The therapeutic efficacy of drugs is dependent upon the ability of a drug to reach its target, and drug penetration into tumors is limited by abnormal vasculature and high interstitial pressure. Chemotherapy is the most common systemic treatment for cancer but can cause undesirable adverse effects, including toxicity to the bone marrow and gastrointestinal system. Therefore, nanotechnology-based drug delivery systems have been developed to reduce the adverse effects of traditional chemotherapy by enhancing the penetration and selective drug retention in tumor tissues. A thorough knowledge of the physical properties (e.g., size, surface charge, shape, and mechanical strength) and chemical attributes of nanoparticles is crucial to facilitate the application of nanotechnology to biomedical applications. This review provides a summary of how the attributes of nanoparticles can be exploited to improve therapeutic efficacy. An ideal nanoparticle is proposed at the end of this review in order to guide future development of nanoparticles for improved drug targeting in vivo.
The first discovery of enhanced permeability and retention (EPR) by Matsumura and Maeda [
Tumor vasculature is well characterized as hyperpermeable, immature, and with elevated interstitial fluid pressure, all of which are conducive to an EPR effect. This effect can vary significantly, not only among patients, but also across different tumor types and even changes for the same tumor over time [
An ideally designed NP should avoid clearance by the mononuclear phagocytic system, should remain in the blood circulation for a long time to ensure sufficient accumulation in the targeted tissues, should be internalized by the target tissue, and finally should have low toxicity. Modifying the physical properties of NPs such as size, charge, and shape, could result in changes in the therapeutic efficacy [
Active versus passive tumor targeting. In active targeting, the drug needs a receptor at the tumor surface, whereas in passive targeting, the drug enters the target cells passively.
Once introduced in the human body, NPs will face many obstacles before eventually interacting with the tumor including the protein corona and other biological barriers.
Nanoparticles are being intensely researched as vehicles to deliver therapeutic drugs to a diseased site. It has become clear that slight changes in the physicochemical properties of NPs have significant biological implications. Most NPs that come into contact with biological materials are coated by a wide variety of proteins, which is named the “protein corona.” One component of the NP corona (called opsonins) can enhance the NP uptake by the RES. Under physiologic conditions, the corona may alter the NP properties by masking its surface characteristics [
This figure shows how NPs are coated with proteins once they enter the blood circulation; after a short period of time, proteins came in close contact and form soft corona, and then a final hard protein corona is formed around the NPs containing a fingerprint specific for each individual and tumor.
Some studies have suggested that the formation of the protein corona is an undesirable process; however, others have discussed the advantages of this formation, such as reducing the cytotoxic effect, eliminating undesirable interactions with the immune system, and facilitating cellular internalization [
As was said before, a single change in the physical properties of NPs may change the composition of the protein corona. Treuel and Nienhaus [
For example, immunoglobulin binding to the NPs is called particle opsonisation and as a consequence leads to a rapid receptor-mediated phagocytosis uptake [
The corona may also increase the targeting capability of the NPs, if the binding site of the NPs is governed by the protein corona itself. In order to exploit this mechanism, it is necessary to understand which proteins deliver the NPs to which location [
At the present time, a large gap still exists in the understanding of the basic laws that govern the protein corona formation. Since the corona is the first interaction between the NPs and the tumor, it is essential in the future to establish a mathematical model to predict NP-surface interactions. What is clear now is that the final corona around the NP contains a so-called “fingerprint,” which is related to the type of tumor, the physical characteristics of the NPs, and the stage of the tumor.
Once administered, NPs may encounter many obstacles in reaching the target site. For intravenously administered NPs, the first barrier is the reticuloendothelial system (RES) consisting of the liver and spleen, which rapidly removes many particles from the circulation. In addition, the endothelium of blood vessels within the target tissues is also a barrier [
If the NPs succeed in escaping from the blood capillaries, they face a third barrier in the interstitial space composed of collagen and elastic fibers composed of glycosaminoglycans and other proteins that form the extracellular matrix (ECM). In diseases such as liver fibrosis and neoplasia, the collagen content is higher than that of normal tissues [
Some NPs will release their contents spontaneously once they have extravasated into the tumor, while other release their contents in response to a stimulus such as hyperthermia, laser exposure, or magnetic fields. The released drug will interact as usual with nearby cells. Because NPs cannot simply enter the target cells via diffusion, the next barrier for NPs is the plasma membrane. The mechanisms by which NPs are internalized by the target cells include pinocytosis, phagocytosis, or endocytosis [
The mechanism of internalization depends on the NP properties as well as the size and type of cells involved. If NPs are released from endosomes and lysosomes, they can diffuse in the cytoplasm and could enter the cell nucleus. Usually the membrane of the nucleus does not allow entry of NPs larger than 9 nm, providing yet another barrier [
The two most commonly studied parameters that affect NPs biodistribution are the size and the shape of nanoparticles; however, the charge and the coating surface of the NPs may play some role in biodistribution.
The therapeutic effect of NPs can be limited by their nonspecific systemic biodistribution, which can cause systemic toxicity and lead to reduced concentrations of drug delivered into the tumor (less than 5%). In order to enable diverse application of NPs, it is crucial to study the biodistribution of different-sized NPs, to gain a clear idea of what size NPs to use and for what kind of treatment.
Sonavane et al. [
The size of the NPs will also affect their clearance from the circulation. Renal clearance is very rapid for particles with diameters smaller than 5-6 nm, while clearance by the liver and the spleen is rapid for larger particles, above 200 nm in diameter [
Cytotoxicity is also affected by NP size; the smaller the size, the greater the toxicity. Gao et al. [
Biodistribution of NPs with different sizes in the liver, spleen, tumor, kidney, brain, and lung.
Authors | NP size | Liver | Spleen | Tumor | Kidney | Brain | Lung | Other |
---|---|---|---|---|---|---|---|---|
Li et al. [ | 6.2, 24.3, 42.5, and 61.2 nm mean diameter | High 42.5 and 61.2 nm | High 42.5 and 61.2 nm | 6.2 and 24.3 nm | 6.2 and 24.3 nm | 6.2 and 24.3 nm | 6.2 and 24.3 nm | |
Sonavane et al. [ | 15, 20, and 100 nm | High % for all | High % for all | 15 > 20>100 nm | High % for all | (i) 15 nm low % | (i) 15 and 20 nm high % | (i) 15 nm absent |
Tate et al. [ | 20 and 100 nm | High 20 nm < 100 nm | High for all | 20 > 100 nm | 20 < 100 nm | Traces | High | — |
Takeuchi et al. [ | 20, 50, and 100 nm | High % for all | High for all | 20 > 50>100 nm | 20, 50, and 100 nm Moderate | (i) 20 nm moderate% | Moderate | Traces |
Dziendzikowska et al. [ | −20 and 200 nm silver NP(AgNPs) | (i) 20 nm high % (24 h) | (i) 20 nm high (7 days) | Absent for both | (i) High % 20 nm | (i) 20 nm Moderate % | (i) 20 nm high % after 7 days | (i) 20 nm traces |
It can be concluded that the smaller the size of NPs, the more accumulation found in the spleen, liver, and lung than the kidney; a moderate concentration could accumulate in the tumors and only a low quantity is able to cross the blood brain barrier to accumulate in the brain, whereas the higher the size (+100 nm), the greater distribution in the liver, kidney, and spleen. None of these studies found a good distribution in the brain and only traces of large diameters were found in the tumor.
Effect of varying the NPs size on tissue biodistribution of patient with breast cancer. A 100 nm NPs mostly distribute in the liver, spleen, and kidney, and traces could be found in the breast, whereas, for 20 nm NPs, they mostly distribute in the kidney, spleen, and liver; a moderate amount is able to reach the breast tumor and traces were found in the brain.
While NP size is the principal parameter that affects macrophage uptake, the shape of the NP also plays a major role in enhancing or inhibiting the uptake and biodistribution [
When NPs come into contact with macrophages, the contact angle that initially occurs subsequently dictates the rate of internalization. A particle that aligns with its long axis parallel to the cell membrane would be internalized more slowly than NPs that align with the short axis parallel to the cell membrane. The rod-shaped NPs are internalized more quickly when they are perpendicular to the axis of the cell
Effect of contact angle on the internalization efficacy. Nanoparticles having a prolate ellipsoid morphology (major axis 0.35–2 nm, minor axis 0.2–2 nm) had the slowest internalization rate and the highest attachment rate in comparison to spheroidal morphology (radius 0.26–1.8 nm) and oblate ellipsoidal nanoparticles (major axis 0.35–2.5 nm, minor axis 0.2–2 nm) [
Thus, it can be concluded that the size, shape, and the aspect ratio are the major factors that affect the macrophage uptake of NPs.
The surface charge on NPs is usually measured as the zeta potential (
Negatively charged NPs have a higher diffusion coefficient and penetrate the skin more rapidly, whereas positively charged NPs show the opposite behavior [
It seems that the distribution of NPs in the kidney is not affected by the NP charge [
Hepatic clearance can be influenced by the NP surface charge. NPs with high negative (<−10 mV) or positive (>10 mV) surface charge were efficiently cleared by the liver Kupffer cells from the blood circulation [
Effect of different NPs charges on tissue biodistribution: charged NPs are cleared rapidly by the immune system.
Authors | NPs type | Charge | Uptake | Biodistribution |
---|---|---|---|---|
Xiao et al. [ | PEG-micellar nanoparticles | Surface charge: high negative (<−10 mV) and high positive | High uptake by slightly negative charged NPs | All charged NPs cleared by the Kupffer cells |
He et al. [ | Polymeric NPs | Negative (−10 mV) neutral and positive charge (+35 mV) | High uptake of slight negative charged NP | Liver > spleen > lung > tumor > kidney > blood |
Walczak et al. [ | Polystyrene NPs 50 nm | Negative (−7, 7 mV) positive NPs and neutral | High uptake of negatively charged NPs than the neutral and positive one | Kidney > heart > stomach > small intestine |
Verma et al. [ | Encapsulated paclitaxel | Negative pectin NPs | — | (i) Major accumulation in liver > kidney > lung > spleen |
NPs deployed in vivo can be protected from the immune system using various types of coating. Polyethylene glycol (PEG) has been used widely because it is biocompatible, chemically inert, and soluble in water and organic solvent [
Despite the advantages of using PEG as coating, several new reviews describe the immunogenic properties of PEG which is characterized by the production of antibodies against PEG after the first injection of PEG-NPs. This causes accelerated blood clearance (ABC) after the second injection [
Many factors affect the PEGylation of NPs including the PEG polymer identity, the composition, density, hydrophobicity, and the nature of the proteins. These criteria should be properly regulated and adapted to avoid unfavorable effects of PEGylation [
In Table
Effect of NPs coating on tissue biodistribution.
Authors | Nanoparticle | Coating added | Distribution |
---|---|---|---|
Zhang et al. [ | Gold NPs | Zwitterionic polycarboxybetaine (PCB) | PK behavior was unchanged, no antiuricase detected, no anti-PCB antibodies detected |
Rodriguez et al. [ | 160 nm nanobeads | CD47 “self” peptides | Prolonged drug circulation by delaying phagocytic clearance by the liver and spleen |
Kreuter et al. [ | poly(butyl cyanoacrylate) nanoparticles | Polysorbate 80 | enhanced drug delivery beyond the blood-brain barrier |
Parodi et al. [ | Nanoporous silicon particles (NPS) | Membranes purified from white blood | Prolonged circulation time |
Hu et al. [ | Polymeric nanoparticles | Erythrocyte membrane | Prolonged circulation time |
Romberg et al. [ | Liposome | Poly(hydroxyethyl-L-asparagine) (PHEA) | Longer blood circulation times than PEG liposomes. The second injection less rapidly cleared from the circulation than the second dose of PEG liposomes |
Lila et al. [ | Liposome | Polyglycerol (PG) | Reduced effect of ABC when using polyglycerol compared to PEG |
The physicochemical properties of NPs (size, shape, charge, and surface coating) influence both tissue biodistribution and tumor uptake. Some properties play a major role on biodistribution and a minor role in tumor uptake. Furthermore, some properties are more pronounced in vitro than in vivo. In this part, we will discuss each property and how it may affect the tumor uptake.
Intravenously administered NPs should be able to circulate in the bloodstream for a long time to have a good chance of reaching the tumor vasculature and then extravasating into the tumor tissue. Additionally, these NPs should not cross the vessel walls in normal tissues thereby causing adverse effects. As the pore size of normal vessels is between 6 and 12 nm, this would suggest that nanoparticles should be larger than that size [
The next consideration is the interaction between NPs and the openings in the tumor vessel wall. There are three kinds of interactions: hydrodynamic interactions due to forces induced by the motion of the particles within the fluid medium; steric interactions due to collisions of the particles with the wall; and electrostatic interactions due to attraction or repulsion between charged particles and the negatively charged glycocalyx on the surface of the vessel wall [
These types of interaction are controlled by the ratio between the sizes of the particles and the size of the openings in the vessel wall. When this ratio is small, transport is facilitated, whereas the transport of particles that approach the size of the openings is hindered and the particles are unable to pass through the wall [
Different techniques can be used to alter the NP size. Wong et al. proposed a multistage system where 100 nm NPs (QDGelNPs) with a core composed of gelatin and a surface covered with quantum dots (QDs) “shrink” to 10 nm nanoparticles after extravasation from leaky regions of the tumor vasculature. Protease enzymes in the tumor degrade the 100 nm gelatin NPs, releasing smaller 10 nm NPs from their surface [
By referring to Table
Effect of NPs size on tumor penetration: the smaller the size, the higher the probability of tumor uptake.
Author | Nanoparticle type | Nanoparticle size | Tumor type | Tumor penetration efficacy |
---|---|---|---|---|
Cabral et al. [ | Drug loaded polymeric micelles | 30, 50, 70, 100 nm | Two cancer type (high and low permeable) | Only 30 nm penetrate poorly permeable cancer |
Ezealisiji and Okorie [ | Silver NPs | 22, 58, 76, 378 nm | Dermatological application | 22 nm exhibit the highest cumulative amount (penetration) |
Arvizo et al. [ | Gold NPs (without any surface modification) | 5, 10, 20 nm | Human umbilical vein endothelial cells | 20 nm Maximum effect anti-angiogenic effect(VFGF inhibition) |
Peretz et al. [ | Gold nanoparticles | 15, 30, 90, 150 nm | Head and neck cancer cells | 15 nm best binding capacity to cancer cells & 90 nm is optimal for cell targeting and tumor accumulation |
Popović et al. [ | Quantum dots | 12, 60, 125 nm | Melanoma in mouse | Rapid penetration for `12 nm NP |
Sonavane et al. [ | Gold nanoparticles | 15, 50, 100, 200 nm | Mice (different organ), intravenous administration | 15 nm wide organ distribution, only 15 and 50 nm pass blood brain barrier |
Huang et al. [ | PVP-coated iron oxide nanoparticles (PVP-IOs) | 37–120 nm | Hepatic lesion in mouse | 37 nm greatest cellular uptake |
Hemant et al. [ | Gold NPs | 1 to 125 nm (intravenous) | Different pore size | Rapid penetration for `12 nm NP |
Huang et al. [ | Gold nanoparticles (AuNPs) | 2, 6, 15 nm | Breast cancer cells | 2 and 6 nm Maximum tumor uptake and permeability. 2 & 6 nm found in nucleus and cytoplasm whereas 15 nm only in cytoplasm |
The behavior of the NPs in contact with the cell membrane was studied in detail by Islam et al. in order to elucidate the effect of particle size that came into contact with the cells; they developed a model which enabled multiscale simulations under both diffusion and advection (horizontal flow) conditions (see Figure
Illustration of the time-adaptive BD algorithm: the green circle represents the NPs, the large gray area represents the cells, and
Nanoparticles can have different shapes, including filamentous, spherical, rod-like, or discoidal. Different techniques can be used to create a specific shape, including jet and flash imprint lithography (J-FIL) [
Filamentous nonmaterial (e.g., potato virus X) has been reported to have superior tumor-homing and pharmacokinetic properties compared to spherical particles [
Filamentous NPs (filomicelles) persisted in the circulation longer than spherical particles. When they are PEGylated (i.e., coated with polyethylene-glycol), this effect of filomicelles was further enhanced. Filomicelles have been shown to enter cells under static incubation conditions [
Table
Effect of different shapes of NPs on tumor penetration.
Author | Nanoparticle type | Nanoparticle shape used | Type of treatment | Efficacy |
---|---|---|---|---|
Agarwal et al. [ | Gold NPs | Nanohydrogel; cylindrical; nanorods; spherical NPs | 3D spheroid model | Better effect of cylindrical hydrogel NPs |
Christian et al. [ | Micelles | Filamentous and spherical | Mouse xenograft tumor | High tumor accumulation of filamentous |
Lui et al. [ | Single-walled carbon nanotube (SWNT) | Carbon nanotubes | Cancer in mice | Tumor targeting effect |
Bartczak et al. [ | Gold NPs | Spherical, rod, hollow, silica-gold, core shell | Human endothelial cell uptake | High cellular uptake for the spherical and the lowest for the hollow shapes |
Tak et al. [ | Shaped silver NPs (AgNPs) | Rods, spherical, triangular | Skin permeability in hairless mice | Nanorods had maximum penetration |
Champion et al. [ | Nonspherical polystyrene particles | Spherical and filamentous | Cancer | Spherical shapes showed better tumor homing |
Champion and Mitragotri [ | Non-cross-linked polystyrene (PS) | Spheres, ellipsoids, elliptical disks, prolate ellipsoids, rectangular disks | Uptake by macrophages (phagocytosis) | Elongated NPs showed negligible phagocytosis |
Kessentini and Barchiesi [ | Gold NPs | Nanorods; spheroids; cylinders; capped cylinders, nanoshells; hollow nanospheres | Shallow skin cancer and deeper cancer | (i) Nanospheres for shallow cancer |
Bruckman et al. [ | PEGylated tobacco mosaic virus | Nanorods and nanospheres | Blood circulation | Prolonged circulation of nanorods better than nanospheres |
Geng et al. [ | Paclitaxel-loaded filomicelles | Spherical and filamentous (filomicelle) | Blood vessels of rats and mice | Longer circulation of filomicelles |
Uhl et al. [ | Polymeric NPs | Sphere, short rod, long rod | Microfluidic device (transport in blood vessel) | Best treatment required combination of different shaped NPs administered at different times |
All the studies agreed that nanorods, discoidal, and micelles showed better tumor targeting accumulation and longer circulation. One study found better cellular uptake of spherical NPs compared to other shapes.
After escaping uptake by the macrophages, NPs should be able to marginate toward the wall of the blood vessels. Spherical NPs tend to remain in the center of the blood flow resulting in a decreased binding rate to the cells, whereas rod-shaped NPs tend to undergo a lateral drift depending on the orientation of their angles of contact [
Once NPs succeed in margination to the wall of the blood vessels, they have to be transported to their target site through a combination of binding and diffusion. NPs are able to accommodate many targeting ligands on their surface, unlike small-molecule drugs [
The effect of the NP shape on tumor internalization is somewhat controversial. Some studies report the advantage of rod and cylindrical shaped NPs over other shapes, while, on the contrary, other studies have found better internalization for spherical shapes compared to nonspherical shapes [
One important concept should be introduced when we are discussing the binding capacity of NPs, that is, the active fractional area (AFAC). For a sphere, the AFAC is defined as (
How different NP shapes could affect the binding avidity of NPs.
Gratton et al. [
There is an urgent need to design smart NPs that initially have a high aspect ratio (rod, filamentous, etc.) to achieve better circulation, then to change into a low aspect ratio (spherical shape) when they come into contact with the tumor to achieve better internalization.
Almost all of the components of the tumor microenvironment carry an electrostatic charge. The glycocalyx causes the blood vessels to be slightly negatively charged, whereas the hyaluronic acid existing in the interstitial space and the collagen fibers carry a small positive charge. Consequently, the electrostatic interaction between the tumor microenvironment and the NPs plays an important role in drug delivery [
A mathematical model was developed to determine how the NP surface charge affects the transport across the vessel wall [
A new concept relating to charge density has been introduced, in which the charge of the NP is a function of the pore size. Electrostatic attraction that improves transvascular flux is in competition with hydrodynamic and steric interactions [
In order to deliver the appropriate NP to a specific cancer site, a deep understanding of the type of tumor is crucial. For example, in breast cancer, the pore size exceeds 1
Surface charge is another key parameter that determines the NP performance, due to the fact that tumor cells are slightly negatively charged. Therefore, it is considered that positively charged NPs could be taken up better by the cells due to “electrostatic adhesion-mediated targeting” [
Neutral or negatively charged NPs may travel for longer distances inside the tumor tissues than positively-charged NPs. Thus a “delayed charge reversal profile” could be a good choice because the tumor penetration could be enhanced without affecting the cellular internalization [
Positively charged NPs have been shown to better target tumor vessels, but after extravasation, a switch to a neutral charge allowed more rapid diffusion of the NPs within the tumor tissue [
Effect of NPs surface charge on tumor uptake: it seems that positively charged NPs and slightly negative display a good tumor uptake.
Authors | Nanoparticle types and charge | Treatment/study | Efficacy |
---|---|---|---|
Xiao et al. [ | NPs with high negative and high positive charge | Tumor cellular uptake | High uptake of slight negative and slight positive NPs |
Gou et al. [ | NPs with different charge | Tumor cell uptake | Delayed charge reversal strategy could improve therapeutic effect |
Graf et al. [ | High positive NPs | Stability in physiological media | Effective cellular internalization |
He et al. [ | Polymeric NPs negative(−40 mV) and positive charge (+35 mV) | Tumor uptake | Slight negative charge accumulate more efficiently in tumor |
Chen et al. [ | Positive and negative NPs | Tumor uptake | High uptake of positively charged Nps increase uptake of both charge under hypoxic conditions |
Stylianopoulos et al. [ | Positive NPs switched into neutral inside the tumor | Cancer (tumor targeting) | Positive NPs: Effective tumor targeting & neutral charge allowed quicker diffusion of the nanoparticles to the tumor tissue |
By referring to Tables
Coating NP is elementary to achieve better circulation time and reduced phagocytosis, whereas, in contact with the tumor tissue, many studies found that PEG may act as an obstacle hindering the interaction of the NPs with the target cells. Some proteins are capable of translocating through the cell membrane efficiently without compromising their integrity [
In a similar approach, Kale and Torchilin [
This promising strategy to improve the penetration capacity of NPs is hampered by the lack of cell specificity and the mode of delivery is not well understood. In an attempt to inhibit the nonspecific interaction of CPP with the blood stream, a novel strategy has been introduced by Ding et al. [
Liu et al. studied the effect of surface charge and the particle size of CPP on cellular internalization. They found that the zeta potential is the key predictor of transduction efficiency, whereas the size of the CPP has a minor effect on cell permeability [
In Table
Effect of adding different types of coatings to the NPs.
Author | NPs type and size | Type of added ligant | Treatment | Effect/distribution | Benefit |
---|---|---|---|---|---|
Liu et al. [ | Coated BVP-PLA-NPs 177 and 319 nm | BVP | IV administration | Liver, spleen, heart, brain | NPs penetrate the BBB, avoid the RES, prolong the half-life of BVP |
Takeuchi et al. [ | Gold NPs 20, 40 and 80 nm | PEG | IV administration | Usefulness of PEG with smaller NPs size | Reduced accumulation in liver, spleen, improved delivery to the brain |
Ezealisiji and Okorie [ | Ag NPs | Peg, PG, Tween, NaLSo4 | Dermatological application (skin penetration) | Maximum penetration efficacy of NaLSo4 followed by PG | Improved skin penetration |
Hu et al. [ | PEG-PLA nanoparticles | Peptide F3 PEG-PLA nanoparticles | IV treatment of glioma | Enhanced accumulation at the tumor site and deep penetration into the glioma parenchyma | Improved parenchyma penetration |
The maximum penetration was achieved by the NaLSO4 followed by PG and then PEG [
The major factors that improve the tissue biodistribution of NPs are the physicochemical properties, whereas the major factor that affects the cellular uptake is the coating.
From Tables
In terms of which shape would be best, it can be concluded from Table
Ideally, a combination of the three different shapes deployed at different times could be the best for getting drugs to the tumor. Specifically, starting with large NPs, which can transport high amounts of the drug early in the treatment time frame, followed by small NPs as the vasculature recovers, and the transport of large bulky NPs becomes increasingly difficult [
The key factor that determines the efficacy of passive targeting is the surface area and size of the NPs. Nanoparticles of different sizes behave in a qualitatively different manner. Dqivedi et al. [
It seems that the so-called EPR effect is very size-dependent, and it can be slow and not very efficient compared to active targeting [
Furthermore, using a mathematical model, Islam et al. [
A very important point should be noted here is that the addition of coatings and ligands to NPs does not, in itself, have much effect on tissue distribution, which is mainly dependent on the physicochemical properties of the NPs. The ligands and coatings act to improve the intracellular uptake by the target cells and do not necessarily have any effect in improving the tumor targeting [
Once the NPs succeed in coming in close contact with the target cells, it is more advantageous to remove the surfactant coating to achieve better cellular uptake as it has been shown in many studies that the ligands may be an obstacle for effective cellular uptake [
In Figure
Proposed ideal NPs characteristics. When NPs are in the blood circulation, it is advantageous to have a larger size (>100 nm) nonspherical shaped NP, with a neutral charge to achieve better circulation and tumor accumulation. Once in contact with the tumor, it is more advantageous to have positively charged or slight negatively charged NPs with a smaller size (<12 nm) and a lower aspect ratio. The surfactants should be removed once the NPs enter the extracellular matrix (ECM).
Smart or stimulus-responsive NPs could allow them to act as a type of “nanorobot,” having certain properties while circulating in the blood circulation and changing their properties when they come into contact with the tumor. These changes could include not only the size, but also the shape, the charge, and the coatings.
It seems nowadays that the concept of “one fits all” does not apply anymore. Nanocarriers should be customized to the specific target to achieve the best result. Furthermore, local cancer therapy such as subcutaneous administration starts to be the preferred administration root, since smaller volumes can be injected, meaning lower injection times and shorter hospitalization for patients [
Important questions that require answers include what technology we need to safely and precisely manipulate the nanoparticles properties and what is the influence of the administration route on the tumor biodistribution and tumor uptake. Developing effective strategies to modify tumor properties such as degradation of the extracellular matrix is another field to be investigated in the near future.
Accelerated blood clearance
Breviscapine BVP
Cell penetrating peptide
Extracellular matrix
Enhanced permeability and retention
Food and Drug Administration
Jet and flash imprint lithography
Mononuclear phagocytic system
Nanoparticle
Personalized protein corona
Polyethylene glycol
Polylactic acid
Quantum dots
Reticuloendothelial system
Ultraviolet.
The authors declare that they have no conflicts of interest.