Multi-Approach Design and Fabrication of Hybrid Composites for Drug Delivery and Cancer Therapy

Drug delivery systems (DDS) have been developed in the last decades to improve the pharmacological properties of free drugs by modifying their pharmacokinetic profile and biodistribution. Major limitations for newly developed drug molecules are the poor water solubility and stability, which can be addressed by DDS. These can protect the drugs from the potentially harsh external conditions found in the biological fluids, and improve their dissolution rate by different strategies, overall increasing the therapeutic activity of the drugs. Additionally, chemotherapeutic agents are nonspecific in nature, leading to deleterious off-target side effects, and poor therapeutic efficacy. Therefore, targeted therapy plays a very important role in cancer treatment, although not without obstacles, since DDS have to overcome a number of biological barriers following their intravenous administration, including renal clearance or opsonization-mediated phagocytosis and efficient extravasation to the tumor. Mesoporous silicon (PSi) micro- and nanoparticles offer numerous benefits for biomedical applications, in particular for drug delivery. Along with a great biocompatibility and biodegradability, PSi possess mesopores (2‒50 nm), where the drugs can be easily loaded and confined in their amorphous state avoiding extensive crystallization, thus, increasing their dissolution rate. However, the release of drugs from this platform is uncontrolled and fast, necessitating the use of strategies to tune the drug release. In this thesis, multiple approaches were used for the design and fabrication of hybrid composites for drug delivery and cancer therapy, including PSi and polymer‒drug conjugate-based DDS produced by different modalities of the microfluidics technology and pH-switch nanoprecipitation. First, the loading and release of drugs with different solubility characteristics from PSi were investigated, and further PSi-lipid and polymer-composites were developed to control the drug release profiles. Overall, it was achieved both a sustained release of hydrophilic and hydrophobic molecules loaded on the PSi and also a reduced initial burst release from the bare PSi particles. Next, PSi-based nanovectors were envisaged for antitumoral applications. A smart PSi-based hybrid nanocomposite with stealth properties was developed, consisting of a pH-responsive polymeric structure assembled on the surface of drug-loaded PSi nanoparticles. This nanocomposite was extremely efficient avoiding drug release from PSi under physiological conditions, while allowing the release of the drug upon acidification of the medium. Remarkably, the nanocomposites avoided extensive macrophage recognition and phagocytosis. Thereupon, a tumor targeted theranostic nanoplatform with dual pH- and magnetic-response capacity was designed. The DDS consisted of a polymeric-drug conjugate nanoparticle containing an imaging agent and decorated with a tumor homing peptide for targeted drug delivery, which was successfully applied for intracellular triggered drug release. Overall, the hybrid composites based on PSi and a polymer-drug conjugate represented an advanced contribution to the field of drug delivery and cancer therapy, and in particular to the development of PSi as a platform for advanced drug delivery applications.Lähestymistapoja lääkeannosteluun ja syöpähoitoon tarkoitettujen yhdistelmävalmisteiden kehittämiseen ja valmistamiseen Uudet lääkeaineet ovat usein huonosti veteen liukenevia, mikä vaikeuttaa niiden annostelua potilaille tai saattaa jopa estää niiden pääsyn markkinoille. Tästä syystä on kehitetty erilaisia menetelmiä, joilla niukkaliukoisista lääkeaineista saadaan tehtyä lääkevalmiste. Valmisteet voivat kuitenkin joissakin tapauksissa sisältää myrkyllisiä apuaineita tai vaatia potilaalle mahdollisesti kivuliaan tai epämukavan annostelutavan. Lisäksi syöpälääkkeiden tapauksessa vaaditaan erityistä huomiota. On tunnettua, että solunsalpaajahoidoissa käytettävät kemoterapeuttiset aineet ovat luonteeltaan epätarkkoja mikä aiheuttaa haitallisia sivuvaikutuksia muualle kuin kohteena olevaan kudokseen sekä johtaa usein matalaan terapeuttiseen tehoon. Siksi viime vuosikymmeninä on kehitetty lääkeannostelumuotoja, joilla voisi parantaa vapaan lääkeaineen farmakologisia ominaisuuksia, muokkaammalla aineiden farmakokineettista profiilia sekä biologista jakautumista. Annostelumuodoilla voidaan eri tavoin parantaa lääkeaineiden liukenemisnopeutta sekä suojella näitä entsymaattiselta hajoamiselta tai hajoamiselta maha-suolikanavassa kulkeutumisen aikana. Lisäksi, kun käytetään edistyneitä lääkkeen annostelumuotoja syövän hoidossa, pystytään rajoittamaan syöpälääkkeiden sivuvaikutuksia ja lisäämään terapeuttista tehoa, välttämällä lääkeaineen ennenaikainen vapautuminen verenkierrossa sekä kohdentamalla aineet kasvainalueelle. Tässä väitöstyössä kehitettiin ja valmistettiin lääkeannosteluun sekä syöpähoitoon tarkoitettuja huokoinen pii- tai polymeeri-lääkeaine −pohjaisia yhdistelmävalmisteita. Valmistusmenetelmät perustuvat mikrofluidiikkaan tai pH-kytkin nanosaostukseen. Väitöstyön ensimmäisessä osassa hahmotellaan lääkeannostelumuotojen käyttöä veteen niukkaliukoisten lääkeaineiden liukenemisnopeuden parantamisessa, samalla kun aineiden vapautumista säädetään pitkäaikaisen terapeuttisen vaikutuksen aikaansaamiseksi. Väitöstyön toinen osa keskittyy kasvainten hoitoon.Siinä kuvataan lääkeannostelumuotojen kykyä estää syövänvastaisten aineiden vapautuminen verenkiertoa kuvastavissa fysiologisissa olosuhteissa sekä näiden kykyä kohdentaa vapautuminen kasvainympäristöön

In vivo dual-delivery of glucagon like peptide -1 (GLP-1) and dipeptidyl peptidase-4 (DPP4) inhibitor through composites prepared by microfluidics for diabetes therapy

Oral delivery of proteins is still a challenge in the pharmaceutical field. Nanoparticles are among the most promising carrier systems for the oral delivery of proteins by increasing their oral bioavailability. However, most of the existent data regarding nanosystems for oral protein delivery is from in vitro studies, lacking in vivo experiments to evaluate the efficacy of these systems. Herein, a multifunctional composite system, tailored by droplet microfluidics, was used for dual delivery of glucagon like peptide-1 (GLP-1) and dipeptidyl peptidase-4 inhibitor (iDPP4) in vivo. Oral delivery of GLP-1 with nano- or micro-systems has been studied before, but the simultaneous nanodelivery of GLP-1 with iDPP4 is a novel strategy presented here. The type 2 diabetes mellitus (T2DM) rat model, induced through the combined administration of streptozotocin and nicotinamide, a non-obese model of T2DM, was used. The combination of both drugs resulted in an increase in the hypoglycemic effects in a sustained, but prolonged manner, where the iDPP4 improved the therapeutic efficacy of GLP-1. Four hours after the oral administration of the system, blood glucose levels were decreased by 44%, and were constant for another 4 h, representing half of the glucose area under the curve when compared to the control. An enhancement of the plasmatic insulin levels was also observed 6 h after the oral administration of the dual-drug composite system and, although no statistically significant differences existed, the amount of pancreatic insulin was also higher. These are promising results for the oral delivery of GLP-1 to be pursued further in a chronic diabetic model study.Peer reviewe

Microfluidic assembly of multistage porous silicon-lipid vesicles for controlled drug release

A reliable microfluidic platform for the generation of stable and monodisperse multistage drug delivery systems is reported. A glass-capillary flow-focusing droplet generation device was used to encapsulate thermally hydrocarbonized porous silicon (PSi) microparticles into the aqueous cores of double emulsion drops, yielding the formation of a multistage PSi–lipid vesicle. This composite system enables a large loading capacity for hydrophobic drugs.Peer reviewe