Stimuli responsive drug delivery systems composed of biocompatible materials for the controlled delivery of chemotherapeutic drugs

Abstract

Introduction: To bring a drug into the market from its synthesis, it takes almost 15 years with a cost of more than $500 million. However, most of the drugs suffer from high side effects, poor adsorption, poor solubility, high drug dosing, minimum efficiency, uncontrolled and nonspecific delivery with high cytotoxicity, which limit their uses. [1, 2] With respect to the chemotherapeutic drugs, the concern should be more because most of the anticancer drugs are highly toxic to the healthy cells and damage the same along with the cancer cells, which results in severe side effects for the patients. [3] These problems can be overcome and toxicity can be reduced if the drugs are delivered through a vehicle that delivers the drugs on demand. To achieve these, a drug delivery system (DDS) having virtues like a) biocompatibility, b) biodegradability, c) ability to release drugs in a controlled way d) high drug loading capacity etc. is required. [4] There are different types of DDS derived from biomolecules, organic molecules and inorganic materials in the past few decades. Among all, liposomal DDS have found pronounced application during the last few years because of their low cytotoxicity, biocompatibility and biodegradability. Liposome based DDS (Doxil, DaunoXome, Mycet etc.) are already approved by FDA and available in the market. [5] Although both organic-based DDS and inorganic-based DDS have been used for a long time, both the systems suffer from problems associated with the drug loading and controlled release. So; it is important to search for a new delivery system which are free from these difficulties. Metal organic framework (MOF) like hybrid materials, which has advantages of both organic as well as inorganic DDS, can be one of the solution for this purpose. [6] Recently, zeolitic imidazole framework (ZIF) which are one kind of MOFs, due to some interesting properties (high loading capacity, biocompatibility and biodegradability) were used as a DDS for various drugs. [7] On the other side, purely inorganic material e.g. mesoporous silica nanoparticles (MSN) because of their large pore volume, high surface area, high drug loading capacity, have become promising for different biomedical applications including bioimaging, bone repairing, drugdelivery etc. [8] But conventional MSN suffer from low drug loading, uncontrolled release rate, cytotoxicity etc. To overcome these problems, several strategies e.g. functionalization of silica with polymer, coating with metal oxides, conjugation with biopolymer etc. have been adopted in the last few year. [9] In this respect, composite materials made from MSN and other hybrid materials (e.g. MOF, ZIF) can be one of the solutions to solve these problems. Therefore, to explore different DDS for chemotherapeutic drugs, in this thesis we described six different DDS based on functionalized liposome, MOFs, ZIFs, MSN, MOF-MSN composite and ZIF-MSN composite. All the DDS presented in this thesis are biocompatible and biodegradable and able to release drugs in a controlled manner over a certain period of time under different external stimuli. Two anticancer drugs ellipticine and Doxorubicin (DOX) were used as model drugs to check the ability of the DDS under different external triggering agents. 1.2. Objectives: The main objective of this thesis is to develop stimuli responsive drug delivery system (DDS) for controlled delivery of chemotherapeutic drugs. On-demand drug delivery or controlled drug release in a particular tissue can be achieved using external stimuli. Although various stimuli are reported so far; but pH gradients remain always a better choice to the scientist to design stimuli-responsive DDS. The reason is that the pH of the human body varies widely from 3 to 7.4 and this wide range gives an opportunity to design DDS that responds towards pH change. For these purpose, in this thesis, different DDS have been prepared, characterized and used for the encapsulation and controlled release of two anticancer drugs ellipticine and DOX. Controlled delivery of ellipticine was accomplished using functionalized liposome and controlled release of DOX was achieved by all other DDS. The drug release can be easily tuned by playing with the external stimuli (e.g. pH). The thesis not only describes the preparation and application of the DDS but it also address different important issues as discussed below. (a) Although liposomes have been used for a long time for developing DDS but bare liposome cannot control the drug release and drug leakage is a commonproblem. How the premature drug release can be controlled and how the stability of the liposome can be increased? (b) The room temperature synthesis of MOFs is a big challenge and use of toxic solvents during the synthesis limits their biological application. So, there is a need to develop room temperature synthetic methodology replacing the toxic solvents and in this respect water would be the best replacement. The thesis highlights how the room temperature synthesis of MOFs in aqueous medium can be achieved? Is it possible to encapsulate the drug molecules without any modification of MOF in post synthetic period? How the drug release can be controlled? (c) So far ZIFs are not used for the controlled delivery of positively charged drugs (e.g. DOX) as ZIFs are positively charged. Is it possible to encapsulate DOX in ZIFs? If so, how the release can be controlled under external stimuli? How the DDS behave in presence of biomimetic surroundings (e.g. in presence of liposome, micelle)? (d) Synthesis of mesoporous silica nanoparticles (MSN) and hollow mesoporous silica nanoparticles (HMSN) are multistep process and complicated. Is it possible to prepare MSN and HMSN in a more feasible method? If possible, then, are they suitable as stimuli responsive DDS? These points are explained clearly in this thesis. (e) Bare MSN suffer from drug leakage and premature drug release. The important question is how to inhibit the drug leakage and fast release from MSN? Is there any possibility to solve these by forming composite of MSN with other materials? These problems are addressed by combining MSN with MOFs and ZIFs and thoroughly investigated as composite DDS for controlled delivery of DOX in presence of pH stimuli.