Biodegradable PEG-poly(ω-pentadecalactone- co - p -dioxanone) nanoparticles for enhanced and sustained drug delivery to treat brain tumors

Intracranial delivery of therapeutic agents is limited by penetration beyond the blood-brain barrier (BBB) and rapid metabolism of the drugs that are delivered. Convection-enhanced delivery (CED) of drugloaded nanoparticles (NPs) provides for local administration, control of distribution, and sustained drug release. While some investigators have shown that repeated CED procedures are possible, longer periods of sustained release could eliminate the need for repeated infusions, which would enhance safety and translatability of the approach. Here, we demonstrate that nanoparticles formed from poly(ethylene glycol)-poly(u-pentadecalactone-co-p-dioxanone) block copolymers [PEG-poly(PDL-co- DO)] are highly efficient nanocarriers that provide long-term release: small nanoparticles (less than 100 nm in diameter) continuously released a radiosensitizer (VE822) over a period of several weeks in vitro, provided widespread intracranial drug distribution during CED, and yielded significant drug retention within the brain for over 1 week. One advantage of PEG-poly(PDL-co-DO) nanoparticles is that hydrophobicity can be tuned by adjusting the ratio of hydrophobic PDL to hydrophilic DO monomers, thus making it possible to achieve a wide range of drug release rates and drug distribution profiles. When administered by CED to rats with intracranial RG2 tumors, and combined with a 5-day course of fractionated radiation therapy, VE822-loaded PEG-poly(PDL-co-DO) NPs significantly prolonged survival when compared to free VE822. Thus, PEG-poly(PDL-co-DO) NPs represent a new type of versatile nanocarrier system with potential for sustained intracranial delivery of therapeutic agents to treat brain tumors

Developing pharmacokinetic models for nano drug delivery systems

Trabalho Final de Mestrado Integrado, Ciências Farmacêuticas, 2021, Universidade de Lisboa, Faculdade de Farmácia.A área dos nanomedicamentos é interdisciplinar e complexa com fontes de literatura terciárias, sobre a forma de manuais, emergentes desde os 2010 e, ainda assim, os processos que sustentam a farmacocinética e a farmacodinâmica de nanomedicamentos ainda não estão totalmente caracterizados. O objetivo desta monografia é apresentar, para os indivíduos que podem ser relativamente novos na área de nanomedicamentos, as propriedades farmacocinéticas de nanopartículas, as abordagens na modelação farmacocinética, e demonstrar a aplicação destes princípios em exemplos tanto de investigação fundamental, quanto no desenvolvimento e otimização bio galénica de nanomedicamentos. Aqui são descritas as etapas farmacocinéticas de absorção, distribuição, metabolização e eliminação referentes a nanomedicamentos, com realce nos aspetos que distinguem estes processos daquilo que é observado quando se trata de medicamentos “convencionais”. É também fornecida uma discussão sobre conceitos essenciais necessários para discussão de modelação farmacocinética usados nas abordagens compartimentais, mecanísticas, e baseadas na fisiologia. Diversos assuntos tangentes como corrente interesse na área de oncologia, extrapolação interespécies em estudos pré-clínicos e aspetos regulamentares associados são também brevemente abordados. Esta monografia foi realizada com base nas publicações disponíveis nas bases de dados de PubMed e Science Direct até ao mês de setembro do ano 2021. Este trabalho não é único e assemelha-se as revisões de Moss D. M. e Siccardi M., de Glassman P. M. e Muzakantov V. R., ou de Yuan D. et al quanto a organização bem como aos conteúdos.(1–3) A farmacocinética que descreve os medicamentos “convencionais” baseados na distribuição de substâncias ativas começa apenas quando as etapas finais de libertação e degradação das nanopartículas já começam a ocorrer. A existência simultânea de entidades particuladas e moleculares complica a descrição, otimização, desenvolvimento e avaliação regulamentar de novas formulações de nanomedicamentos. Isto, juntamente com a falta de técnicas analíticas adequadas para a quantificação de nanopartículas em meios biológicos, torna os estudos de modelação farmacocinética de nanomedicamentos um desafio.Nanomedicines are a complex and highly interdisciplinary field with recently emerging Textbooks as tertiary literature sources since 2010s, and yet the processes that underpin the pharmacokinetics and pharmacodynamics of nano drug delivery systems are not fully characterized. The aim of this monograph is to introduce the pharmacokinetic dispositions, pharmacokinetic modelling approaches, and to demonstrate application of these principles in examples of both basic research and NDDS development to individuals who may be relatively new to the field of nanomedicine. In this monograph are described the pharmacokinetic steps of absorption, distribution, metabolization and elimination particular to nano drug delivery systems, primarily focusing aspects that distinguish NDDS from “conventional” drugs. A description of essential concepts necessary for discussions of PK modelling in compartmental, mechanistic, and physiology-based approaches are also provided. Various related topics including growing interest in cancer therapy, interspecies extrapolation in pre-clinical study settings, and reglementary affairs related to NDDSs are also briefly addressed. Writing of this monograph was conducted after browsing information available in the PubMed and Science Direct databases up to September 2021. This work is not unique and resembles the reviews by Moss D. M. and Siccardi M., Glassman P. M. and Muzakantov V. R., and Yuan D. et al, in their structure, subject and contents.(1–3) Pharmacokinetics that describes small molecule active substances, begin only when the final steps of nanoparticles fate of release and degradation had begun. Simultaneous existence of both particulate and molecular entities complicates the description, optimization, development, and regulatory assessment of new nano formulations. This together with the lack of appropriate analytical techniques for nanoparticle quantification in biologic media makes pharmacokinetic modelling studies of NDDSs challenging

Brain-Targeted Drug Delivery

Brain diseases currently affect one in six people worldwide; they include a wide range of neurological diseases, from Alzheimer’s and Parkinson’s diseases to epilepsy, brain injuries, brain cancer, neuroinfections, and strokes. The treatment of these diseases is complex and limited due to the presence of the blood–brain barrier (BBB), which covers the entirety of the brain. The BBB not only has the function of protecting the brain from harmful substances; it is also a metabolic barrier and a transport regulator of nutrients/serum factors/neurotoxins. Knowing these characteristics when it comes to the treatment of brain diseases makes it easier to understand the lack of efficacy of therapeutic drugs, resulting from the innate resistance of the BBB to permeation. To overcome this limitation, drug delivery systems based on nanotechnology/microtechnology have been developed. Brain-targeted drug delivery enables targeted therapy with a higher therapeutic efficacy and fewer side effects because it targets moieties present in the drug delivery systems

Numerical simulation of transdermal delivery of drug nanocarriers using solid microneedles and medicated adhesive patch

Open Access via the Elsevier agreementPeer reviewedPublisher PD

Desarrollo de nanocápsulas lipídicas como estrategia para facilitar el paso a través de la barrera hematoencefálica de fármacos que actúan a nivel del sistema nervioso central

Tesis de la Universidad Complutense de Madrid, Facultad de Farmacia, Departamento de Farmacia Galénica y Tecnología Alimentaria, leída el 17/09/2018. Tesis formato europeo (compendio de artículos)Diseases affecting the central nervous system (CNS) should be regarded as a major health challenge due to their steadily rising incidences and to the current lack of effective treatments given the hindrance to brain drug delivery imposed by the blood-brain barrier (BBB). Some of the described delivery strategies to circumvent the BBB such as the direct intracerebral administration and the artificial disruption of the tight junctions involve high risk of neurological damage. Hence, every effort is currently being devoted to achieving efficient transport across the brain endothelium with targeted drug carriers following minimally-invasive intravenous injection. In particular, nanomedicine is chiefly germane to the field of chemotherapy wherein dose availability at the target site cannot be enhanced by dose increase for fear of severe side effects. Since efficient brain targeting should not solely rely on passive targeting, brain active targeting of nanomedicines into the CNS is being explored...Las patologías que afectan al sistema nervioso central representan un desafío terapéutico por su incidencia creciente y la limitación del acceso a sistema nervioso central de la mayoría de fármacos administrados por vía sistémica por parte de la barrera hematoencefálica. Algunas de las estrategias para sortear esta barrera, incluyendo la administración intracerebral o la disrupción artificial de sus uniones estrechas, suponen un elevado riesgo de daño neurológico. Por ello, actualmente se persigue diseñar transportadores de fármacos capaces de atravesar de manera eficiente el endotelio cerebral tras su administración intravenosa. En concreto, la vectorización de antineoplásicos en nanotransportadores para el tratamiento de tumores cerebrales supondría un sustancial avance en terapéutica por la reducción de efectos secundarios derivados de su distribución sistémica. Dado que la distribución de transportadores a sistema nervioso central no puede depender en exclusiva de la vectorización pasiva, a fin de favorecer su paso a través de la barrera hematoencefálica, se está investigando la incorporación de distintos ligandos a estos sistemas. El objetivo global de esta tesis doctoral es diseñar, desarrollar y evaluar a nivel preclínico un nanotransportador lipídico capaz de atravesar la barrera hematoencefálica para vectorizar fármacos a nivel del sistema nervioso central tras una administración intravenosa. Este objetivo general se desglosa en tres objetivos específicos Estudiar los parámetros experimentales determinantes en la obtención de nanocápsulas lipídicas mediante el método térmico de inversión de fases para habilitar la producción de nanocápsulas lipídicas bajo demanda. Desarrollar una novedosa estrategia de funcionalización de nanocápsulas lipídicas con cannabidiol para favorecer su distribución a sistema nervioso central y evaluar su potencial in vitro e in vivo. Encapsular cannabidiol en el núcleo oleoso de las nanocápsulas y evaluar in vitro su eficacia como sistemas de liberación prolongada con actividad frente a la línea celular U373MG de glioblastoma humano. Asimismo, se persigue evaluar la estrategia de funcionalización con cannabidiol para potenciar la captación por células de glioma. En cuanto a los resultados, la obtención de nanocápsulas lipídicas con tamaños de partícula predeterminados para aumentar las posibilidades de éxito de tratamientos de patologías del sistema nervioso central puede conseguirse mediante el método térmico de inversión de fases, pues el diámetro volumen se ajusta a un modelo matemático en una variable (el cociente másico entre la fase interna oleosa y el tensioactivo). Este modelo es válido para nanocápsulas blancas y cargadas con fármaco. Además, una disminución de tamaño de las nanocápsulas lipídicas en el intervalo 20-60 nm incrementa en 2,5 y 1,6-2,5 veces su paso a través de la barrera hematoencefálica in vitro e in vivo, respectivamente. Por otra parte, la funcionalización de las nanocápsulas lipídicas con el fitocannabinoide cannabidiol aumenta el paso a través de barrera hematoencefálica 4,3 y 2,5 veces in vitro e in vivo, respectivamente. Una disminución de tamaño de las nanocápsulas lipídicas incrementa 3 veces la captación por células de glioma. Asimismo, el tamaño de las nanocápsulas lipídicas condiciona la liberación de fármacos: nanocápsulas de 20 nm cargadas con cannabidiol reducen invariablemente 3 veces los valores de concentración inhibitoria 50 en comparación con sus homólogas de 50 nm. Además, la funcionalización de nanocápsulas lipídicas con cannabidiol aumenta la captación por células de glioma 3,4 veces. Como conclusión, las nanocápsulas lipídicas, cargadas y funcionalizadas con cannabidiol, son prometedores candidatos para el tratamiento de gliomas con capacidad de vectorización a través de barrera hematoencefálica y de células de glioma. Su potencial terapéutico debe ser evaluado en modelos animales de glioma.Depto. de Farmacia Galénica y Tecnología AlimentariaFac. de FarmaciaTRUEunpu

Nanoparticle-facilitated functional and molecular imaging for the early detection of cancer

Cancer detection in its early stages is imperative for effective cancer treatment and patient survival. In recent years, biomedical imaging techniques, such as magnetic resonance imaging, computed tomography and ultrasound have been greatly developed and have served pivotal roles in clinical cancer management. Molecular imaging (MI) is a non-invasive imaging technique that monitors biological processes at the cellular and sub-cellular levels. To achieve these goals, MI uses targeted imaging agents that can bind targets of interest with high specificity and report on associated abnormalities, a task that cannot be performed by conventional imaging techniques. In this respect, MI holds great promise as a potential therapeutic tool for the early diagnosis of cancer. Nevertheless, the clinical applications of targeted imaging agents are limited due to their inability to overcome biological barriers inside the body. The use of nanoparticles has made it possible to overcome these limitations. Hence, nanoparticles have been the subject of a great deal of recent studies. Therefore, developing nanoparticle-based imaging agents that can target tumors via active or passive targeting mechanisms is desirable. This review focuses on the applications of various functionalized nanoparticle-based imaging agents used in MI for the early detection of cancer

Electroencapsulation and electrospraying of pharmaceutical materials in preparation for oral drug delivery applications

In bi-polar parallel nozzle electroencapsulation, two oppositely charged droplet jets are produced by electrospraying (electrostatic atomization), a method of extracting micro- or nanodroplets from a body of liquid using electrical forces. The two species of droplets are attracted to each other due to Coulombic forces. Upon contact, droplets of similar size can merge into a single-phase, or form a core-shell capsule structure, depending on the mutual miscibility of the liquids. In this work, an electroencapsulation setup was designed and experimented for the single-step production of two types of drug carrier particles of 10–50 μm in size: wrinkled, solid Eudragit L 100 enteric polymer micromatrix particles; and spherical microcapsules consisting of a solid Eudragit E 100 polymer shell and a liquid glycerol core. The carrier particle payload consisted of a model drug (griseofulvin); or griseofulvin loaded, mesoporous silicon (PSi) nano- and microparticles, which themselves are functional drug carriers. The goal was to obtain the carrier particle payloads as either stable drug dispersions in a disordered solid state, or non-agglomerated PSi nanoparticle dispersions, to enhance the drug dissolution properties at release. The carrier formulations would effectively render the payload in the form of an inert micropowder for purposes of handling and dosing. In oral administration, the formulations were to shield the payload from intestinal metabolism, and to restrain its release until arrival to target pH-conditions. The carrier particles were characterized to evaluate these properties. The micromatrix particles were proven stable and gastro-resistant in vitro. Griseofulvin dissolution and absorption properties improved significantly, the latter especially for the drug loaded PSi payloads. Finally, the efficiency of the asymmetric core-shell microcapsule production was optimized using Taguchi techniques. In conclusion, electroencapsulation was found to be a potentially feasible method to improve the oral bioavailability of poorly soluble drugs. Furthermore, partially crystalline piroxicam microparticles were produced by electrospraying, and characterized. The crystalline phase was shown to consist of a previously unknown, stable polymorphic form of piroxicam. The result suggests the method could provide a unique way to produce novel drug polymorphs. Thus, it is possible that the dissolution properties of certain drug materials could be improved sufficiently to facilitate oral administration, without the necessity to use more complex formulations

A Systematic Correlation of Nanoparticle Size with Diffusivity through Biological Fluids

Nanomedicine, the application of nanotechnology for medical purposes, has been widely identified as a potential solution for today‟s healthcare problems. Nanomedicine uses the "bottom-up‟ principles of nanoscale engineering to improve areas of medicine which have previously been considered undevelopable. One of the enduring challenges for medicine is the design of innovative devices able to overcome biological barriers, allowing drugs and therapeutics to effectively reach their correct location of action. Biological barriers are a defence mechanism of the body which are extremely well-evolved to protect the body from foreign and harmful particles. Therapeutic drugs and devices, which are not harmful, are often identified by the body as dangerous because their composition differs from native and accepted entities. The traversal of these biological barriers, such as mucus, remains a bottleneck in the progress of drug delivery and gene therapy. The mucus barrier physically limits the motion of particles due to its complicated mesh structure which obstructs the particles' traversal path. Mucus fibres can also adhere to the particles, entrapping them and restricting their motion. Particle traversal of mucus is carried out by passive diffusion. As diffusion has traditionally been defined by the Stokes-Einstein equation as inversely proportional to particle radius, it follows that reducing particle sizes into the nanoscale would result in increased diffusive ability. These predictions, however, do not consider the obstructive effects of the complicated mesh structure for the case of mucus. The exact effect of reducing particle size into the nanoscale for diffusion through mucus is therefore unknown. Multiple Particle Tracking was used to obtain real-time movies of the diffusion of nanoparticles, ranging from 12nm – 220nm in diameter, through mucus samples. The experimental data generated was used to systematically correlate the relationship between particle size and diffusivity through mucus. This study reveals that nanoparticles, smaller than the average pore size in the mucus mesh structure, can diffuse through lower viscosity pores which pose less resistance to diffusive motion, allowing nanoparticles to travel at up to four times the speed expected from the bulk viscosity of the mucus. This type of information can help researchers understand the importance of size for therapeutic nanoparticles, allowing researchers to decide whether attempts to decrease nanoparticle size at the expense of other functionality are worthwhile

Image-based predictive modelling frameworks for personalised drug delivery in cancer therapy

Peer reviewe

Biodegradable Polymeric Biomaterials in Different Forms for Long-acting Contraception and Drug Delivery to the Eye and Brain

Efficacy of many of the new and existing therapeutics is often hampered by the lack of an effective and compliant method of delivery. Typically, drugs have poor water solubility, short half-lives, and low permeability across the biological membranes. The result is low bioavailability of the drugs at the target site and can cause toxicity and side effects at high doses. Often the conventional dosage forms fail to overcome these limitations. In the recent decades, biodegradable polymeric drug delivery systems have emerged as promising candidates to solve the challenges of poor solubility, low permeability and sustained release owing to the advantages of biocompatibility, versatility, and tunable drug release. Polyesters and polysaccharides are the most common polymers that were explored for drug delivery applications because of their unique advantages including non-toxic nature, wide availability, relatively low cost, and flexibility in chemistry. Although a major progress has been in the field of drug delivery, still there are unmet medical needs which require new materials for delivering drugs such as, injectable systems that can achieve long-term contraception (five months or longer) at low cost, and drug delivery systems that can enhance the permeability of drugs across ocular/blood-brain barriers and sustain release as well for treating chronic diseases such as diabetic retinopathy in the eye and Alzheimer’s disease in the brain. Therefore, this research has evaluated the potential of different biodegradable polymeric biomaterials based on polyesters or polysaccharides for long-acting contraception and drug delivery to the eye and brain to resolve the issues such as poor compliance and adherence to the existing contraceptive dosage forms or poor solubility and permeability of the drugs across ocular/blood-brain barriers. The first system includes polyester-based injectable in situ forming depot systems (ISD) for long-acting contraception. The aim of this project was to develop injectable ISD system containing levonorgestrel (LNG) for contraceptive effect for five months or longer after single shot that helps to reduce unintended pregnancies with high patient compliance and low cost. A series of LNG-containing ISD formulations were designed by employing unique strategies which include the use of poly(lactic acid-co-glycolic acid), poly(lactic acid) with different biodegradable properties, and blends of these polyesters, use solvent mixtures of N-methyl-2-pyrrolidone, triethyl citrate, benzyl benzoate, and vary the polymer/solvent ratios, and various drug loadings. The formulations were evaluated for viscosity, initial burst, in vitro and in vivo long-term release. In vivo investigation in rats showed the sustained-release pharmacokinetic profile of LNG from the ISD formulations for at least five months and continued for more than seven months depending on the composition, and the vaginal cytology studies have demonstrated that formulations have successfully suppressed the rat estrous cycle. After the end of the treatment, a rapid and predictable return of fertility was observed in rats. The optimized lead formulation has shown promising injectability (23 G) and low initial in vivo burst profiles. The results suggested that the developed LNG-ISD formulations have a great potential for developing into future robust affordable long-acting contraceptive products for improving patient compliance and adherence. Another type of polymeric biomaterial systems that were evaluated in this study includes polysaccharide-based biodegradable nanoparticles for drug delivery across ocular and blood-brain barriers. Depending on the need of the therapeutic application, two types of polysaccharide-based nanoparticles were investigated for their drug delivery feasibility which includes: (a) Poly(N-isopropylacrylamide-co-Dextran-lactateHEMA) nanogels for the potential delivery of hydrophilic peptide (insulin) across ocular barriers for the treatment of diabetic retinopathy. The in vitro, and ex vivo studies showed that the developed nontoxic nanogels have great potential to enhance the drug permeability across ocular barriers including the in vitro retinal pigment epithelium, sclera and cornea barriers for treating diabetic retinopathy; and (b) β-cyclodextrin-poly(β-amino ester) nanoparticles as potential drug carriers to enhance the solubility and blood-brain barrier (BBB) permeability of 17-N-allylamino-17-demethoxygeldanamycin (17-AAG) to treat Alzheimer’s disease. The nanoparticles sustained the release of 17-AAG for at least one week in vitro and showed increased permeability (2-fold) of the 17-AAG across BBB in vivo in mice, and resulted in enhanced expression of the Hsp70 protein in the brain. In conclusion, the developed biodegradable polymeric biomaterials have shown potential to be used in long-acting contraception and drug delivery to the eye and brain