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Development of Drug Delivery Systems (DDS)

Three generations of DDS

The essential three generations or stages of drug delivery systems development are described as follow.
First generation of DDS groups simple nanoparticles, which are produced from biodegradable, biocompatible and hydrophobic polymers. The common hydrophobic polymers used to produce such DDS are poly(lactic acid) (PLA), poly(glycol acid) (PGA) and their copolymers as poly(lactide-co-glycolide) (PLGA) [1, 2], peptides and proteins [3-5] for instance. Polyanhydrides were also used as controlled release vehicles [6]. Whatever the polymer used to produce such DDS, these first generation DDS exhibit one main drawback that is to be trapped and removed from blood circulation by the reticuloendothelial system (RES) after the adsorption of opsonins (circulating proteins) on DDS surface.
To overcome this drawback, nanoparticles surface must be modified using a hydrophilic polymer to enhance the repulsion of proteins. This surface modification enables nanoparticles to prolong their circulation time. This type was called Second generation of DDS. The hydrophilic poly(ethylene glycol) was commonly used to produce a hydrophilic shell onto the nanoparticle and this modification is called PEGylation. In this case, hydrophilic PEG chains repulse opsonins and nanoparticles remain in the circulation of blood for a prolonged period. Such nanoparticles are called “stealthy DDS” [7]. Nanoparticles with hydrophilic surface can also be obtained with some other hydrophilic chains. In our lab, polysaccharidic hydrophilic dextran shell has been many times reported [8-10] Further modifications of second generation DDS was made to produce targeting drug delivery systems. Such modifications were made by introduction of specific groups like antibodies against tumor, carbohydrates or peptides that are recognized by cells receptors. This generation is called third generation DDS.
Some DDS based on biodegradable materials were approved by Food and Drug Administration (FDA) and are on the market, as shown in Figure 2 [11].

DDS based on amphiphilic copolymers

Scientists were very interested to develop drug delivery systems based on block amphiphilic copolymers due to their remarkable chemical flexibility [12]. Moreover, their block constituents are generally immiscible, leading to one microphase separation. Since the different blocks are linked together by covalent bonds, the microphase separation is spatially limited and results in self-assembled structures. In the beginning of 90s, the first DDS based on A-B diblock copolymers were investigated by Kataoka’s group [13]. These DDS were based on PEG and poly(aspartic acid) modified by 4-phenyl-1-butanol, PEG-b-poly(ethylene imine) and PEG-b-polylysine. At the same time, another independent Kabanov’s group investigated DDS based on triblock copolymers which are poly(propylene oxide)-b-poly(ethylene oxide)-b- poly(propylene oxide) (PEO-b-PPO-b-PEO). Such DDS are actually under phase III clinical evaluation in Canada. Unfortunately, some problems occur when using such self-assembly structures in human body. For instance, after injection in blood stream, destabilization of such polymeric micelles was observed that leads to a rapid dissociation of the structure and to a burst release of drug. To tackle this problem, various innovative approaches have been tested to modify the micelle cores chemistry [14]: a) To increase the hydrophobicity of the core by attaching pendant groups to the hydrophobic part, such as fatty acids, benzyl groups or cholesterol [15-17]. b) To introduce hydrogen-bond interactions in the core [18]. c) To promote electrostatic interactions by introducing oppositely charged groups in the core [13]. d) To post-crosslink the core via chemical, thermal or photo-induced polymerization [19].
Some examples of amphiphilic copolymers used to produce drug delivery systems and their corresponding encapsulated drugs are resumed in Table 1 [20].

Methods of nanoparticles formation

In the beginning, we would like to mention the definition of nanospheres that may be nanoparticles or nanocapsules (Figure 3). Nanoparticles are composed by a full solid core and nanocapsules present a liquid core. Nanospheres are colloidal objects in the range 10–1000 nm [21, 22].
Nanoparticles can be conveniently prepared by direct polymerization of monomers using classical polymerizations [23]. But, some others methods are commonly used to prepare nanoparticles based on amphiphilic copolymers. One can mention: 1) Nanoprecipitation, 2)
Emulsion/organic solvent evaporation, 3) Dialysis methods that mainly lead to micelle-like structure and sometimes form nanoparticles depending on the copolymer nature.

Nanoprecipitation method

Nanoprecipitation method is a simple, fast and reproducible method, which is widely used for the preparation of nanoparticles. It is also called “solvent displacement method”. Fessi et. al. demonstrated nanoprecipitation since 1989 [24]. Nanoprecipitation system consists of three basic components: the polymer (synthetic, semi synthetic or natural), the solvent (usually organic phase) and the non-solvent (aqueous phase) of the polymer. Used organic solvent (i.e., ethanol, acetone, THF or dioxane) has to be miscible in water and easily removable by evaporation. Due to this reason, acetone is the most frequently employed polymer solvent [24-26]. The basic principle of this technique is based on a rapid addition of the polymer solution into the non-solvent phase resulting in the formation of small particle containing polymers chains when the organic solvent diffuses into the water phase, as shown in Figure 4 [24, 27]. After evaporation of organic solvent then centrifugation, solid nanoparticles are recovered.
Lince et al. [28] indicated that the process during nanoprecipitation comprises three stages: nucleation, growth and aggregation. The rate of each step determines the particle size and the driving force of these phenomena is the ratio of polymer concentration over the solubility of the polymer in the solvent/nonsolvent mixture. The separation between the nucleation and the growth stage is the key factor for uniform particle formation.
The key variables determining the success of this method and affecting the physicochemical properties of nanoparticles are associated with the conditions of adding the organic phase into the aqueous one: copolymer concentration, organic phase injection rate, aqueous phase agitation rate, the method of organic phase addition (position of needle of syringe during addition as inside or above the aqueous phase) and the organic/aqueous phases ratio. Likewise, recovered nanoparticles characteristics are influenced by the nature and weight fraction of blocks in copolymer [29, 30].
In our lab, dextran-g-PLA glycopolymers have been nanoprecipitated successfully [8], for instance. As shown in the Table 2, other amphiphilic copolymers have been used into nanoprecipitation[9]. As shown in Table 2, stabilizing agent may be required for some polymer during nanoprecipitation.

Dialysis method

Dialysis is one another technique to produce small and narrow-distributed nanoparticles [24, 31]. Dialysis is performed against a non-solvent that is miscible with the organic solvent used to dissolve polymers (Figure 5). This method is based on osmosis where a spontaneous net movement of organic solvent molecules through the partially permeable membrane occurs. The displacement of the solvent inside the membrane is followed by the progressive aggregation of copolymer chains due to their loss of solubility. This leads to the formation of homogeneous suspensions of nanoparticles [32]. Usually, copolymers that are insoluble in volatile organic solvents like acetone, THF and DCM or that are soluble in DMF, DMSO, are dialyzed.
Recently, scientists modified this dialysis method by dissolving copolymers in organic solvent that is miscible in water then adding dropwise this solution into water to form nanoparticles. The organic solvent was then removed by dialysis. This method is called nanoprecipitation-dialysis method. Some examples of nano-objects were fabricated by this method. For instance, dextran vesicular carriers [33] have been produced with using block copolymers based on poly(DL-lactide-co-glycolide) [34].
Before studying the self-assembly of amphiphilic copolymers by dialysis, it is very important to estimate the Critical Water Content (CWC), that depends on the copolymer solution concentration. CWC is the critical value of water content to add into the copolymer organic solution, at which the copolymers start to self-associate. Below this CWC, copolymer chains are unassociated. When the addition of water progresses further, more and more copolymer chains associate to form micelles and the concentration of the copolymers in single-chain form decreases. In addition, Critical Micelle Concentration (CMC) of copolymers may be estimated at this CWC. Eisenberg et. al. reported one method to estimate the Critical Water Content (CWC) [35]. The method is measuring scattered light intensity as a function of added water content.
For instance, Schubert et. al. estimated CWC for amphiphilic supramolecular graft copolymers that are based on a poly(methyl methacrylate) (PMMA) backbone with PEG side chains linked to the backbone via a ruthenium(II)-terpyridine complexe (Figure 6)[36] .
The authors dissolved their copolymer in DMF and determined counts per second (CPS) as a function of added water volume as shown in Figure 7. They studied the behavior of three copolymers (A, B, C see Figure 6) with different ratio of hydrophobic/hydrophilic ratio. At low added water content, CPS is low because graft copolymer chains exist as unimers. Then, an increase in CPS is observed because of the formation of aggregates, as proven by the observation of a correlation function. Finally, CPS reaches a plateau value as an indication that the aggregates are already frozen at these water contents and do not further modify their structure (grow for instance). It should however be noted that the CWC of sample A was lower than CWC for B, than CWC for C, according to the increase of hydrophilic PEG blocks weight fraction in copolymers as shown in Figure 7.

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Table of contents :

Chapter (I)Bibliography
I) Introduction
II) Drug Delivery Systems
II.1) Development of Drug Delivery Systems (DDS)
II.1.1) Three generations of DDS
II.1.2) DDS based on amphiphilic copolymers
II.2) Methods of nanoparticles formation
II.2.1) Nanoprecipitation method
II.2.2)Dialysis method
II.2.3) Emulsion/organic solvent evaporation method
II.2.3.a) Single emulsion technique
II.2.3.b) Double emulsion technique
II.3) Smart or sensitive drug delivery systems
II.3.1) pH-sensitive DDS
II.3.2) Thermosensitive DDS
II.3.3) Light sensitive DDS
II.3.3.a) Shifting the hydrophilic-hydrophobic balance
II.3.3.a.1) Reversible shifting hydrophilic-hydrophobic balance
II.3.3.a.2) Irreversible shifting hydrophilic hydrophobic balance
II.3.3.b) Breaking block junction (Figure 14-b)
II.3.3.b.1) Irreversible Breaking Junction
II.3.3.b.2) Reversible Breaking block junction
II.3.3.c) Main degradation (Figure 14-c)
II.3.3.d) Reversible cross-linking (Figure 14-d)
II.3.4) Dual-Stimuli responsive DDS
II.3.4.a) Photo- and pH-Responsive Micelles
II.3.4.b) Photo- and Thermo-Responsive Micelles
II.3.4.c) Multi-Responsive Micelle
II.4) Conclusion
III) Reversible-Deactivation Radical Polymerization techniques
III.1) Reversible-Addition Fragmentation chain Transfer (RAFT)
III.2) Nitroxide Mediated radical Polymerization (NMP)
III.3) Atom transfer radical polymerization
III.3.1) Mechanism of ATRP
III.3.2) Effect of transition metal
III.3.3) Effect of Ligand
III.3.4) Effect of Initiator case of (alkyl halide)
III.3.5) Development of ATRP technique
III.3.5.a) Activator Generated by Electron Transfer (AGET ATRP)
III.3.5.b) Activator ReGenerated by Electron Transfer (ARGET-ATRP)
III.3.5.c) Initiators for Continuous Activator Regeneration (ICAR) ATRP
III.3.5.d) Supplemental Activators and Reducing Agents (SARA ATRP)
III.3.5.e) Electrochemically induced ATRP (eATRP)
III.3.5.f) Photochemically induced ATRP (h􀏅 ATRP)
III.4) RDRP via outer Sphere Electron Transfer (SET) mechanism
III.4.1) How did Percec discover RDRP via outer Sphere Electron Transfer mechanism?
III.4.2) Various types of SET
III.4.2.1) Single-electron transfer degenerative chain transfer living radical polymerization (SET-DTLRP)
III.4.2.2) Single-Electron Transfer Living Radical Polymerization (SET-LRP)
III. Comparing SET-LRP and ATRP mechanisms
III. Factors affecting SET-LRP
III. Effect of zero-valent metal
III. Effect of solvent
III. Effect of Initiator
III. The effect of ligand
III. The effect of adding external CuBr2
III. The effect of inhibitor
III. Monomers
III.5) Conclusion
I) Introduction
II) Synthesis of Photo-sensitive Homopolymer PNBA
III) Synthesis of Amphiphilic Light-Responsive Dextran-g-poly(o-nitrobenzyl acrylate) Glycopolymers
IV) Synthesis of Amphiphilic Light-Responsive Dextran-b-poly(o-nitrobenzyl acrylate)
I) Introduction
II) Elaboration and characterization of nanoparticles
II.1) Nanoprecipitation of Dex-g-PNBA
II.2) Emulsion/Organic Solvent Evaporation method
II.2.1) Surfactant properties of alkynated dextran
II.2.2) Formation of nanoparticles without or with an in situ CuAAC
III) Zeta potential and thickness of dextran shell
III.1) Zeta potential theory
III.2) Case of nanoparticles based on Dex-g-PNBA (FPNBA %= 75% and 85% ) prepared by
III.3) Case of nanoparticles prepared via the emulsion/organic solvent evaporation
IV) Stability of nanoparticles
IV.1) Stability against salt
IV.2) Stability against SDS
V) Effect of UV-light
V.1) Light irradiation of PNBA
V.2) Light irradiation of nanoparticles made by nanoprecipitation
V.2.1) Evolution of nanoparticles chemistry versus irradiation
V.2.1.a) 1H NMR spectroscopy
V.2.1.b) FT-IR spectroscopy
V.2.1.c) pH-meter
V.2.1.d) UV-Vis spectroscopy
V.2.1.e) Conclusions
V.2.2) Selection of optimum experimental conditions using DLS
V.2.2.a) Effect of the medium
V.2.2.b) Mode of irradiation
V.2.2.c) Effect of dispersions concentrations
V.2.2.d) Effect of the UV-lamp power
V.2.2.e) Conclusions
V.2.3) Nile Red Release
V.2.3.a) Release of encapsulated Nile Red dye via diffusion
V.2.3.b) Release of Nile Red under irradiation
V.2.4) Effect of power lamp
V.3) Nanoparticles via Emulsion/Solvent Evaporation method
VI) What is the future of our smart DDS after injection and irradiation?
VII) Cytotoxicity test
VIII) Overall conclusions


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