical trial. CONCLUSIONS: The results confirm the suitability and safety of the developed printlets for use in the clinical trial. The required technical information from The Spanish Medicines Agency for this clinical trial application was compiled to serve as guideline for healthcare professionals seeking to apply for and conduct clinical trials on 3DP oral dosage forms.

Development of Mixed Micelles for Enhancing Fenretinide Apparent Solubility and Anticancer Activity Against Neuroblastoma Cells.

INTRODUCTION/OBJECTIVES: The purpose of the study was to evaluate the suitability of mixed micelles prepared with D-α-tocopheryl polyethylene glycol succinate (TPGS) and 1,2- distearoyl-glycero-3-phosphoethanolamine-N-[methoxy(polyethyleneglycol)-2000] (DSPE-PEG) to encapsulate the poorly soluble anticancer drug fenretinide (4-HPR). METHODS: After assaying the solubilization ability of the surfactants by the equilibrium method, the micelles were prepared using the solvent casting technique starting from different 4-HPR:TPGS: DSPE-PEG w/w ratios. The resulting formulations were investigated for their stability under storage conditions and upon dilution, modelling the reaching of physiological concentrations after intravenous administration. The characterization of micelles included the determination of DL%, EE %, particle size distribution, Z-potential, and thermal analysis by DSC. The cytotoxicity studies were performed on HTLA-230 and SK-N-BE-2C neuroblastoma cells by the MTT essay. RESULTS: The colloidal dispersions showed a mean diameter of 12 nm, negative Zeta potential, and a narrow dimensional distribution. 4-HPR was formulated in the mixed micelles with an encapsulation efficiency of 88% and with an increment of the apparent solubility of 363-fold. The 4-HPR entrapment remained stable up to the surfactants' concentration of 2.97E-05 M. The loaded micelles exhibited a slow-release behaviour, with about 28% of the drug released after 24 h. On the most resistant SK-N-BE-2C cells, the encapsulated 4-HPR was significantly more active than free 4-HPR in reducing cell viability. CONCLUSION: Loaded micelles demonstrated their suitability as a new adjuvant tool potentially useful for the treatment of neuroblastoma.

Oral Patch/Film for Drug Delivery-Current Status and Future Prospects.

In recent years, there has been extensive research into drug delivery systems aimed at enhancing drug utilization while minimizing drug toxicities. Among these systems, oral patches/films have garnered significant attention due to their convenience, noninvasive administration, ability to bypass hepatic first-pass metabolism, thereby enhancing drug bioavailability, and their potential to ensure good compliance, particularly among special patient populations. In this review, from the perspective of the anatomical characteristics of the oral cavity and the advantages and difficulties of oral drug delivery, we illustrate the design ideas, manufacturing techniques, research methodologies, and the essential attributes of an ideal oral patch/film. Furthermore, the applications of oral patches/films in both localized and systemic drug delivery were discussed. Finally, we offer insights into the future prospects of the oral patch/film, aiming to provide valuable reference for the advancement of oral localized drug delivery systems.

Silica 3D printed scaffolds as pH stimuli-responsive drug release platform.

Silica-based scaffolds are promising in Tissue Engineering by enabling personalized scaffolds, boosting exceptional bioactivity and osteogenic characteristics. Moreover, silica materials are highly tunable, allowing for controlled drug release to enhance tissue regeneration. In this study, we developed a 3D printable silica material with controlled mesoporosity, achieved through the sol-gel reaction of tetraethyl orthosilicate (TEOS) at mild temperatures with the addition of different calcium concentrations. The resultant silica inks exhibited high printability and shape fidelity, while maintaining bioactivity and biocompatibility. Notably, the increased mesopore size enhanced the incorporation and release of large molecules, using cytochrome C as a drug model. Due to the varying surface charge of silica depending on the pH, a pH-dependent control release was obtained between pH 2.5 and 7.5, with maximum release in acidic conditions. Therefore, silica with controlled mesoporosity could be 3D printed, acting as a pH stimuli responsive platform with therapeutic potential.

Advances in Novel Biomaterial-Based Strategies for Spinal Cord Injury Treatment.

Spinal cord injury (SCI) is a highly disabling neurological disorder. Its pathological process comprises an initial acute injury phase (primary injury) and a secondary injury phase (subsequent chronic injury). Although surgical, drug, and cell therapies have made some progress in treating SCI, there is no exact therapeutic strategy for treating SCI and promoting nerve regeneration due to the complexity of the pathological SCI process. The development of novel drug delivery systems to treat SCI is expected to significantly impact the individualized treatment of SCI due to its unique and excellent properties, such as active targeting and controlled release. In this review, we first describe the pathological progression of the SCI response, including primary and secondary injuries. Next, we provide a concise overview of newly developed nanoplatforms and their potential application in regulating and treating different pathological processes of SCI. Then, we introduce the existing potential problems and future clinical application perspectives of biomedical engineering-based therapies for SCI.

Activin A-Targeted Therapy in Cancer: An Updated Review on Challenges and Opportunities in Clinical Translation.

Activin A (ActA) is a cytokine from the TGF-ß superfamily that mediates a vast number of physiological mechanisms, mainly through the SMAD signaling pathway. Growing evidence indicates that ActA overexpression is also correlated with poor prognosis in cancer patients and several tumor characteristics, including cancer proliferation, metastasis, immunosuppression, drug resistance, cachexia, and cancer-associated fibroblast activation. As such, ActA-targeted therapy has been viewed as a potential adjuvant therapy alongside other anti-cancer modalities that may result in more efficient anti-cancer effects, such as stronger immune responses, overcoming drug resistance, reversing cachexia, etc. However, despite its interesting concept, targeting ActA is not without certain challenges and considerations. Indeed, ActA has unexpectedly shown anti-tumor effects in some cases, which might be explained by differences in the expression levels of different ActA receptors on the cell surface, activation of non-SMAD pathways, and imbalance in ActA levels. Besides, many of the current ActA antagonists lack enough specificity and, as a result, bind to non-ActA receptors as well. Furthermore, ubiquitous expression of ActA in the body can cause serious adverse effects following systemic administration. Furthermore, to address these issues, anti-ActA monoclonal antibodies and nanoparticle drug delivery systems have recently been suggested to target ActA with better precision in the affected area. In this review, first, we provide the different implications of ActA in cancer. Then, we discuss the recent insights into targeting ActA signaling as an adjuvant therapy alongside other anti-cancer modalities, as well as the possible challenges and novel opportunities on the path of clinical translation.

Molecular Imprinting Technology for Advanced Delivery of Essential Oils.

Essential oils (EOs) hold therapeutic potential, but their conventional delivery systems have some limitations. This review focuses on the critical review and discussion of research related to EO delivery systems. The review also explores how molecular imprinting technologies (MIT) can advance EO delivery. MIT offer several techniques, namely covalent, non-covalent, and semi-covalent imprinting, creating targeted cavities that selectively bind and release EOs. These approaches promise significant advantages including increased selectivity, controlled release, and protection from environmental degradation. However, some challenges related to the stability and biocompatibility of MIPs remain unsolved. Integrating nanotechnology through methods like nanoparticle imprinting and some lithographic techniques seems promising to overcome these limitations. Some recently established models and systems used for EO-related research are paving the way for a more efficient and targeted EO delivery approach to harnessing the therapeutic power of EOs. Therefore, some recent and future research seems promising, and eventually it will increase the effectiveness of MIP-based EO delivery systems.

Biodegradable Polymeric Nanoparticle-Based Drug Delivery Systems: Comprehensive Overview, Perspectives and Challenges.

In the last few decades, there has been a growing interest in the use of biodegradable polymeric nanoparticles (BPNPs) as the carriers for various therapeutic agents in drug delivery systems. BPNPs have the potential to improve the efficacy of numerous active agents by facilitating targeted delivery to a desired site in the body. Biodegradable polymers are especially promising nanocarriers for therapeutic substances characterized by poor solubility, instability, rapid metabolism, and rapid system elimination. Such molecules can be efficiently encapsulated and subsequently released from nanoparticles, which greatly improves their stability and bioavailability. Biopolymers seem to be the most suitable candidates to be used as the nanocarriers in various delivery platforms, especially due to their biocompatibility and biodegradability. Other unique properties of the polymeric nanocarriers include low cost, flexibility, stability, minimal side effects, low toxicity, good entrapment potential, and long-term and controlled drug release. An overview summarizing the research results from the last years in the field of the successful fabrication of BPNPs loaded with various therapeutic agents is provided. The possible challenges involving nanoparticle stability under physiological conditions and the possibility of scaling up production while maintaining quality, as well as the future possibilities of employing BPNPs, are also reviewed.

Lectin-modified drug delivery systems - Recent applications in the oncology field.

Chemotherapy with cytotoxic drugs remains the core treatment for cancer but, due to the difficulty to find general and usable biochemical differences between cancer cells and normal cells, many of these drugs are associated with lack of specificity, resulting in side effects and collateral cytotoxicity that impair patients' adherence to therapy. Novel cancer treatments in which the cytotoxic effect is maximized while adverse effects are reduced can be implemented by developing targeted therapies that exploit the specific features of cancer cells, such as the typical expression of aberrant glycans. Modification of drug delivery systems with lectins is one of the strategies to implement targeted chemotherapies, as lectins are able to specifically recognize and bind to cancer-associated glycans expressed at the surface of cancer cells, guiding the drug treatment towards these cells and not affecting healthy ones. In this paper, recent advances on the development of lectin-modified drug delivery systems for targeted cancer treatments are thoroughly reviewed, with a focus on their properties and performance in diverse applications, as well as their main advantages and limitations. The synthesis and analytical characterization of the cited lectin-modified drug delivery systems is also briefly described. A comparison with free-drug treatments and with antibody-modified drug delivery systems is presented, emphasizing the advantages of lectin-modified drug delivery systems. Main constraints and potential challenges of lectin-modified drug delivery systems, including key difficulties for clinical translation of these systems, and the required developments in this area, are also signalled.

Advances, limitations and perspectives in the use of celecoxib-loaded nanocarriers in therapeutics of cancer.

Cancer is highlighted as a major global health challenge in the XXI century. The cyclooxygenase-2 (COX-2) enzyme rises as a widespread tumor progression marker. Celecoxib (CXB) is a selective COX-2 inhibitor used in adjuvant cancer therapy, but high concentrations are required in humans. In this sense, the development of nanocarriers has been proposed once they can improve the biopharmaceutical, pharmacokinetic and pharmacological properties of drugs. In this context, this article reviews the progress in the development of CXB-loaded nanocarriers over the past decade and their prospects. Recent advances in the field of CXB-loaded nanocarriers demonstrate the use of complex formulations and the increasing importance of in vivo studies. The types of CXB-loaded nanocarriers that have been developed are heterogeneous and based on polymers and lipids together or separately. It was found that the work on CXB-loaded nanocarriers is carried out using established techniques and raw materials, such as poly (lactic-co-glicolic acid), cholesterol, phospholipids and poly(ethyleneglycol). The main improvements that have been achieved are the use of cell surface ligands, the simultaneous delivery of different synergistic agents, and the presence of materials that can provide imaging properties and other advanced features. The combination of CXB with other anti-inflammatory drugs and/or apoptosis inducers appears to hold effective pharmacological promise. The greatest advance to date from a clinical perspective is the ability of CXB to enhance the cytotoxic effects of established chemotherapeutic agents.

Measuring Erosion of Biodegradable Polymers in Brimonidine Drug Delivery Implants by Quantitative Proton NMR Spectroscopy (q-HNMR).

Erosion of biodegradable polymeric excipients, such as polylactic acid (PLA) and polylactic-co-glycolic acid (PLGA), is generally characterized by microbalance for the remaining mass of PLA and/or PLGA and Gel Permeation Chromatography (GPC) for molecular weight (MW) decrease. For polymer erosion studies of intravitreal sustained release brimonidine implants, however, both microbalance and GPC present several challenges. Mass loss measurement by microbalance does not have specificity for excipient polymers and drug substances. Accuracy of the remaining mass by weighing could also be low due to sample mass loss through retrieval-drying steps, especially at later drug release (DR) time points. When measuring the decrease of polymer MW by GPC, trace amounts of polymeric degradants (oligomers and/or monomers) trapped inside the implants during DR tests may not be measurable due to sensitivity limitations of the GPC detector and column MW range. Previous efforts to measure remained PLGA weight of dexamethasone micro-implants using qNMR with external calibration have been performed, however, these measurements do not account for chemical structure changes (i.e. LA to GA ratio changes from time zero) of PLGA implants during drug release tests. Here, a qNMR method with an internal standard was developed to monitor the following changes in micro-implants during drug release tests: 1. The remaining overall PLA/PLGA mass. 2. The remaining lactic acid (LA), glycolic acid (GA) unit and PLGA's lauryl ester end group percentages. 3. The trace content of PLA/PLGA oligomers as degradants retained in the implants. Unlike microbalance analysis, qNMR has both specificity for drug substance, excipient polymer, and accuracy due to minimal implant loss during sample preparation. Compared to the overall PLA/PLGA remaining mass generally monitored in erosion studies, the percentage of remaining LA, GA, and the ester end group provide more information about the microstructure change (such as hydrophobicity) of PLA/PLGA. Additionally, the qNMR method can complement GPC methods by measuring the change of remaining PLA and PLGA oligomer concentrations in brimonidine implants, with tenfold less sample and no MW cutoff. The qNMR method can be used as a sensitive tool for both polymer excipient characterization and kinetics studies of brimonidine implant erosion.

Drug Delivery from a Ring Implant Attached to Intraocular Lens: An in-silico Investigation.

Multiple iterations required to design ocular implants, which will last for the desired operational period of months or even years, necessitate the use of in-silico models for ocular drug delivery. In this study, we developed an in-silico model to simulate the flow of Aqueous Humor (AH) and drug delivery from an implant to the Trabecular Meshwork (TM). The implant, attached to the side of the intraocular lens (IOL), and the TM are treated as porous media, with their effects on AH flow accounted for using the Darcy equation. This model accurately predicts the physiological values of Intraocular Pressure (IOP) for both healthy individuals and glaucoma patients, as reported in the literature. Results reveal that the effective diffusivity of the drug within the implant is the critical parameter that can alter the bioavailability time period (BTP) from a few days to months. Intuitively, BTP should increase as effective diffusivity decreases. However, we discovered that with lower levels of initial drug loading, BTP declines when effective diffusivity falls below a specific threshold. Our findings further reveal that, while AH flow has a minimal effect on the drug release profile at the implant site, it significantly impacts drug availability at the TM.

Bone scaffolds-based localized drugs delivery for osteosarcoma: current status and future perspective.

A common malignant bone neoplasm in teenagers is Osteosarcoma. Chemotherapy, surgical therapy, and radiation therapy together comprise the usual clinical course of treatment for Osteosarcoma. While Osteosarcoma and other bone tumors are typically treated surgically, however, surgical resection frequently fails to completely eradicate tumors, and in turn becomes the primary reason for postoperative recurrence and metastasis, ultimately leading to a high rate of mortality. Patients still require radiation and/or chemotherapy after surgery to stop the spread of the tumor and its metastases, and both treatments have an adverse influence on the body's organ systems. In the postoperative management of osteosarcoma, bone scaffolds can load cargos (growth factors or drugs) and function as drug delivery systems (DDSs). This review describes the different kinds of bone scaffolds that are currently available and highlights key studies that use scaffolds as DDSs for the treatment of osteosarcomas. The discussion also includes difficulties and perspectives regarding the use of scaffold-based DDSs. The study may serve as a source for outlining efficient and secure postoperative osteosarcoma treatment plans.

A review of chitosan polysaccharides: Neuropharmacological implications and tissue regeneration.

One of the current challenges in targeting neurological disorders is that many therapeutic molecules cannot cross the blood-brain barrier (BBB), which limits the use of natural molecules in nervous tissue regeneration. Thus, the development of new drugs to effectively treat neurological disorders would be a challenge. Natural resources are well known as a source of several therapeutic agents for the treatment of neurologic disorders. Recently, chitosan (CTS) and its derivatives from arthropod exoskeletons, have attracted much attention as a drug delivery system to transport therapeutic substances across the BBB and thanks to other neuroprotective effects including the participation to the CNS regenerations scaffolds to replicate the extracellular matrix and microenvironment of the body. This review will discuss the place of natural resource therapy in targeting neurological disorders. In particular, it will highlight recent understanding and progress in the applications of CTS as drug delivery systems and their therapeutic effects on these disorders through tissue regeneration, as well as the molecular mechanisms by which they exert these effects.

New Horizons in Antiretroviral Drug Delivery Systems for HIV Management

INTRODUCTION: Human Immunodeficiency Virus (HIV) infection is still a major global problem, whose drug treatment consists of prophylactic prevention and antiretroviral combination therapy for better pharmacological efficacy and control of the circulating virus. However, there are still pharmacological problems that need to be overcome, such as low aqueous solubility of drugs, toxicity, and low patient adherence. Drug delivery technologies can be used to overcome these barriers. OBJECTIVE: This review summarized the latest drug delivery systems for HIV treatment. Initially, an overview of the current therapy was presented, along with the problems it presents. Then, the latest drug delivery systems used to overcome the challenges imposed in conventional HIV therapy were discussed. CONCLUSION: This review examines innovative approaches for HIV treatment, where various drug delivery systems have shown significant advantages, such as high drug encapsulation, improved solubility, and enhanced bioavailability both in vitro and in vivo. Strategies like cyclodextrins, solid dispersions, microneedles, and nanoparticles are explored to address challenges in drug solubility, bioavailability, and administration routes. Despite progress, obstacles like limited clinical trials and industrial scalability hinder the widespread adoption of these formulations, emphasizing the need for further research and collaboration to optimize and ensure accessibility of innovative HIV therapies, mainly in regions where access to HIV treatment is scarce and remains a challenge.