Preparation of pH-sensitive nanoparticles of poly (methacrylic acid) (PMAA)/poly (vinyl pyrrolidone) (PVP) by ATRP-template miniemulsion polymerization in the aqueous solution
GuoxiaChen & Junxiu Liu &YadongYang &LijuanZhang &
Min Wu & Henmei Ni
Received: 4 January 2015 /Revised: 10 February 2015 /Accepted: 23 February 2015 # Springer-Verlag Berlin Heidelberg 2015
Abstract Employing polymethacrylic acid (PMAA) as the template and N-vinyl pyrrolidone (N-VP) as monomer, the
ATRP-template miniemulsion polymerization was carried out in the aqueous medium by using MBP/CuBr/bpy as initiator. The results were characterized by dynamic light scattering (DLS), transmission electron microscope (TEM), and gel permeation chromatography (GPC). It was observed that the stable particles exhibited amphoteric pH sensitivity, namely that in the range of pH 3.0 to 5.0, the particles precipitated, whereas beyond the range the particles were stable and swollen as pH varied. Moreover, the pH range was variable according to the molecular weight of PVP. The results of GPC indicated that the molecular weight of template polymer
PMAA was duplicated by the daughter polymer PVP. Being noncross-linked, unlike the common microgels, the hydrodynamic diameter dramatically increased in a very narrow pH range, e.g., pH 5.5 –6 and 2.0–2.5. Finally, the nanoparticles of PMAA/PVP were applied for the controlled release of rifampicin (RFP) and doxorubicin (DOX).
Keywords ATRP . pH sensitivity . Poly(methacrylic acid) .
Poly(N-vinyl pyrrolidone) .Miniemulsion polymerization
Particles of sensitive polymer allowing a drastical variation of physical state, stimulated by the change of external environment such as temperature [1–5] and pH [6–9], have attracted great interests in the fields of biomedicine and bioapplications.
These particles are considered as the ideal carriers for the drug delivery in human body. Therefore, most of sensitive polymers are biocompatible and water-soluble. For example, poly(N - isopropylacrylamide) (PNiPAm)  is a thermosensitive polymer, exhibiting the change of water solubility at ca 33 °C, whilst poly(methacrylic acid) (PMAA)  is a pH-sensitive polymer which shows the variation of water solubility at different pH. Since the loci of bioapplications are aqueous, the survival of particles consisting of these polymers prior to the drug delivery is always an important topic in the design and preparation of particles, especially for the pHsensitive particles. A lot of methods have been developed to prepare the particles sizing from nanometers to micrometers such as the emulsion polymerization, dispersion/precipitation polymerization, and self-assembly of block polymers as well . However, comprehensively reviewing these methods, methodologically, two strategies have been applied, namely utilizing the hydrophobic polymer segments or aggregates to control the dissolution of water-soluble polymer and crosslinking the water-soluble polymer chains. The latter is well known as the hydrogel. On the view of metabolism, the best drug delivery system (DDS) is those metabolizable easily and quickly soon after the drug is released. Accordingly, the disadvantages of these two strategies are obvious. For example, except for rare hydrophobic polymer like polylactic acid, most hydrophobic polymers are not degradable. As for the hydrogel, it is also difficult to be degraded due to crosslinking structure. Therefore, it is necessary to develop a new type of DDS that is readily to be metabolized.
On the other hand, since the changes of temperature and pH in the body are very weak, the sharp response of particles to a weak stimulus is needed. It is not difficult for the temperaturesensitive polymer, PNiPAM, because its volume sharply
G. Chen : J. Liu :Y. Yang : L. Zhang :M. Wu :H. Ni (*)
School of Chemistry and Chemical Engineering, Southeast
University, Southeast University Road 2, Nanjing 211189, China e-mail: firstname.lastname@example.org
Colloid Polym Sci
DOI 10.1007/s00396-015-3554-3 expands at the low critical solution temperature [1–3]. However, for pH-sensitive polymers like polymethacrylic acid, the volume change is largely dependent to the dissociation of carboxylic acid. The volume gradually expands as pH increases until pH=4.5 near to pKa of methacrylic acid [4, 8, 9]. Moreover, the low pH such as 4.5 is unrealistic in the body on the view of application. Therefore, many approaches have been developed to improve its pH sensitivity [4–12]. A common approach applied to adjust the pH at which the polymer exhibits sharp volume change is the addition of polymers carrying amide or amino groups. For example, the microspheres of poly (MAA-co-acrylamide (AAm)) cross-linked by N, N′methylene bis (acrylamide) (MBA) exhibit a sharp volume transition at pH 4.5 . In particular, the amphoteric microgel of poly (MAA-co-N,N′-dimethylamino ethylenemethacrylate (DMAEMA)) shows a special pH sensitivity. It shrinks in the pH range from pH 6.5 to 8, but greatly expands at pH either less than 6.5 or higher than 8. Additionally, the range of pH can be adjusted with different ratios of MAA and DEAEMA.
However, these microgels are all prepared in ethanol and, unfortunately, cross-linked. In aqueous solution, these microgels cannot be prepared. Therefore, it is necessary to develop a method to prepare the pH-sensitive microgel without cross-linking and simultaneously adjust the pH to the bioenvironmental pH, i.e., pH 6–7, at which the response takes place.
It is well known that the insoluble complexes can formwith two soluble polymers such as polyacrylic acid–polyethylene oxide (PAAc-PEO) and PAAc-polyvinyl pyrrolidone (PVP) in the aqueous solution [11, 12]. Inspired by it and combined with the knowledge of template polymerization  and the mechanism of particle formation [14–16], in this paper, a new method is proposed to prepare the pH-sensitive particles consisted of two water-soluble polymers without crosslinking in the aqueous solution. As shown in Scheme 1, a template polymer H-bond interacts with a monomer. After the template polymer saturated adsorbs the monomer, a globule forms. Selecting an appropriate initiation system that is able to dominantly partition within the globule, the polymerization of monomer will take place solely in the globule and create a nanoparticle. Since the saturated concentration of monomer in the globule is determined by the unit ratio of template polymer and monomer, the length of daughter polymer is adjustable. Accordingly, if a pH-sensitive polymer such as PMAA is selected as the template polymer, whilst PVP is chosen as the daughter polymer, the pH sensitivity of particles will be variable according to length of PVP. This approach has been proven to be feasible . In our previous work, the formation of globule with PVP and MAA was confirmed.