Development of Drug Targeting and Delivery in Cervical Cancer.

The complex drug delivery barrier in the eye reduces the bioavailability of many drugs, resulting in poor therapeutic effects. It is necessary to investigate new drugs through appropriate delivery routes and vehicles. Nanotechnology has utilized various nano-carriers to develop potential ocular drug delivery techniques that interact with the ocular mucosa, prolong the retention time of drugs in the eye, and increase permeability. Additionally, nano-carriers such as liposomes, nanoparticles, nano-suspensions, nano-micelles, and nano-emulsions have grown in popularity as an effective theranostic application to combat different microbial superbugs. In this review, we summarize the nano-carrier based drug delivery system developments over the last decade, particularly review the biology, methodology, approaches, and clinical applications of nano-carrier based drug delivery system in the field of ocular therapeutics. Furthermore, this review addresses upcoming challenges, and provides an outlook on potential future trends of nano-carrier-based drug delivery approaches in ophthalmology, and hopes to eventually provide successful applications for treating ocular diseases.

Prolonged Suppression of Neuropathic Pain by Sequential Delivery of Lidocaine and Thalidomide Drugs Using PEGylated Graphene Oxide

Implants providing controlled, local release of active substances are of interest in different medical applications. Therefore, the focus of the present article is the development of implant-associated diffusion- or chemically controlled local drug delivery (LDD) systems based on biodegradable polymeric drug carriers. In this context, we provide new data and review our own recently published data concerning the drug release behavior of diffusion-controlled LDD systems in relation to the kind of polymer, drug content, coating mass/thickness, and layer composition. We demonstrate that polymers allow a wide range of control over the drug release characteristics. In this regard, we show that the glass transition temperature of a polymer has an impact on its drug release. Additionally, the blending of hydrophobic, semicrystalline polymers with amorphous polymers leads to an increase in the rate of drug release compared with the pure semicrystalline polymer. Moreover, the percentage loading of the embedded drug has a considerable effect on the rate and duration of drug release. Furthermore, we discuss chemically controlled LDD systems designed for the release of biomolecules, such as growth factors, as well as nanoparticle-mediated LDD systems. With our own published data on drug-eluting stents, microstents, and cochlear implants, we highlight exemplary implant-associated LDD systems designed to improve implant performance through the reduction of undesirable effects such as in-stent restenosis and fibrosis.

The development of drug‐eluting coatings based on hyaluronic acid (HA) is especially promising for implant‐associated local drug delivery (LDD) systems, whose implantation provokes high insertion forces, as, for instance, cochlear implants or drug‐coated balloons (DCB). The lubricious character of HA can then reduce the coefficient of friction and serve as drug reservoir simultaneously. In this context, we investigated several plasma‐ and wet‐chemical methods for the deposition of HA‐based coatings with LDD function on polyamide 12 as a model implant surface, conventionally used for DCB. In contrast to aminosilane, epoxy silane surface layers allowed the covalent attachment of a smooth and uniform HA base layer, which provided good adherence of further HA layers deposited by manual dip coating at a subsequent processing stage. The applied HA‐crosslinking procedure during dip coating influences the transfer and release of paclitaxel, which could be reproducibly incorporated via infiltration. While crosslinking with N‐(3‐dimethylaminopropyl)‐N′‐ethylcarbodiimide hydrochloride provided HA coatings on DCB, which allowed for an efficient paclitaxel transfer upon expansion in a vessel model, crosslinking with glutardialdehyde resulted in a slower drug release being more appropriate for implants with longer residence time in the body. The developed HA coating is hence well suited for spontaneous and sustained LDD.

The field of drug delivery has shown promise through Nanocarrier-based drug delivery systems (NDDS) by making targeted cancer therapy more precise with effective drug delivery methods. Therapeutic agents get encapsulated within nanoparticles through these systems, improving bioavailability while permitting controlled release capabilities and tumor cell-specific targeting effects that reduce harm to healthy tissue. Recent developments in NDDS prioritize creating better carrier systems using liposomes, dendrimers, and polymeric nanoparticles to enhance drug accumulation in tumor areas. Therapeutic performance has benefited significantly from implementing targeted mechanisms that use ligand-receptor connections and enhanced permeability and retention (EPR) effect. The research analyzes modern developments of NDDS in the oncology medical field while assessing its transformative influence on future cancer therapy methods. The assessment incorporates extensive clinical trial and experimental study research to evaluate these systems regarding their toxicity-reducing properties and drug-delivery optimization and survival rate enhancements for personalized cancer therapy.

Chapter 11 - Carbon dots as carriers for the development of controlled drug and gene delivery systems

Nanocarrier-based drug delivery systems have seen tremendous developments in recent years, enabled by rapid advances in both nano-scale technologies and in silico modelling tools. The articles published in this research topic capture a snapshot of this rapidly developing area, focusing on computational modelling methods that complement recent experimental approaches to studying nanocarrier intravascular drug delivery (NIVDD) systems. It has long been recognized that there is a need for the development of more standardized frameworks for in silico preclinical trials. Five papers are included in this special issue, and it is our hope that they can address this need by bringing together a broad range of recent approaches and highlighting their promises and limitations.The first paper by Buchete et al. is a comprehensive review of both main historical events resulting in the development of NIVDD systems and the broad range of multiscale physics-based approaches employed by different groups. The first section introduces nanoparticle (NP)-based drug delivery approaches, highlighting systematically ideas related to aspects such as NP types, approaches for NP loading with useful drugs and concepts related to the effective targeting and biophysical interactions (i.e., that ultimately modulate delivery) of drug-carrying NPs with their cellular targets. The second section illustrates the primarily molecular modelling-based approaches involved in microscale and mesoscale modelling, illustrating the corresponding molecular-level concepts and implications, from NP-functionalization and loading to form a NIVDD system to the NC's molecular interactions in the blood, including the formation of a protein corona, to the delivery stage when the desired targets (e.g., extracytosolic cellular membrane surfaces in the targets) are finally reached. Notably, multiscale modelling approaches of complex molecular processes, such as the complex NIVDD coverage by proteins while located in the blood, are also illustrated and discussed. The third and final section highlights the larger, macroscale aspects of functionalized NIVDD systems, covering physical properties such as the convection and diffusion of nanoparticles in biological media in general and blood vessels and capillaries, in particular. It is illustrated how models based on computational fluid dynamics (CFD) are needed and used to describe larger-scale processes such as particle-wall interactions in capillaries, related to triggering receptor-ligand reactions at vascular areas of interest. Ultimately, the CFD-based approaches can be both improved by the microscale molecular-level models presented in the second section and can provide a useful benchmark themselves (i.e., in a multiscale feedback loop) for achieving improved accuracy at both scales in a self-consistent manner.Another paper by Li et al. (Southeast University, Nanjing, China) presents recent developments in cancer treatment regarding the use of nanomaterials for iron homeostasis. Cells in highly vascularized tumor tissue exhibit a large increase in iron uptake, required for their pronounced growth, migration and possible invasion stages related to cancer proliferation. This paper illustrates the author's experience with a novel class of nanocarriers using iron chelating agents such as deferoxamine (DFO), deferasirox (DFX) and Dp44mT, which showed promise in being used in conjunction with different types of nanoparticles. This approach can advance the current NIVDD toolbox of systems that can be used to target selectively and efficiently cancer cells and tumors and impair their proliferation by modulating their access to iron.A third paper by Domenico Fuoco (Department of Chemical Engineering, Polytechnique Montréal, Montréal, QC, Canada) presents another interesting high-level view of using NPs as nanocarriers from a more user-facing perspective, providing not only a pragmatic summary of the recent concepts and key points involved in practical development of NIVDD systems, including pointers to different types of NP materials and nanotechnologies, but also to public and private-access databases and information sources that could be consulted for identifying recent developments in this field. Notably, the review highlights emerging biomedical aspects that need to be considered for improving the clinical outcomes of NIVDD systems, such as their "stealth effect" (i.e., the biophysical and biomolecular properties that can allow them to avoid recognition by the immune system and trigger their premature clearing). Other related aspects are also discussed, such as cellular or even molecular "Trojan-horse" strategies that may be used to improve both delivery efficiency and targeting specificity. Engineering, University of Cyprus, Nicosia, Cyprus) introduces a novel complex mathematical modelling approach to study and quantify the combined effects of both mechanotherapy and sonopermeation on tumor treatment. Once again, the accurate modelling of a cancer tumor's microenvironment (TME) can play a key role in modulating both its development and its response to various treatments (e.g., exposing the tumor to IV-delivered nanocarriers). This paper lays the foundations of developing an automatic and systematic modeling framework, including explicitly three principal states of nanocarrier-based drug delivery (i.e., (i) encapsulation/functionalization of the chemotherapeutic agent, (ii) free diffusion of the agent in the tumor interstitial space, and

Gels are attractive candidates for drug delivery because they are easily producible while offering sustained and/or controlled drug release through various mechanisms by releasing the therapeutic agent at the site of action or absorption. Gels can be classified based on various characteristics including the nature of solvents used during preparation and the method of cross-linking. The development of novel gel systems for local or systemic drug delivery in a sustained, controlled, and targetable manner has been at the epitome of recent advances in drug delivery systems. Cross-linked gels can be modified by altering their polymer composition and content for pharmaceutical and biomedical applications. These modifications have resulted in the development of stimuli-responsive and functionalized dosage forms that offer many advantages for effective dosing of drugs for Central Nervous System (CNS) conditions. In this review, the literature concerning recent advances in cross-linked gels for drug delivery to the CNS are explored. Injectable and non-injectable formulations intended for the treatment of diseases of the CNS together with the impact of recent advances in cross-linked gels on studies involving CNS drug delivery are discussed.

Aim. To analyze and systematize data on modern and promising nanotechnological methods (in particular, nanogels and nanoparticle composites) for the treatment of periodontitis with a focus on local drug delivery systems. Materials and methods. The method of systematic review and biblio-semantic analysis of scientific medical literature was used for the analysis; 78 sources of information were processed, of which 13 were selected for detailed review. The PubMed, Scopus, Web of Science, and Google Scholar databases were also used to search for information. The study object was modern nanotechnological drug delivery systems. Results. Nanoparticle-hydrogel composites (nanogels) show significant advantages over individual components, providing multi-medication therapy, high bio-adhesiveness, and controlled drug release. The high potential of chitosan as a multifunctional platform for antimicrobial and regenerative therapy has been confirmed. Conclusions. Nanogel systems are a promising platform for local drug delivery in periodontal pockets, capable of providing a targeted, controlled therapeutic effect and overcoming the problem of the short residence time of traditional dosage forms.

New generation, drug-eluting stents used in the treatment of coronary and peripheral atherosclerotic disease (CPAD) significantly reduced restenosis and revascularization rates as well as frequency of thrombosis as compared to bare metal stents and first-generation drug eluting stents. However, despite fast development of this technology several reports have been published recently that describe cases of late and very late stent thrombosis, restenosis and neoatheroslerosis within arterial segments with previously implanted stents. For this reason many research are being conducted with the aim to design alternative methods for intra-arterial drugs delivery in order to reduce restenosis and revascularization rates, yet eliminating adverse effects mentioned above. One of possibilities is lipophilic and antiproliferative drug coated balloon technology, which offers high drug concentration in arterial tissue and restenotic effect in selected clinical situations despite the short balloon inflation time. A particularly interesting option is intra-arterial delivery of drugs with different mechanisms of action, regardless of their lipophilicity by loading them into biodegradable nanospheres. In this paper, currently used systems for local drug delivery have been described including their limitations and opportunities. In addition, we provided a brief description of the project sponsored by Polpharma Scientific Foundation, which aimed to evaluate potentials of local delivery of biodegradable nanospheres loaded with everolimus, which could be used to reduce restenosis rate after stent implantation.

Drug delivery strategies and systems for HIV/AIDS pre-exposure prophylaxis and treatment

The integration of diagnosis and therapy into one nanoplatform, known as theranostics, has attracted increasing attention in the biomedical areas. Herein, we first present a cancer cell targeting imaging and drug delivery system based on engineered thioether-bridged periodic mesoporous organosilica nanoparticles (PMOs). The PMOs are stably and selectively conjugated with near-infrared fluorescence (NIRF) dye Cyanine 5.5 (Cy5.5) and anti-Her2 affibody on the outer surfaces to endow them with excellent NIRF imaging and cancer targeting properties. Also, taking the advantage of the thioether-group-incorporated mesopores, the release of chemotherapy drug doxorubicin (DOX) loaded in the PMOs is responsive to the tumor-related molecule glutathione (GSH). The drug release percentage reaches 84.8% in 10 mM of GSH solution within 24 h, which is more than 2-fold higher than that without GSH. In addition, the drug release also exhibits pH-responsive, which reaches 53.6% at pH 5 and 31.7% at pH 7.4 within 24 h. Confocal laser scanning microscopy and flow cytometry analysis demonstrate that the PMOs-based theranostic platforms can efficiently target to and enter Her2 positive tumor cells. Thus, the smart imaging and drug delivery nanoplatforms induce high tumor cell growth inhibition. Meanwhile, the Cy5.5 conjugated PMOs perform great NIRF imaging ability, which could monitor the intracellular distribution, delivery and release of the chemotherapy drug. In addition, cell viability and histological assessments show the engineered PMOs have good biocompatibility, further encouraging the following biomedical applications. Over all, the systemically engineered PMOs can serve as a novel cancer cell targeting imaging and drug delivery platform with NIRF imaging, GSH and pH dual-responsive drug release, and high tumor cell targeting ability.

Dual-hydrogel thermoresponsive system with bioinspired pore control for drug delivery

Some cancers such as human breast cancer, prostate cancer, and lung cancer easily metastasize to bone, leading to osteolysis and bone destruction accompanied by a complicated microenvironment. Systemic administration of bisphosphonates (BP) or denosumab is the routine therapy for osteolysis but with non-negligible side effects such as mandibular osteonecrosis and hypocalcemia. Thus, it is imperative to exploit optimized drug delivery systems, and some novel nanotechnology and nanomaterials have opened new horizons for scientists. Targeted and local drug delivery systems can optimize biodistribution depending on nanoparticles (NPs) or microspheres (MS) and implantable biomaterials with the controllable property. Drug delivery kinetics can be optimized by smart and sustained/local drug delivery systems for responsive delivery and sustained delivery. These delicately fabricated drug delivery systems with special matrix, structure, morphology, and modification can minimize unexpected toxicity caused by systemic delivery and achieve desired effects through integrating multiple drugs or multiple functions. This review summarized recent studies about optimized drug delivery systems for the treatment of cancer metastatic osteolysis, aimed at giving some inspiration in designing efficient multifunctional drug delivery systems.

Targeted drug delivery has gained recognition in modern therapeutics and attempts are being made to explore the potential of cell biology-related bioevents in the development of specific and target-oriented systems. In connection to modern therapeutic systems, most of the emphasis has been laid upon the bioconjugated drug delivery systems. Bioconjugates involve the linking of two or more molecules to form a novel complex having the combined properties of its individual components. The nature of the linking agent between the pharmacologic agent and the delivery-augmenting moiety dictates the degree of successful delivery and its outcome. The component for the bioconjugated drug delivery includes receptors and ligands, where the receptors act as molecular targets or portals whereas ligands with receptors provide selective and specific trafficking towards the targeting site. Recently, a number of bioconjugated systems have been discovered for the site-specific presentation and delivery of various bioactive substances using biorelevant ligands, including antibodies, glycoprotein, viral proteins, and molecules of endogenous origin. In this review, the potential of transferrin (Tf) and Tf conjugates of liposomes in site-specific drug delivery systems are discussed. Tf is an abundant component of serum with the capacity to bind and transport iron, while Tf receptor (TfR), a dimeric transmembrane glycoprotein, is present on the surface of the most proliferating, higher eukaryotic cells. Tf expression is also found in nonproliferating tissues, such as hepatocytes, tissue macrophages, pituitary cells, pancreatic islet cells, and the endothelium of brain capillaries. Tumor cells frequently carry elevated numbers of TfRs compared with corresponding normal cells, and reduced serum levels of Tf are often observed in patients with tumors. In the past, various strategies have been developed, which include coupling of the liposomal surface with Tf by using various linking agents. Low-molecular weight drugs and proteins as well as liposomes can be linked with Tf. The Tf-coupled vesicular system is physicochemically stable in the bioenvironment and is site-specific. The aim of coupling liposomes with Tf is to improve the physical and biochemical stability of liposomes and make them appropriate for targeting specific organs and cells. Tf may be widely applied either as a carrier or targeting ligand in the active targeting of anticancer agents, proteins, and genes to primarily proliferating malignant cells that overexpress TfRs. Tf has been used as a molecular conjugate to deliver DNA to erythroleukemic, lung, and liver cell lines. Tf can also be modified with the positive charge N-acylurea groups to make them suitable for electrostatic binding of DNA, in order to achieve a well defined DNA-binding ligand for receptor-mediated gene transfer. Association of Tf with lipoplexes, in particular the negatively charged ternary complexes, significantly overcomes the inhibitory effect of serum and facilitates efficient transfection in many cell lines, including HeLa, K-562 cells, and lung carcinoma cells Calu-3 and H-292 cells. Tf-lipoplex has demonstrated high efficiency in tumor-targeted gene delivery and long-term therapeutic accuracy in systemic p53 gene therapy for both human head and neck cancer and prostate cancer. Tf and Tf-coupled liposomal drug delivery systems may prove particularly valuable to enable the use of a drug that seems to be ineffective or toxic if delivered systematically. The delivery of drugs to the brain has been particularly challenging because of the presence of the blood-brain barrier, which restricts the passage of most therapeutic agents into the brain. Therefore, active targeting of the brain is crucial for effective treatment of brain diseases. The anti-TfR antibody, such as OX26, when coupled with therapeutic agents, has shown potential in drug and gene delivery to the brain.