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

A computational framework for identifying design guidelines to increase the penetration of targeted nanoparticles into tumors

Targeted nanoparticles are increasingly being engineered for the treatment of cancer. By design, they can passively accumulate in tumors, selectively bind to targets in their environment, and deliver localized treatments. However, the penetration of targeted nanoparticles deep into tissue can be hindered by their slow diffusion and a high binding affinity. As a result, they often localize to areas around the vessels from which they extravasate, never reaching the deep-seeded tumor cells, thereby limiting their efficacy. To increase tissue penetration and cellular accumulation, we propose generalizable guidelines for nanoparticle design and validate them using two different computer models that capture the potency, motion, binding kinetics, and cellular internalization of targeted nanoparticles in a section of tumor tissue. One strategy that emerged from the models was delaying nanoparticle binding until after the nanoparticles have had time to diffuse deep into the tissue. Results show that nanoparticles that are designed according to these guidelines do not require fine-tuning of their kinetics or size and can be administered in lower doses than classical targeted nanoparticles for a desired tissue penetration in a large variety of tumor scenarios. In the future, similar models could serve as a testbed to explore engineered tissue-distributions that arise when large numbers of nanoparticles interact in a tumor environment.Human Frontier Science Program (Strasbourg, France)David H. Koch Institute for Integrative Cancer Research at MIT (Marie D. and Pierre Casimir-Lambert Fund)National Institutes of Health (U.S.) (Grant U54 CA151884)National Cancer Institute (U.S.) (Koch Institute Support (Core) Grant P30-CA14051

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

Peer reviewe

Doctor of Philosophy

dissertationWhen a patient is presented with locally advanced prostate cancer, it is possible to provide treatment with curative intent. However, once the disease has formed distant metastases, the chances of survival drops precipitously. For this reason, proper management of the disease while it remains localized is of critical importance. Treating these malignant cells with cytotoxic agents is effective at cell killing; however, the nonspecific toxicity profiles of these drugs often limit their use until the disease has progressed and symptom palliation is required. Incorporation of these drugs in nanocarriers such as polymers help target them to tumors with a degree of specificity, though major vascular barriers limit their effective delivery. In this dissertation, it is shown that plasmonic photothermal therapy (PPTT) can be used to help overcome some of these barriers and improve delivery to prostate tumors. First, the concept of using PPTT to improve the delivery of macromolecules to solid tumors was validated. This was done by measuring the tumor uptake of albumin. Next, the concept of targeting gold nanorods (GNRs) directly to the tumor's vasculature to better modulate vascular response to heating was tested. Surface conjugation of cyclic RGD (Arg-Gly-Asp) to GNRs improved their binding and uptake to endothelial cells in vitro, but not in vivo. Nontargeted GNRs and PPTT were then utilized to guide the location of polymer therapeutic delivery to prostate tumors. #-(2-hydroxypropyl)methacrylamide (HPMA) copolymers, which were designed to be targeted to cells previously exposed to heat shock, were used in this study. Treatment of tumors with PPTT facilitated a burst accumulation of the copolymers over 4 hours, and heat shock targeting to cells allowed them to be retained for an extended period of time. Finally, the tumor localization of the HPMA copolymers following PPTT was evaluated by magnetic resonance imaging (MRI). These results show that PPTT may be a useful tool to enhance delivery of polymeric drug carriers to locally advanced prostate tumors

Recapitulation of complex transport and action of drugs at tumor microenvironment using tumor-microenvironment-on-chip

Targeted delivery aims to selectively distribute drugs to targeted tumor tissue but not to healthy tissue. This can address many of clinical challenges by maximizing the efficacy but minimizing the toxicity of anti-cancer drugs. However, complex tumor microenvironment poses various barriers hindering the transport of drugs and drug delivery systems. New tumor models that allow for the systematic study of these complex environments are highly desired to provide reliable test beds to develop drug delivery systems for targeted delivery. Recently, research efforts have yielded new in vitro tumor models, the so called tumor-microenvironment-on-chip, that recapitulate certain characteristics of the tumor microenvironment. These new models show benefits over other conventional tumor models, and have the potential to accelerate drug discovery and enable precision medicines. However, further research is warranted to overcome their limitations and to properly interpret the data obtained from these models. In this article, key features of the in vivo tumor microenvironment that are relevant to drug transport processes for targeted delivery was discussed, and the current status and challenges for developing in vitro transport model systems was reviewed

EPR Effect-Based Tumor Targeted Nanomedicine

I am honored to undertake the work for Guest Editor for this Special Issue of EPR Effect-Based Tumor Targeted Nanomedicine for the Journal of Personalized Medicine. It has already been 35 years since we published the concept of the EPR effect for the first time. The discovery of the new concept of EPR effect gave an impetus effect of growth momentum in nanomedicine, and numerous works are focused on tumor delivery, although the initial idea was based on vascular permeability in infection-induced inflamed tissue, where we discovered bradykinin in the key mediator of vascular permeability.I know, however, there are pros and cons to EPR effect. Cons stem either from a poor understanding of EPR effect, or somehow a biased view of the EPR effect, or from the tumor models being used, particularly in the clinical settings where vascular blood flow is so frequently obstructed. I hope scientists in the clinic, or basic researchers working on the tumor drug delivery, will join the forum of this Special Issue and express their data and opinions.The scope of this issue includes an in-depth understanding of the EPR effect, and issues associated with tumor microenvironment and also further exploitation of EPR effect in human cancer. In addition, new strategies for enhancement of the EPR effect using nanomedicine will be welcome, which is as important as the EPR effect itself. These papers cover not only cancer therapy, but also imaging techniques using nanofluorescent agents, including photodynamic therapy for inflammation, and boron neutron capture therapy

Magnetic Drug Targeting: Developing the Basics

Focusing medicine to disease locations is a needed ability to treat a variety of pathologies. During chemotherapy, for example, typically less than 0.1% of the drugs are taken up by tumor cells, with the remaining 99.9% going into healthy tissue. Physicians often select the dosage by how much a patient can physically withstand rather than by how much is needed to kill all the tumor cells. The ability to actively position medicine, to physically direct and focus it to specific locations in the body, would allow better treatment of not only cancer but many other diseases. Magnetic drug targeting (MDT) harnesses therapeutics attached to magnetizable particles, directing them to disease locations using magnetic fields. Particles injected into the vasculature will circulate throughout the body as the applied magnetic field is used to attempt confinement at target locations. The goal is to use the reservoir of particles in the general circulation and target a specific location by pulling the nanoparticles using magnetic forces. This dissertation adds three main advancements to development of magnetic drug targeting. Chapter 2 develops a comprehensive ferrofluid transport model within any blood vessel and surrounding tissue under an applied magnetic field. Chapter 3 creates a ferrofluid mobility model to predict ferrofluid and drug concentrations within physiologically relevant tissue architectures established from human autopsy samples. Chapter 4 optimizes the applied magnetic fields within the particle mobility models to predict the best treatment scenarios for two classes of chemotherapies for treating future patients with hepatic metastatic breast cancer microtumors