3. Why nanocarriers?
Targeted delivery of therapeutic agents
3
Wicki et al., 2015
• Increased efficacy • Decreased side effects • Selective drug release
4. Why nanocarriers?
Changed drug properties and nanocarrier multifunctionality
4
Ferrari, 2005
• Increased drug solubility and stability
• Protection from biodegradation
• Prolonged circulation time
• Simultaneous diagnostics and therapy (theranostics)
5. Challenges and current limitations:
physiological barriers and tumor heterogeneity
5
Adapted from
Rosenblum et al., 2018
Tumor heterogenity
Enhanced permeability
and retention effect (EPR)
is highly variable between
patients and tumors
Hiding from the immune
system
Escaping the endo-
lysosomal system
6. Challenges and current limitations:
nano-bio interactions
6
Rosenblum et al., 2018
Nano-bio interactions
7. Challenges and current limitations:
nano-bio interactions
7
Rosenblum et al., 2018
Particle properties
Pharmacokinetics Release of therapeutics
Cellular uptake and trafficking
Biodistribution
Tumor microenvironment
8. Challenges and current limitations:
safety concerns
8
Complement activation
Hemolysis
Inflammation
Oxidative stress
Impaired mitochondria
Wicki et al., 2015
Size/Size Distribution
Surface Charge
Shape
Porosity
Hydrophobicity
Surface chemistry
Ligand characteristics
Drug loading/release
Biodegradability
Stability/storage
Sterility
Batch-tobatch reproducibility
9. Challenges and current limitations:
in vivo model issues
9
• Most of our current understanding of nanoparticle
behaviour in vivo is based on animal data.
• The development of animal models that closely mimic the
heterogeneity and anatomical histology of human tumors is
crucial.
10. Challenges and current limitations:
manufacturing issues
10
• Physico-chemical properties must be
controlled on a batch-to-batch basis.
• High cost of raw materials.
• Multistep production process required.
11. Opportunities and challenges of nanotherapeutic
strategies
11
Increased efficacy
Decreased side effects
Selective drug release
Prolonged circulation time
Increased drug stability
Theranostics
Physiological barriers
Tumor heterogenity
Nano-bio interactions
Safety concerns
In vivo model issues
Manufacturing issues
12. Literature
12
Ferrari, M. (2005). Cancer nanotechnology: opportunities and challenges. Nature reviews
cancer, 5(3), 161.
Rosenblum, D., Joshi, N., Tao, W., Karp, J. M., & Peer, D. (2018). Progress and challenges towards
targeted delivery of cancer therapeutics. Nature communications, 9(1), 1410
Shi, J., Kantoff, P. W., Wooster, R., & Farokhzad, O. C. (2017). Cancer nanomedicine: progress,
challenges and opportunities. Nature Reviews Cancer, 17(1), 20.
Wicki, A., Witzigmann, D., Balasubramanian, V., & Huwyler, J. (2015). Nanomedicine in cancer
therapy: challenges, opportunities, and clinical applications. Journal of controlled release, 200,
138-157.
14. Challenges and current limitations:
physico-chemical characterization of nanomaterials
14
Wicki et al., 2015
Physico-Chemical Charecterization
Size/Size Distribution
Surface Charge
Shape
Porosity
Hydrophobicity
Surface chemistry
Ligand characteristics
Drug loading/release
Biodegradability
Stability/storage
Sterility
Batch-tobatch reproducibility
Editor's Notes
The limits of conventional cancer therapies, particularly the Lack of selective delivery of anti-cancer compounds and the need to increase the efficacy of the treatment has led to the development and application of various nanotechnologies for cancer treatment. A wide range of nanomaterials based on various compounds have been employed for the development of new cancer therapeutics. These include lipid or polymer based nanocarriers, inorganic nanoparticles, drug conjugates and even viral nanoparticles using tumor-homing viruses (viruses which preferentially replicate in tumor cells) engineered to express therapeutic proteins.
Nanocarriers - nanoparticles loaded with anti-cancer compounds.
Drug conjugates: The active agents are covalently linked to targeted antibodies and peptides or to polymers. The conjugate is usually mono- or oligomeric, intended to improve targeted delivery of the drug without necessarily impacting on drug solubility, stability, or biodegradability.
There are different strategies for targeted delivery of therapeutic agents using nanocarriers. These techniques aim to make the treatment more efficient, Decrease side effects and allow Selective drug release.
Passive targeting strategy can alter the biodistribution of drugs by allowing them to accumulate preferably at the tumor site with the phenomenon known as enhanced permeability and retention effect (EPR). This effect is due to leaky tumour vasculature and poor lymphatic drainage so the nanoparticles accumulate in the tumor area. However, studies show, that this is not very efficient. That’s why more advanced targeting techniques were developed. In the case of active targeting, a high-affinity ligand is attached to the surface of a nanocarrier. The ligand binds selectively to a receptor on the target cell which allows targeted delivery of the drug. The ligand must be chosen in a way to allow binding to the target cells while minimizing binding to healthy cells which is in itself a difficult task.
Even though passive targeting has many flaws, they are most clinically available nanocarrier-based cancer therapeutics. A number of passively targeted NCs are currently in clinical use while actively targeted nanomedicine drugs have been developed at a preclinical level, a few have entered early clinical testing and none of them have been approved for commercial use yet.
For efficient targeting, nanocarriers should also be stable enough to avoid premature release and degradation of the drug in the circulation. To precisely control drug release, various stimuli-responsive NPs have been developed. In general, these NPs are designed to recognize environmental changes associated with either the Turmor MicroEnvironment and tumour cells (for example, pH) or to be activated by external stimuli (for example, heat, light, magnetic field or ultrasound), triggering the release of the payload . The advantage of using stimuli-responsive systems is obvious: the drug is released through a trigger present in the neoplastic tissue, thus minimizing systemic exposure to the compound. Some nanocarriers are responsive to magnetic field so the nanocarrier can be guided to the tumor with high specificity and release its payload at the target site using a stimulus, such as heat.
Packing drugs into nanocarriers may also change some properties of the drug, for example Uptake and delivery of poorly soluble drugs may be increased by enveloping the compound in a hydrophilic nanocarrier. At the same time, this may increase chemical and in vivo stability, protecting it from biodegradation and prolonging its’ circulation time.
Another good feature of nanocarriers is the opportunity to make them multifunctional. Multifunctional nanocarriers have the capability to perform several functions in parallel, such as co-delivery of drugs for combination therapies, or simultaneous diagnosis and therapy. Numerous types of multifunctional nanocarriers have been developed at the proof-of-concept level and are expected to enter clinical development shortly.
Thousands of publications suggest that nanomedicine therapeutics are effective in cancer treatment, both in vitro and in vivo. However, only very few nanocarrier-based cancer therapeutics have successfully entered clinical trials and only about 15 passively targeted nanocarriers have been approved for clinical use so far.
Thus, it is important to address the challenges in developing optimized nanomedicine products for clinical use.
As discussed previously, passive targeting techniques rely on EPR effect, which allows the nanocarriers to accumulate in the tumor. however it is increasingly clear that EPR varies substantially between both patients and tumour types, and even within the same patient or tumour type over time. Nevertheless, only a small percentage of these NCs accumulate even in high-EPR xenografted tumors.
In addition, nanocarriers have to hide themselves from phagocytes, otherwise the clearence of NCs will occur, reducing their half-life and effective dose.
Many nanomedicines act on intracellular targets so the uptake of NCs by the target cells and their escape from the endo-lysosomal system is crucial for these types of therapeutics to work.
Heterogeneity of the tumor and its stroma can severely impact the efficacy of drugs delivered by passive and active targeting. For passive targeting this can result in reduced transport of the compound into the tumor and the majority of active, cell-specific NCs target a single cell-surface receptor on tumor cells so it may target some tumor cells and ignore the others. The complexity and the heterogeneity of tumours make it clear that careful patient selection is required to identify those most likely to benefit from a given nanotherapy. Of course scientists are working hard on these issues and promising solutions have been developed.
When a NP enters a biological environment (for example, blood), its surface is rapidly covered by various biomolecules (typically proteins), leading to the formation of a so called ‘corona’. The adsorption of proteins alters the properties of nanocarriers and may lead to mistargeting.
The properties altered are size, stability and surface properties that may change the biodistribution, cellular uptake and trafficking of the nanoparticle, pharmacokinetics, release of the drug, interactions with Tumor Microenvironment, and toxicity.
There may be undesirable interactions between NCs and the immune system, which in turn could lead to immunostimulation or immunosuppression.
To address this issue several studies have extensively characterized the protein corona (for example, its composition, density, conformation, thickness, affinity and dynamics) on certain nanomaterials but still too little is known.
Also, the use of nanoparticles makes it necessary to address toxicity issues for the human health and environment. Multiple factors modulate the toxicity of nanomaterials, such as size, shape, surface area, and others. The many variables involved make it hard to fully toxicologically characterize nanomedicine products. Acute toxicity of nanomedicine compounds usually are complement activation, hemolysis, inflammation, oxidative stress, or impaired mitochondrial function.
Apart from medical issues, environmental concerns have also been expressed.
It is important to point out that most of our current understanding of NP behaviour in vivo is based on animal data, and its translation to NP behaviour in humans remains largely unexplored. Diverse animal models are currently available, however, no single model can fully reproduce all aspects of human malignancy. The translation of nanotherapeutics may be greatly improved by the development of animal models that mimic closely the heterogeneity and anatomical histology of human tumours.
Manufacturing of nanomedicine products for commercialization is technically challenging. Usually, preclinical and early clinical studies are carried out with a small amount of nanomaterial. In large-scale production, batch-to-batch variations of physical and chemical properties may occur. Therefore, manufacturing of nanoparticle based cancer therapeutics at an industrial level requires tight control of physico-chemical properties on a batch-to-batch basis. This makes the chemistry, manufacturing, and control process more demanding. Well-defined production steps are required. The high costs of the raw materials and the need for a multistep production process make the production of nanomedicine therapeutics expensive. This may discourage pharmaceutical companies from taking up large-scale production of nanocarriers and/or make these drugs too expensive for the majority of human population.
To sum up, nanotherapeutics offer great opportunities and even though nanomedicine is very promising, there are many challenges to be addressed. When we‘ll gain a more full understanding nanoparticle behaviour in biological systems and cancer itself, nanoparticles might be one of the more promising approaches to treatment. However this might take a lot of time, since cancer is a very complex disease.
In general, the main physico-chemical features of nanocarriers are structure, composition, size, surface properties, porosity, charge, and aggregation behavior. even small variations in nanoparticle properties and physicochemical characteristics can dramatically affect NC behavior and can alter biocompatibility, toxicity, extravasation, accumulation, interactions with physiological barriers, tumor microenvironment and in vivo outcomes. Therefore, nanomedicine products should be characterized on a batch-to-batch basis, using multiple methods. Nanocarriers may interact with biological fluids (e.g. blood serum) or biomolecules (e.g. proteins) as discussed earlier, which may lead to aggregation or agglomeration of particles and other issues. Such interactions can significantly alter the function of nanomedicine compounds in biological systems.
There is a substantial need to improve quality assessment of nanomaterials by developing well-defined and reproducible standards. Moreover, in vitro and in vivo models accurately representing the clinical setting must be developed.