Nanotechnology has the potential to revolutionize cancer diagnosis and therapy. Advances in protein engineering and materials science have contributed to new nanoscale targeting approaches that may bring new hope to cancer patients.
Active approaches achieve this by conjugating nanocarriers containing chemotherapeutics with molecules that bind to overexpressed antigens or receptors on the target cells.
Nanocarriers can offer many advantages over free drugs. They:
• protect the drug from premature degradation;
• prevent drugs from prematurely interacting with the biological environment;
• enhance absorption of the drugs into a selected tissue (for example, solid tumour);
• control the pharmacokinetic and drug tissue distribution profile;
• improve intracellular penetration.
For rapid and effective clinical translation, the nanocarrier should:
• be made from a material that is biocompatible, well characterized, and easily functionalized;
• exhibit high differential uptake efficiency in the target cells over normal cells (or tissue);
• be either soluble or colloidal under aqueous conditions for increased effectiveness;
• have an extended circulating half-life, a low rate of aggregation, and a long shelf life.
The use of different pharmaceutical nanocarriers has become one of the most important areas of nanomedicine. Nanocarriers first reached clinical trials in the mid-1980s, and the first products, based on liposomes and polymer–protein conjugates, were marketed in the mid-1990s. Later, therapeutic nanocarriers based on this strategy were approved for wider use and methods of further enhancing targeting of drugs to cancer cells were investigated. For a summary of this methods you can read the post entitled 'Cancer nanotechnology, the most important challenges and achievements'.
Nanocarriers are nanosized materials (diameter 1–100 nm) that can carry multiple drugs and/or imaging agents. Nanocarriers can also be used to increase local drug concentration by carrying the drug within and control-releasing it when bound to the targets.
Nanocarriers encounter numerous barriers en route to their target, such as mucosal barriers and non-specific uptake. To address the challenges of targeting tumors with nanotechnology, it is necessary to combine the rational design of nanocarriers with the fundamental understanding of tumor biology.
Despite the variety of novel drug targets and sophisticated chemistries available, only four drugs (doxorubicin, camptothecin, paclitaxel, and platinate) and four polymers have been repeatedly used to develop polymer–drug conjugates.
Lipid-based carriers have attractive biological properties, including general biocompatibility, biodegradability, isolation of drugs from the surrounding environment, and the ability to entrap both hydrophilic and hydrophobic drugs. Through the addition of agents to the lipid membrane or by the alteration of the surface chemistry, properties of lipid-based carriers, such as their size, charge, and surface functionality, can easily be modified.
Liposomes, polymersomes, and micelles represent a class of amphiphile-based particles. Liposomes are spherical, self-closed structures formed by one or several concentric lipid bilayers with inner aqueous phases. They vary in size from 50 to 1,000 nm and can be loaded with a variety of hydrophilic drugs into their inner aqueous compartment and, sometimes, even with water insoluble drugs into the hydrophobic compartment of the phospholipid bilayer.
They are biologically inert and biocompatible. Drugs included in liposomes are protected from the destructive action of external medium. Liposomal vehicles are very effective candidates for noninvasive imagining and targeted drug delivery. I have done my scientific master thesis on Pegilated liposomes for tumor diagnosis and treatment.
If you are interested to research further you can find my publication, along with other interesting researches, at the Journal of Liposome Research, entitled 'In vitro studies on 5-florouracil-loaded DTPA-PE containing nanosized pegylated liposomes for diagnosis and treatment of tumor'. Given their long history, liposome-based carriers serve as a classic example of the challenges encountered in the development of nanocarriers and the strategies that have been tried. For example, PEG has been used to improve circulation time by stabilizing and protecting micelles and liposomes from opsonization, which is a plasma protein deposition process that signals Kupffer cells in the liver to remove the carriers from circulation.
In addition to rapid clearance, another challenge is the fast burst release of the chemotherapeutic drugs from the liposomes. To overcome this phenomenon, doxorubicin, for example, may be encapsulated in the liposomal aqueous phase by an ammonium sulphate gradient.
This method achieves a stable drug entrapment with negligible drug leakage during circulation, even after prolonged residence in the blood stream.
In clinical practice, liposomal systems have shown preferential accumulation in tumours, via the EPR effect, and reduced toxicity of their cargo. I will not go into detail on the EPR effect, because we talked about it in the article 'Cancer nanotechnology, the most important challenges and achievements'. If you want to learn more on the EPR effect please read it.
However, long-circulating liposomes may lead to extravasation of the drug in unexpected sites. The most commonly experienced clinical toxic effect from the PEGylated liposomal doxorubicin is the hand-foot syndrome, but that can be addressed by changing the dosing and scheduling of the treatment.
Other challenges facing the use of liposomes in the clinic include the high production cost, fast oxidation of some phospholipids, and lack of controlled-release properties of encapsulated drugs.
Polymersomes on the other hand have an architecture similar to that of liposomes, but they are composed of synthetic polymer amphiphiles. However, as with polymer therapeutics, there are still no clinically approved strategies that use active cellular targeting for lipid-based carriers.
Micelles, which are self-assembling closed lipid monolayers with a hydrophobic core and hydrophilic shell, have been successfully used as pharmaceutical carriers for water-insoluble drugs.
Organic nanoparticles include dendrimers, viral capsids and nanostructures made from biological building blocks such as proteins.
Dendrimers are synthetic, branched macromolecules that form a tree-like structure whose synthesis represents a relatively new field in polymer chemistry. Polyamidoamine dendrimers have shown promise for biomedical applications because they can be easily conjugated with targeting molecules, imaging agents, and drugs, have high water solubility and well-defined chemical structures, are biocompatible, and are rapidly cleared from the blood through the kidneys, made possible by their small size (<5nm), which eliminates the need for biodegradability.
In vivo delivery of dendrimer–methotrexate conjugates using multivalent targeting results in a tenfold reduction in tumour size compared with that achieved with the same molar concentration of free systemic methotrexate. This work provided motivation for further pre-clinical development, and a variety of dendrimers are now under investigation for cancer treatment.
Although promising, dendrimers are more expensive than other nanoparticles and require many repetitive steps for synthesis, posing a challenge for large-scale production.
Inorganic nanoparticles are primarily metal based and have the potential to be produced with near monodispersity. Inorganic materials have been extensively studied for magnetic resonance imaging and high-resolution superconducting quantum interference devices. Inorganic particles may also be functionalized to introduce targeting molecules and drugs. Specific types of recently developed inorganic nanoparticles include nanoshells and gold nanoparticles.
Nanoshells (100–200 nm) may use the same carrier for both imaging and therapy. They are composed of a silica core and a metallic outer layer. Nanoshells have optical resonances that can be adjusted to absorb or scatter essentially anywhere in the electromagnetic spectrum, including the near infrared region, where transmission of light through tissue is optimal. Absorbing nanoshells are suitable for hyperthermia-based therapeutics, where the nanoshells absorb radiation and heat up the surrounding cancer tissue.
Scattering nanoshells, on the other hand, are desirable as contrast agents for imaging applications. Recently, a cancer therapy was developed based on absorption of NIR light by nanoshells, resulting in rapid localized heating to selectively kill tumours implanted in mice. Tissues heated above the thermal damage threshold displayed coagulation, cell shrinkage and loss of nuclear staining, which are indicators of irreversible thermal damage, whereas control tissues appeared undamaged.
A similar approach involves gold nanocages which are smaller (<50 nm) than the nanoshells. These gold nanocages can be constructed to generate heat in response to NIR light and thus may also be useful in hyperthermia-based therapeutics. Unlike nanoshells and nanocages, pure gold nanoparticles are relatively easy to synthesize and manipulate.
Non-specific interactions that cause toxicity in healthy tissues may impede the use of many types of nanoparticles, but using inorganic particles for photo-ablation significantly limits non-specific toxicity because light is locally directed. However, inorganic particles may not provide advantages over other types of nanoparticles for systemic targeting of individual cancer cells because they are not biodegradable or small enough to be cleared easily, resulting in potential accumulation in the body, which may cause long-term toxicity.
The choice of an appropriate nanocarrier is not easy, and the few existing comparative studies are difficult to interpret because several factors may simultaneously affect biodistribution and targeting. In addition, developing suitable screening methodologies for determining optimal characteristics of nanocarriers remains a challenge. Therefore, successful targeting strategies must be determined experimentally on a case-by-case basis, which is a pretty hard work.
Systemic therapies using nanocarriers require methods that can overcome non-specific uptake by mononuclear phagocytic cells and by non-targeted cells. It is also not clear to what extent this is possible without substantially increasing the complexity of the nanocarrier and without influencing commercial scale-up.
Improved therapeutic efficacy of targeted nanocarriers has been established in multiple animal models of cancer, and currently more than 120 clinical trials are underway with various antibody-containing nanocarrier formulations.
For the doctor, in addition to enhancing confidence through the ability to image the type and location of the tumor, it is undoubtedly needed to construct appropriate therapeutic regimens. Similar to combination drug strategies that may be personalized to optimize treatment regimens, oncologists in the near future may be presented with the ability to choose specific nanocarrier/targeting molecule combinations which could lead to improved therapeutic outcomes and reduced costs.
To further investigate how cancer develop and the pathways of cancer development you can read my post 'How does cancer develop?'
References:
1. Allen, T. M. Long-circulating (sterically stabilized) liposomes for targeted drug-delivery. Trends Pharmacol. Sci. 15, 215–220 (1994).
2. Duncan, R., Vicent, M.J., Greco, F. & Nicholson, R.I. Polymer-drug conjugates: towards a novel
approach for the treatment of endrocine-related cancer. Endocrine-Relat. Cancer 12, S189–S199 (2005).
3. Wong, H.L. et al. A new polymer-lipid hybrid nanoparticle system increases cytotoxicity of doxorubicin
against multidrug-resistant human breast cancer cells. Pharm. Res.23, 1574–1585 (2006).
4. Garcion, E. et al. A new generation of anticancer, drug-loaded, colloidal vectors reverses multidrug
resistance in glioma and reduces tumor progression in rats. Mol. Cancer Ther. 5, 1710–1722 (2006).
5. Lee, E. S., Na, K. & Bae, Y.H. Doxorubicin loaded pH-sensitive polymeric micelles for reversal of
resistant MCF-7 tumor. J. Control. Release 103, 405–418 (2005).
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