D.
Crespy
*ab,
L. P.
Lv
a and
K.
Landfester
a
aMax Planck Institute for Polymer Research, Ackermannweg 10, 55118 Mainz, Germany. E-mail: crespy@mpip-mainz.mpg.de
bVidyasirimedhi Institute of Science and Technology (VISTEC), 555 Moo 1 Payupnai, Wangchan, Rayong 21210, Thailand
First published on 3rd February 2016
Nanocapsules are key components in new technologies related to biomedicine and materials science. However, their long-term fate after use is still largely ignored. We discuss here a sustainable approach where the products of degradation of the nanoparticles play a significant role in their application because they are also functional molecules. The polymer shell of the nanocapsules is chemically engineered so that the degradation products formed upon chemical damage are useful after their normal use.
We discuss here a sustainable approach where the products of degradation of nanoparticles play a predominant role because they are also functional molecules. This approach considers the lifetime of the nanoparticles. Therefore nanoparticles have to be carefully designed, keeping in mind that the material composing the nanoparticles is used to yield functional degradation products. The approach can be combined with retrosynthetic analysis4 with additional conditions concerning the degradation products. Similarly to the renewable carbon index (RCI) for green chemistry, we define here the active molecule index (AMI). The AMI is the percentage of active molecules within all degradation products of the nanoparticles. We briefly review here the different strategies to synthesize nanocontainers that release functional molecules upon their degradation and discuss their AMI values. We envision the future of colloid chemistry for which the Latin adage “multum in parvo” (much in little) will be truly applied by designing efficient nanocontainers that will serve not only during but also after their lifetime.
The function of nanocontainers can be typically fulfilled at low concentrations.10 This means that concerns about cost and renewable feedstock are less important because they do not represent a large fraction of the materials compared to the matrix in which they are embedded. The most important criteria to design the nanocontainers are their functions, the encapsulation efficiency, and their degradation,11 especially when they are employed for biomedical applications. However, nanotoxicology is an issue and there is no consensus yet on the harmonization of experimental procedures to investigate the toxicity of nanoparticles.12 For biomedical applications, the polymer matrix can be degraded by hydrolysis, oxidation, or enzymatic reactions.13 However, the nanoparticles can have a detrimental effect after their primary function is achieved. It was reported for instance that the degradation of nanoparticles of the popular poly(D,L-lactide), poly(ε-caprolactone), and poly(lactide-co-glycolide) displayed high toxicity for all the tested cell lines at high concentration.14 Usually, the amount of polymer matrix in nanoparticles for biomedicine is much larger than the amount of drugs that is encapsulated in the polymer matrix. Similarly, the polymer shells of microcapsules used for self-healing materials are usually non-useful materials. After the delivery of the healing agents, empty microcapsules remain in the matrix and become a preferential location for crack propagation or attack from external media. They are thus detrimental to the properties of the materials. We discuss here how the synthetic approach employed to design nanocontainers can be modified to implement a useful function to the nanocontainers even after their normal use.
The chemical encoding of active substances in a macromolecular chain was introduced by Ringsdorf for the delivery of drugs16 (see Fig. 1). The polymer comprised several segments that have different roles: a segment ensuring the solubilization of the polymer, the pharmacon to be delivered in the body, and one unit for targeted delivery. Many of such polymers do not contain the unit for targeting and are called polymer prodrugs. A now classical method to transport and release drugs is to conjugate them with a polymer.17,18 Such a strategy can be employed to formulate nanoparticles that are constituted of the polymer–drug conjugate. Several approaches were identified: the conjugation of a drug to a pre-synthesized polymer, the conjugation with a monomer followed by polymerization, and the initiation of a polymerization by a functionalized drug.19 The anticancer drug cisplatin was conjugated to a diblock copolymer forming micelles via hydrazone bonds and the drug could be released to the acidic medium of the tumor cell.20 The advantage of such an approach is that the drug is protected during its transport to the tumor cells. Gemcitabine, also an anticancer drug, was conjugated to reversible addition–fragmentation chain transfer (RAFT) agents for polymerizing squalenyl methacrylate21 and methyl methacrylate.22 The polymers could self-assemble to form nanoparticles in water that allowed for a pH-dependent release of gemcitabine. Similarly, alkoxyamines for nitroxide mediated polymerization (NMP) were functionalized with the same drug to yield nanoparticles.23
![]() | ||
Fig. 1 Model of a pharmacologically active polymer. Adapted from ref. 16. |
However, the quantity of drug compared to the polymer is still low. A method to increase the amount of useful active material incorporated, the so-called AMI value, is to use a drug or another active substance as a monomer or to graft it as a side chain of the polymer with a high grafting ratio.
The concept is particularly simple to achieve when polymers are synthesized by polyaddition or polycondensation reaction because the active molecules to be released can be directly used as monomers and be incorporated in the main chain of the polymer. This is the case for instance for p-coumaric acid24 or morphine25 that was used to form biodegradable poly(anhydride-ester) (Fig. 4a and b) with an AMI of 69 and 52%, respectively. If the drug possesses only one reactive group for polycondensation as is the case with the anti-inflammatory drugs naxopren (AMI = 62%) and ibuprofen (AMI = 64%) that have one carboxylic acid functionality, it can be grafted as a pendant group in the side-chain of polyesters (Fig. 4c).26
The AMI number can also be significantly increased by grafting the drugs on the side-chains of polymers. Up to 43 wt% of paclitaxel could be introduced in the side-chain of the polyacrylic acid segment of a block copolymer.27 The polymers could self-assemble into nanoparticles in water and high antitumor activity was observed in vitro. Another method is to use the drug as a monomer in block copolymers that form nanoparticles in water. Thus, more than 50 wt% of the drug camptothecin could be loaded in nanoparticles by using it as a monomer prodrug that can be cleaved by reduction.28
Interestingly, these strategies can be hence converted for preparing polymer nanocontainers that can release active substances during their degradation as shown in Fig. 2. L-Arginine, which can be employed for dentin hypersensitivity, was copolymerized by interfacial polyaddition in water-in-oil miniemulsions to form nanocapsules.29 This means that the chemical encoding of active molecules can be further implemented into polymer nanocontainers. An example of a very efficient system was reported by Kwon et al.30 Nanoparticles were formed with the polymer poly(vanillin oxalate). The particles could deliver the anti-inflammatory and antioxidant vanillin molecule after oxidation and acidification. An elegant approach is to create a drug–drug conjugate to form nanoparticles. The hydrophilic irinotecan and the hydrophobic chlorambucil, both anticancer drugs, were conjugated via a hydrolysable ester linkage.31 The amphiphilic molecules were used to create nanoparticles, which displayed a longer blood retention half-time compared to free drugs. This allowed for the accumulation of the prodrug in tumor tissues and the ester bond could be cleaved by hydrolysis after cellular internalization. Anticancer activity was demonstrated in vitro and in vivo.
![]() | ||
Fig. 2 Scheme of the nanocontainers with encoded active substances that are released during their degradation. |
The ratio of active molecules to be released can be substantially increased not only by employing the aforementioned strategy but also by designing the nanocontainers as core–shell nanoparticles with a functional liquid core instead of homogeneous monolithic nanoparticles.34 For this, block and random copolymers bearing corrosion inhibitors in the side-chain were used to form nanocapsules with a liquid self-healing agent physically entrapped in the core of the nanocapsules (Fig. 3). The release of the corrosion inhibitors triggered a second release of the entrapped self-healing agent and the system could reach an AMI of 56%. The release rate could also be controlled by the structure of the copolymer, i.e. random or block.
![]() | ||
Fig. 3 AFM and SEM images of block copolymer nanocapsules with corrosion inhibitors chemically encoded in the shell for a triggered release of both the corrosion inhibitor and a liquid self-healing agent present in the core of the nanocontainers.34 |
![]() | ||
Fig. 4 Examples of copolymers with active molecules (marked in blue) as pendant groups in their main chains or side chains showing release of these active molecules after cleavage of the corresponding bond.24–26,32–34 |
This journal is © The Royal Society of Chemistry 2016 |