Long-Circulating Polymeric Drug Nanocarriers - American Chemical

Chapter 2

Long-Circulating Polymeric Drug Nanocarriers

Downloaded by VIRGINIA TECH on July 15, 2013 | http://pubs.acs.org Publication Date (Web): November 26, 2012 | doi: 10.1021/bk-2012-1113.ch002

Wei Wu†,‡ and Xiqun Jiang*,† †Laboratory of Mesoscopic Chemistry and Department of Polymer Science & Engineering, College of Chemistry & Chemical Engineering, Nanjing University, Nanjing 210093, P. R. China ‡Nanjing University Yangzhou Institute of Chemistry and Chemical Engineering, Yangzhou, 225000, P. R. China *E-mail: [email protected]

Nano drug delivery systems (NDDS) can transport anticancer agents to tumor sites via enhanced permeability and retention (EPR) effect to enhance the therapeutic effect and reduce side effects. To give full play of the EPR effect, long-term circulation of NDDS is needed, since it provides the NDDS with better chance to reach and interact with tumor. The blood circulation time of NDDS is determined by their combination properties, such as size, shape, stiffness, surface shielding etc., all of which are important and needed to be considered in designing longcirculating NDDS.

Thanks to the leaky vasculature and impaired lymphatic drainage of tumor that allow nano drug delivery systems (NDDS) with suitable size to extravasate and accumulate in tumor (so-called enhanced permeability and retention (EPR) effect), well designed NDDS can transport anticancer agents to tumor sites in highly targeting mode to enhance the therapeutic effect and reduce side effects. To take advantage of the EPR effect, the long-term circulation of NDDS is needed, since it provides the NDDS with better chance to reach and interact with tumor. However, the NDDS administered intravenously are often rapidly cleared from blood by the reticuloendothelial system (RES), whose main responsibility is to protect the body from the invasion of extraneous substances. This clearance process is initiated by opsonize, in which the opsonins, such as IgG or complement fragments, adhere to the surface of the NDDS and mediate

© 2012 American Chemical Society In Functional Nanoparticles for Bioanalysis, Nanomedicine, and Bioelectronic Devices Volume 2; Hepel, M., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2012.


the recognition and phagocytosis of NDDS by RES. Undoubtedly, the natures of NDDS including their size, shape, surface chemistry and chemical composition determine their ability to avoid the adsorption of opsonins and the recognition of RES and their blood circulation time. Therefore, one important way to achieve the prolonged circulation time is to design and modify the NDDS in size, shape, surface chemistry and chemical composition properly. Here, we overview the achievements in the prolongation of circulation time of polymeric nanoparticles that serve as drug carriers, since polymeric nanoparticle is one sort of the most extensively studied drug carriers and have significant superiority in biocompatibility, biodegradation and tunability (1, 2).

PEGylation of Polymeric Nanoparticles Polyethylene glycol (PEG, Figure 1a) is a kind of hydrophilic, electrically neutral, flexible, biocompatible polymer with low immunogenicity and antigenicity. In 1977, Abuchowski et al. first reported their work on increasing the circulation time of bovine liver catalase by covalently combining PEG (3). Since then, PEGylation has been a popular strategy to ensure the stealth-shielding and long circulation of nano drug carriers including polymeric nanoparticles in the research field of biomedicine (4–12). PEG can interact unstrainedly with water via hydrogen bond due to the good fit of their structures, which renders PEG with high hydrophilicity. The hydration and steric exclusion effect of PEG are considered to play important roles in protein repellence (13). Depending on the PEG density, the PEG layer on the surface of nanoparticles can exhibit mushroom or brush-like configuration (Figure 1b). At relatively low surface PEG density, mushroom-like configuration is often adopted to maximize PEG coverage. With the increase of the PEG density, the surface gets more crowded and the PEG chains tend to stretch due to the enhanced interchain interactions, resulting in a brush-like configuration (9, 14, 15).

Figure 1. a) Chemical structure of PEG; b) Cartoon of mushroom and brush-like configurations of PEG on nanoparticle surface. 28 In Functional Nanoparticles for Bioanalysis, Nanomedicine, and Bioelectronic Devices Volume 2; Hepel, M., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2012.


As stated above, PEG layer on the nanoparticle surface can remarkably improve the stealth property of the nanoparticle matrix. The density, thickness and configuration of the PEG chains are crucial determinants of the effect magnitude. Increasing the PEG coverage can increase the protein repellence, however, when the coverage exceeds a certain degree, the stealth property began to decrease due to the decrease of the mobility and flexibility of the PEG chains induced by the crowding condition (16). For different systems, the optimal PEG density can be quite different, that is to say, the optimal points are strongly related to the intrinsic features of the nanoparticle matrix, such as size, shape, surface charge and compositions etc.. For example, 10 wt% PEG content is reported to be optimal for the dispersibility and stealth property of poly(lactic acid) (PLA) nanoparticles (17) or poly(lactide-co-glycolide) (PLGA) nanoparticles (18). By contrast, in another published work, the optimal PEG content is calculated to be 5 wt% for the protein resistance of PLA, PLGA and polycaprolatone nanoparticles (9). The PEGylation of the polymeric nanoparticles can be achieved by different methods. Conjugating Covalently PEG to the Surface of Nanoparticles The PEGylation of polymeric nanoparticles can be implemented by covalently conjugating PEG to the surface of nanoparticles (19, 20). The maximum PEG coverage for this strategy strongly depends on the density of the reactive groups exposed on nanoparticle surface and their reactivity. When the PEG molecule has one group at each terminus, the reactive groups can be remained at the free end of PEG chains after the conjugation and provide the nanoparticles with functional sites for surface conjugation of other functional molecules, such as targeting or therapeutic agents (20). Incorporation of PEG Copolymer into Nanoparticles Another PEGylation strategy is incorporation of amphiphilic PEG copolymers during nanoparticle formation. This strategy is often started from the synthesis of amphiphilic di- or tri-block copolymer with PEG as a hydrophilic segment followed by assembling the copolymers into nanoparticles. During the assembly of the copolymers, core-shell structure would be formed with the hydrophobic segments as the core of and the PEG moieties as the shell which stabilizes the nanoparticles in aqueous medium and render them desirable stealth property. Biocompatible and biodegradable hydrophobic polymers, such as PLA, PLGA and poly(ε-caprolactone) etc., are frequently used as the hydrophobic blocks of the amphiphilic copolymers to fabricate polymeric nanoparticles. The synthesis of this kind of copolymers is generally achieved by ring-opening polymerization of the corresponding monomers with PEG as a macroinitiator (21–23). The PEGylation efficiency fulfilled by the assembly of PEG-containing amphiphilic copolymers is generally good. For example, it has been reported that the nanoparticles prepared from PEG-PLGA copolymer exhibit much better stealth property than those prepared by directly conjugating PEG to pre-made PLGA nanoparticles (24). 29 In Functional Nanoparticles for Bioanalysis, Nanomedicine, and Bioelectronic Devices Volume 2; Hepel, M., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2012.


Apart from the polyesters mentioned above, the natural polymers, For example gelatin, have also been used to synthesize amphiphilic copolymers with PEG as one block by attaching PEG chains covalently to the backbone of these polymers (25). Although PEG possesses many attractive properties, such as good biocompatibility, low immunogenicity, high hydrophilicity and flexibility, chemical inertness and electrical neutrality, especially high anti-biofouling ability, its intrinsic drawbacks have been progressively perceived by many studies. For example, PEG can induce the complement activation (26–35). Many studies showed that a first dose of PEGylated substance injected intravenously would trigger rapid clearance of a subsequent dose of the same substance injected several days after the first injection, which is referred to as the “accelerated blood clearance (ABC) phenomenon”. It is generally acknowledged that the ABC of the second dose is mediated by PEG-specific IgM produced in response to the first injection (27, 33). The time interval between repeated injections, dose, the species of the loading agents and the physicochemical properties of the PEGylated nanoparticles are the factors influencing the extent of the ABC phenomenon, in other words, the ABC phenomenon can be suppressed by adjusting these factors (34). In addition to the complement activation, PEG coating can interfere significantly with the interaction between nanoparticles and cells and the endosomal escape of the nanoparticles, which would adversely affect the intracellular delivery of drug or other bioactive molecules (36, 37). It is worth noting that both the drawbacks of PEG coating stated above are closely related to the molecular weight (MW)- and surface density of PEG chains, that is to say, when increasing either the MW or surface density of PEG, the effect of PEG coating on complement activation and cellular uptake of nanoparticles would be accordingly increased (38–40).

Poly(N-vinylpyrrolidone) (PVP) Stealth Coating of Nanoparticles Just like PEG, PVP (Figure 2) coating can also effectively prolong the residence of nanoparticles in circulation relative to the naked nanoparticles (34, 41–44). Accordingly, PVP has been looked as a promising alternative to PEG in protecting nanoparticles from opsonization and prolonging their circulation time in blood. PVP has good biocompatibility, high hydrophilicity, electrical neutrality, chemical stability and thus is very promising in biomedical applications. PVP is also a cryo/lyoprotectant. This characteristic enables PVP-coated nanoparticles to be readily redispersed in aqueous medium after lyophilization and renders nanoparticles with long-term stability, which is an advantage of PVP over PEG (42). However, comparing to the performance of PEG in stealthiness, it has been found that the PVP-coated nanoparticles exhibit shorter circulation half-lives than those of their PEG counterparts, which should be determined by the nature of the corresponding polymer, for example, the larger chain stiffness of PVP than PEG leads to the distinctive protein adsorption pattern between the nanoparticles coated by the two kinds of polymer and eventually the different stealth properties of the 30 In Functional Nanoparticles for Bioanalysis, Nanomedicine, and Bioelectronic Devices Volume 2; Hepel, M., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2012.


nanoparticles (42). Despite of the slightly inferior stealthness of PVP with respect to PEG, one unique advantage of PVP is greatly favorable to its application as stealth coating of nanoparticles, namely, the PVP-coated nanoparticles do not trigger ABC phenomenon and have reproducible pharmacokinetics and pharmacodynamics profiles, which has been demonstrated by the studies of Ishihara et al. and is greatly significant to prevent unanticipated side effects and preserve pharmacological activity of the encapsulated drug in clinic, though more researches are necessary to corroborate this conclusion (34).

Figure 2. Chemical structure of PVP.

PVP-coated polymeric nanoparticles are generally prepared by the assembly of the amphiphilic block copolymers containing PVP as a hydrophilic segment in aqueous medium (34, 41–45). Upon synthesizing PVP segments by radical polymerization, the introduction of derivable groups at chain ends is very important to their further derivations, which can be achieved by using derivable group-bearing iniators or chain transfer agents in polymerization (46). Xanthate-mediated reverse addition fragment transfer (RAFT) polymerization has been demonstrated to be a desirable method to the synthesis of PVP, since by this method, MW can be well controlled and the xanthate end group on synthesized PVP could be readily converted to thiol, hydroxyl and aldehyde groups that are very useful in their functionalizations (44, 45).

Polybetaine Stealth Coating of Nanoparticles

Figure 3. Chemical structures of poly(carboxybetaine) and poly(sulfobetaine). 31 In Functional Nanoparticles for Bioanalysis, Nanomedicine, and Bioelectronic Devices Volume 2; Hepel, M., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2012.


Polybetaine, such as poly(carboxybetaine) and poly(sulfobetaine) (Figure 3), is a kind of polyzwitterion including anionic and cationic charges on the same repeat unit and can effectively resist opsonization due to their strong hydration via electrostatic interactions and zero net electric charge in physiological condition (47–50). The polybetaine stealth coating of nanoparticles can be implemented by assemblying the amphiphilic block copolymers containing polybetaine as a hydrophilic segment (51) or by surface modifications with polybetaines through surface-initiated radical polymerization (52, 53). In addition, the abundant carboxylic acid groups along the chain of poly(carboxybetaine) enable the modified nanoparticles to be functionalized with different bioactive molecules, such as drug or targeting molecules, and thus provide a desirable platform for multifunctional nanomedicines (47). Very recently, it has been found that poly(carboxybetaine) are able to improve the stability of proteins without sacrificing the binding affinity of proteins (54). This is an exciting finding and makes a great improvement over the current PEGylation technique, which improves the stability of proteins at the expense of their binding affinity. This finding has significant application potential in the field of protein therapy. It is very important to improve the stability of therapeutic proteins because their low stability in physiological conditions would reduce remarkably their bioavailability.

Size Dependence of the Stealth Property of Nanoparticles Particle size is one crucial determinant of their in vivo behavior including blood circulation time. Small molecules and nanoparticles with diameter less than 10 nm are generally considered to be easily cleared from the body by renal excretion (55, 56). On the contrary, too large nanoparticles can not access the tumor through transvascular pores and fenestrations due to the limitation of the pore cutoff sizes (57). Therefore, moderate size is a prerequisite for nanoparticles to achieve long blood circulation and good passive tumor targeting. Many studies have been performed to understand how the size affects on the in vivo behavior of the nanoparticles that have moderate size between 10-200 nm (58–60). Smaller nanoparticles are frequently demonstrated to have better stealth property and thus longer blood circulation than larger ones with similar surface state. As a typical example, Warren C. W. Chan et al. studied systematically the pharmacokinetic behavior of the PEGylated gold nanoparticles with different size and revealed that with the same PEG molecular weight, the smaller PEGylated nanoparticles have longer blood circulation half-life (58).

Effects of Shape and Stiffness on the Blood Circulation of Nanoparticles Other natures of nanoparticles, such as shape and stiffness, also play important roles in the in vivo behavior. Many studies show that non-spherical shape (61–64) and low stiffness (62, 65) are favorable to the prolongation of the blood circulation of nano vehicles. However, due to the difficulty in controlling the shape or stiffness 32 In Functional Nanoparticles for Bioanalysis, Nanomedicine, and Bioelectronic Devices Volume 2; Hepel, M., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2012.

of the nano vehicles under the same material, size, surface chemistry and other parameters, more studies are needed to understand the ultimate effect of shape and stiffness on the in vivo behavior of the nanovehicles.


Conclusions The in vivo behavior of nanoparticles is determined by their combination properties, such as size, shape, stiffness, surface shielding etc., all of which are needed to be considered in designing long-circulating nanoparticles. Although significant advances have been achieved in particle design and fabrication, more extra effort are required to control more precisely the particle parameters and understand more clearly the interactions between nanoparticles and biological milieu that would direct better the design of the nanoparticles for biomedical applications.

Acknowledgments This work was supported by National Natural Science Foundation of China (No. 51033002) and the Natural Science Foundation of Jiangsu Province (No. BK2010303).

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Long-Circulating Polymeric Drug Nanocarriers - American Chemical

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