Venuta, Alessandro (2017) Advanced targeting approaches to drive nanoparticles inside the body. [Tesi di dottorato]

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Item Type: Tesi di dottorato
Lingua: English
Title: Advanced targeting approaches to drive nanoparticles inside the body
Creators:
CreatorsEmail
Venuta, Alessandroalessandro.venuta@unina.it
Date: 11 December 2017
Number of Pages: 148
Institution: Università degli Studi di Napoli Federico II
Department: dep05
Dottorato: phd071
Ciclo di dottorato: 30
Coordinatore del Corso di dottorato:
nomeemail
D'Auria, Maria Valeriamadauria@unina.it
Tutor:
nomeemail
Quaglia, FabianaUNSPECIFIED
Date: 11 December 2017
Number of Pages: 148
Uncontrolled Keywords: Cancer; Nanomedicine; Drug delivery
Settori scientifico-disciplinari del MIUR: Area 03 - Scienze chimiche > CHIM/09 - Farmaceutico tecnologico applicativo
Date Deposited: 19 Dec 2017 11:52
Last Modified: 19 Mar 2019 11:08
URI: http://www.fedoa.unina.it/id/eprint/12237

Abstract

The development of new chemical entities is expensive and time consuming. Therefore, the path taken by research into the last century was directed to find new methods to exploit the already existing pharmaceutical tools. “There’s plenty of room at the bottom” was the title of a lecture delivered in 1959 by Richard Feynman, who introduced the concept of nanotechnology as an important field for future research. This novel science covers areas of biomedical disciplines and engineering involved in the development of materials and devices in the nanometer scale. These systems is nowadays drawing major attention in the medical field for the delivery of therapeutics, especially in the treatment of complex diseases such as cancer. in fact, this malignancy possesses unique features that perfectly suits the concepts underlying nano delivery. Amongst all, the enhanced and permeability retention efffect (EPR) certainly is widely recognized as the rational basis for using nanotherapeutics in the treatment of cancer. EPR is phenomenon by which macromolecules preferentially accumulate in tumor tissues due to immature, tortuous, and multi-fenestrated cancer vessels. Moreover, the opportunity to improve drug pharmacokinetics without affecting the chemical features of the carried molecules, provides not only the ability to overcome several biological obstacles that normally reduce the accumulation of therapeutics into the target area but also to increase their therapeutic impact. The general aim of this thesis was to develop different strategies for the delivery of conventional chemotherapeutics in the field of cancer therapies. Infact, different nanocarriers for cancer treatment have been developed so far basically differing for composition, size and shape, as well as stiffness. Particularly promising are those based on amphiphilic block polyester copolymers (NPs). Polymeric NPs of poly(ε-caprolactone) (PCL) covered with a hydrophilic poly(ethylene glycol) (PEG) can be employed as passive delivery system and possibly decorated with targeting ligands such as folate to accumulate in cancerous tissue. However, the density and conformation of PEG on the surface affect the exposition of small targeting ligands and the receptor mediated cell uptake. In this context Chapter 3 – Shedding light on surface exposition of poly(ethylene glycol) and folate targeting units on nanoparticles of poly(ε-caprolactone) diblock copolymers: beyond a paradigm – is dedicated to PEG-PCL NPs targeted to folate receptor. The impact of preparation method on PEGylation extent and folate surface exposition is fully addressed in the attempt to relate quality attributes of NPs to biological behavior. Although the EPR effect has been postulated to carry NPs and spread inside the cancer tissue, only a small percentage (0.7% median) of the total administered nanoparticle dose is usually able to reach a solid tumor. New strategies based on the microscale and combining different disciplines together such as biology, chemistry, physics and engineering has been proposed to address this issue. The multistage vector (MSV) is an platform that combine nano and microcarriers conceived to overcome the biological obstacles in a sequentially manner. This platform consists of three components. The first stage is a discoidal porous silicon microparticles designed to navigate into the circulatory stream and preferentially adhere to the tumor abnormal endothelial wall. Depending on the application, different types of NPs can be loaded into the pores of the microparticle as second stage. In contrast to the discoidal microparticle, the second stage enter into the cells by exploiting the fenestrature of vascular endothelium and finally releases the third stage, i.e. the therapeutic agent that can be freely selected depending on the application. In addition to this general concept, a new generation of MSV that display additional properties was developed in the attempt to improve the therapeutic performance of the platform. As an example MSV that possesses a biomimetic coating, novel approaches to load multiple types of nanotherapeutics inside the microdiscoidal carrier and more recently the application of this platform to cancer immunotherapy have been proposed. Despite all these applications, this versatile vector has not yet been used to treat brain disease. This is because brain represent a major challange in drug delivery due to the presence of the Blood Brain Barrier (BBB). Within this framework the aim of the project described in Chapter 4 – Strategies to overcome the Blood Brain Barrier (BBB) – is the development of novel approaches based on the combination of micro- and nano-delivery systems to treat brain metastases arisen from primary tumors as melanoma and breast cancer. The idea is to functionalize the micro-vector surface to promote preferential accumulation at the brain microvasculature and after obtaining the intended accumulation, near the endothelial wall, the capacity of transporting simultaneously more than one active component in the porous micro particle. The concept is validated by the development of in vitro and in vivo models. Despite the considerable progress made with NPs, only a limited number of NPs have been approved for clinical use. As an example, Doxil® the first FDA approved formulation for the delivery of Doxorubicin (Dox) is able to reduced systemic side effects compared to the free drugs but not to significantly improve the antitumor effects into the metastatic diseases. This clinical evidence suggests that further delivery approaches needs to be developed and that there is a need for an in depth study of the anatomical knowledge of the EPR. In this context, the aim of the work described in Chapter 2 – Synthesis and characterization of rationally-designed Dextran-Doxorubicin conjugate: a novel strategy to improve the antitumor efficacy of doxorubicin in multiple breast cancer liver metastases – is to develop a rationally-designed Dox-dextran conjugate with appropriate molecular weight (MW) based on estimated EPR effect in established liver metastases to overcome the limited clinical efficacy of PEGylated liposomes and Dox. In the two annexes the development of a novel antibacterial polymeric film of poly(lactic-co-glycolic acid) (PLGA) for the release of nitric oxide (NO) under visible light is reported (Annex I) and a study of the growth of the drug delivery literature published during 1974-2015 was discussed (Annex II).

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