Biomedical Applications

Undoubtedly, the ability to generate nanoparticles and nanostructures in solution and particularly in aqueous solution can be of tremendous benefit for biomedical applications such as therapeutics delivery, tissue engineering, and medical imaging.

In the late 1980s, hydrogels formed by the assembly of block copolymers in water were intensively studied for controlled release applications. The complex mesophase structures formed by the copolymers are ideal for encapsulating and releasing several therapeutic agents in a controlled fashion. In addition, the temperature sensitivity of poly(ethylene oxide) (PEO)-based systems makes these materials very appealing for injectable controlled release systems. This has now expanded into a series of block copolymer-based hydrogels that are rapidly finding applications as functional scaffolds for tissue engineering. Recently, the self-assembling motif has been exploited for the design of peptide copolymers which form very long cylindrical micelles that mimic the extracellular matrix. Similarly, the size of block copolymer micelles and vesicles makes them ideal for therapeutics delivery. Nanoparticles greater than 200 nm in diameter are highly susceptible to opsonization and subsequent phagocytosis by the cells of the immune system. However, particles should also be large enough to avoid excretion via the kidneys. The nanosized dimensions of block copolymer vesicles and micelles provide the advantage of allowing application to the body via direct injection into the blood circulation. Furthermore, the size of micelles and vesicles allows their efficient accumulation in solid tumors via the enhanced permeability and retention (EPR) effect. In addition, there are numerous examples in the literature of the application of amphiphiles to increase the solubility of hydrophobic therapeutic agents, and their subsequent use in drug delivery studies. This can be expanded to hydrophilic therapeutic agents by using vesicles as they are able to enclose aqueous volumes within their structure, allowing encapsulation of both hydrophilic molecules within their aqueous core and hydrophobic molecules within the membrane.

Compared with small amphiphiles, block copolymers offer the advantages of targeting a wider range of compositions and especially molecular weights. Indeed, by varying the copolymer size, we can adjust the size, mechanical properties, and release ability. It is also important to mention that the CACs of amphiphilic copolymers are very low and, in some cases, essentially zero. Thus copolymers have very slow chain exchange dynamics and assemble into locally isolated, non-ergodic structures. In an ergodic system there is equilibrium between molecules in the assembled structure and molecules in solution, but with block copolymers the molecules are essentially locked in the structure, making them non-ergodic. Such slow dissociation rates enable vesicles and micelles to retain their payloads for very long time periods. Furthermore, the absence of molecularly dissolved amphiphilic copolymers in solution prevents cytotoxic interactions with biological phospholipid membranes. These can range from complete cellular membrane dissolution (and hence cell death) in the case of small-molecule surfactants to up-regulation of gene expression and altered cell genetic responses.

The synthetic nature of copolymers also allows the design of interfaces containing various biochemically active functional groups. Several examples of ligand-decorated micelles and vesicles have been reported for targeted delivery applications. In particular, the nonfouling and nonantigenic properties of PEO, and more recently, of poly (2-(methacryloyloxy)ethyl phosphorylcholine) (PMPC) have been combined with hydrophobic polymers in the design of biocompatible nanocarriers. The neutral, and yet very hydrophilic nature of these polymers, permits the design of dense corona with the ability to stabilize either micelles or vesicles that have very limited interactions with proteins and particularly, plasma proteins. Consequently, micelles and vesicles will exhibit very long circulation times in vivo. Particularly remarkable are the data recently reported by Geng et al. showing that PEO-based wormlike copolymer micelles can have circulation times as long as several weeks. As well as the soluble corona, the insoluble domains can also be engineered so as to exploit the sensitivity of specific hydrophobic polymers to external stimuli such as pH, oxidative species, temperature, and hydrolytic degradation. Block copolymer micelles and vesicles are therefore finding applications for the delivery of anticancer drugs and as contrast agents for medical imaging.

Recently, the use of pH-sensitive block copolymer vesicles that achieve high transfection efficiency, exploiting the pH driven transition from vesicles to DNA-complexes. It is not only amphiphilic polymers that can assemble into micelles but, in an aqueous environment, cis-platin and poly(ethylene oxide)-b-poly(R,α-aspartic acid) (PEO-PAA) block copolymers self-assemble into polymer-metal complex micelles. The same concept is repeated in polyion complex micelles, where ionic and nonionic blocks play a crucial role for the final encapsulation and delivery of biological macromolecules such as DNA.