molecules
Review
Cell-Based Nanoparticles Delivery Systems for
Targeted Cancer Therapy: Lessons from
Anti-Angiogenesis Treatments
Paz de la Torre, María Jesús Pérez-Lorenzo, Álvaro Alcázar-Garrido and Ana I. Flores *
Grupo de Medicina Regenerativa, Instituto de Investigación Sanitaria Hospital 12 de Octubre (imas 12), Avda.
de Cordoba s/n, 28041 Madrid, Spain; [email protected] (P.d.l.T.); [email protected] (M.J.P.-L.);
[email protected] (A.A.-G.)
* Correspondence: [email protected] or [email protected]; Tel.: +34-913-908-762
Academic Editors: Alejandro Baeza, Fernando Novio and Juan Luis Paris
Received: 13 December 2019; Accepted: 5 February 2020; Published: 7 February 2020






Abstract: The main strategy of cancer treatment has focused on attacking the tumor cells. Some
cancers initially responsive to chemotherapy become treatment-resistant. Another strategy is to
block the formation of tumor vessels. However, tumors also become resistant to anti-angiogenic
treatments, mostly due to other cells and factors present in the tumor microenvironment, and hypoxia
in the central part of the tumor. The need for new cancer therapies is significant. The use of
nanoparticle-based therapy will improve therapeutic efficacy and targeting, while reducing toxicity.
However, due to inefficient accumulation in tumor sites, clearance by reticuloendothelial organs
and toxicity, internalization or conjugation of drug-loaded nanoparticles (NPs) into mesenchymal
stem cells (MSCs) can increase efficacy by actively delivering them into the tumor microenvironment.
Nanoengineering MSCs with drug-loaded NPs can increase the drug payload delivered to tumor sites
due to the migratory and homing abilities of MSCs. However, MSCs have some disadvantages, and
exosomes and membranes from different cell types can be used to transport drug-loaded NPs actively
to tumors. This review gives an overview of different cancer approaches, with a focus on hypoxia and
the emergence of NPs as drug-delivery systems and MSCs as cellular vehicles for targeted delivery
due to their tumor-homing potential.
Keywords: cancer; angiogenesis; hypoxia; nanoparticles; nanomedicine; nanotechnology;
mesenchymal stem cells; exosomes; cell membrane coating
1. Introduction.
In recent decades, the predominant strategy of cancer treatment focused on the tumor cell.
However, chemotherapeutic agents have a broad toxicity profile and they do not greatly differentiate
between cancerous and normal cells. Furthermore, as a consequence of continual treatment, the
cancerous cell becomes resistant to drugs, leading to therapy failure.
Solid tumors can be assimilated to an organ that, in addition to proliferating tumor cells, includes
stromal cells, infiltrating inflammatory cells, extracellular support matrix and blood vessels, which
together constitute the tumor microenvironment [1]. Anti-angiogenic treatments represented a change
in the strategy against cancer, since the target is no longer the tumor cell but the endothelial cell and,
for the first time, the tumor microenvironment. The blockage of the formation of new vessels in
tumors attempts to inhibit tumor growth and to prevent metastasis. Angiogenesis, the sprouting of
new capillaries from pre-existing vessels, is an adaptive response of tumor cells which allows oxygen
delivery to hypoxic regions in the tumor, thereby sustaining tumor growth [2]. However, the formation
of tumor vasculature is a rapidly growing and highly disorganized process which results in high
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Molecules 2020, 25, 715 2 of 25
interstitial fluid pressure (IFP), hypoxia and low extracellular pH. These vascular abnormalities create
a barrier to drug administration, and are the main cause of tumor multidrug resistance [3].
2. Anti-Angiogenesis Therapy: A Revealing History
Vascular endothelial growth factor (VEGF) is the pivotal molecule in angiogenesis and its
expression in the primary tumor correlates with a greater risk of recurrence and poor prognosis in a
variety of cancers [4]. Other molecules structurally related to VEGF, which bind to the same receptors
have been identified, such as Placental Growth Factor (PLGF), VEGF-B, VEGF-C, VEGF-D and the
viral homologue of VEGF, VEGF-E [5]. VEGF promotes the survival of endothelial cells, and their
proliferation and migration.
The first antiangiogenic agent approved by the Food and Drugs Administration (FDA) and later by
the European Medicines Agency (EMA) was bevacizumad (Avastin, Roche), a humanized monoclonal
antibody anti-VEGF, which binds and neutralizes all VEGF isoforms. Bevacizumad therapy proved
to be of less benefit than expected, causing side effects such as severe bleeding, hypertension and
thromboembolic events. Combined with conventional chemotherapy, bevacizumab demonstrated a
modest but significant increase in overall survival in patients with metastatic colorectal cancer [6].
Other factors and signaling pathways, which directly or indirectly influence the process of
tumor angiogenesis, have also been targets of anti-angiogenic therapy. These include platelet-derived
growth factor (PDGF), fibroblast growth factor (FGF), hepatocyte growth factor (HGF), integrins,
cyclooxygenase (COX-2), metalloproteases MMP-2, MMP-9 and hypoxia-inducible factor (HIF-1).
Angiogenic signaling has also been blocked by the inhibition of specific receptors such as VEGFR-1
and -2, c-Met and PDGFR-β, which are expressed in both tumor and endothelial cells [7]. Furthermore,
several molecules that target more than one pathway have been designed. This is the case of Brivanib,
a VEGF and FGF receptor tyrosine kinase inhibitor, approved for the treatment of colorectal and
hepatocellular carcinomas [8]. Likewise, tyrosine kinase inhibitors (TKIs), by blocking the signaling of
several growth factor receptors, hold a therapeutic advantage over monoclonal antibodies, as they
can simultaneously block multiple angiogenic pathways and potentially have greater efficacy. Some
examples are pazopanib (VEGFR, PDGFR, FGFR, and c-Kit inhibitor), sorafenib (VEGFR, PDGFR, Raf,
c-Kit and Flt-3 inhibitor) and sunitinib (VEGFR, PDGFR and c-Kit inhibitor) which have approval for
the treatment of patients with advanced cancer [9–11].
Despite promising results in preclinical studies, anti-angiogenic treatments have shown insufficient
effectiveness in clinical use. Although anti-angiogenic drugs delayed the progression of the tumor, an
improvement in the overall survival was not achieved, and tumors continued growing [12]. Either
inherently or in acquired form, many tumors are resistant to anti-angiogenic treatments, making them
less effective from a therapeutic perspective.
3. Limits of Anti-Angiogenic Therapy
3.1. Tumor Microenvironment Resistance
Resistance to anti-angiogenic drugs is a common problem found in the treatment of several
carcinomas, such as breast, lung, ovarian, colorectal, kidney and liver, among others. The main
cause of resistance is the redundancy in the angiogenic pathways. There are multiple examples
both at the preclinical and clinical level that the inhibition of one or more proangiogenic factors
results in the induction of others, which would lead to the restoration of angiogenesis [13]. As a
response to anti-angiogenesis, tumor cells begin to produce alternative compensatory proangiogenic
factors. Likewise, the tumor microenvironment has been implicated in tumor response to therapy and
contributes to both intrinsic and acquired drug resistance [14]. Due to the anti-angiogenic treatment,
there is an increase in intra-tumor hypoxia, which acts as chemoattractant for immune cells from bone
marrow. Macrophages, neutrophils, and myeloid-derived suppressor cells have been shown to sustain
angiogenesis by stimulating VEGF-independent pathways [15]. Moreover, these tumor-infiltrating
Molecules 2020, 25, 715 3 of 25
myeloid cells are critical in establishing an immunosuppressive tumor microenvironment, which
promotes tumor evasion and resistance to therapy [16].
3.2. Pro-Metastatic Effect of Anti-Angiogenic Therapies
Significantly, therapeutic inhibition of angiogenesis has been related to increased local invasiveness
and distant metastasis [17]. Changes in tumor cells and in the tumor microenvironment due to the
hypoxic condition generated by anti-angiogenic therapy seems to promote increased migration of tumor
cells. The relationship of hypoxia with more aggressive metastatic cell behavior is well established [18].
Different tumor-dependent mechanisms, mainly driven by the hypoxia-inducible factor HIF-1, could be
involved in metastasis, including the production of pro-metastatic proteins, the disruption of basement
membranes by the secretion of proteolytic enzymes [19] or the alteration of the adhesion molecule
pattern, promoting epithelial to mesenchymal transition [20]. Furthermore, increased hypoxia levels
favor the recruitment of endothelial progenitor cells (EPCs) which promote the formation of a vascular,
pre-metastatic niche [17].
4. New Objective: Targeting Hypoxia
Anti-angiogenesis therapy failure has revealed that overcoming tumor hypoxia must be a principal
objective in the treatment of cancer. Tumor cells growing in a hypoxic environment quickly adapt
and undergo genetic changes to resist hypoxia-induced cell death. Targeting hypoxia is fundamental
not only to prevent metastasis, but also to overcome resistance toward conventional cancer therapies
including chemotherapy, radiotherapy [21] and photodynamic therapy [22], as well as to improve
the clinical efficacy of cancer immunotherapy [23]. Preventing hypoxic condition might become a
suitable strategy, along with current anti-angiogenic therapies, to improve effectiveness and minimize
unwanted effects. As described, HIF-1 is responsible for the tumor adaptive response to oxygen
and nutrient depletion, promoting metabolic changes [24], acidosis, immunosuppression [25,26] and
angiogenesis [27]. Different chemical compounds interfering at different molecular levels in HIF
signaling have been used in both preclinical and clinical studies [28]. Several molecules have been
approved by the FDA and the EMA for use in the treatment of cancer, although limitations in tumor
accumulation and variable systemic toxicity have been reported [29,30]. Topotecan, a topoisomerase 1
inhibitor which indirectly inhibits HIF, is used in the treatment of metastatic ovarian carcinoma and as
a second line treatment for small cell lung cancer [31]. At present, other HIF signaling inhibitors are
being tested in various clinical trials, either as single agents or in combination with other agents for the
treatment of advanced or refractory cancers [32].
5. The Emergence of Nanomedicine
In the last two decades, the use of drugs contained in nanoparticles (NPs) has emerged as a
solution in cancer therapy to direct drug delivery to the tumor and to reduce systemic damage. NPs
size range is between 1 to 100 nm and they allow the absorption of high quantities of drug due to a
large surface area-to-volume ratio. Small molecules, peptides, proteins, DNA or interference RNA have
been loaded into NPs to be delivered to tumors. For biomedical applications, NPs should have a series
of characteristics such as biocompatibility, degradability, stability, delivery efficiency and sustained
release. Different types of NPs, such as organic (liposomes and polymers), inorganic (metallic, metal
oxide, ceramic, and quantum dots) and carbon-based NPs (fullerenes, nanotubes), have been used
in the field of medicine (Figure 1), especially in the treatment and imaging of tumors [33]. Besides
their ability to passively accumulate at the tumor site, nanomaterials can be readily functionalized in
order to improve their active targeting and cellular internalization [34]. To increase the release of the
payload at target sites at the right time, stimuli-responsive NPs have been designed [35]. Interestingly,
there are nanoparticles designed to release conjugated cytotoxic drugs as a response to the special
chemical conditions of the tumor microenvironment, such as acidosis (reviewed in [36]) or hypoxia [37].
Furthermore, nanoscale materials can be aimed to be delivered across traditional biological barriers in
Molecules 2020, 25, 715 4 of 25
the body such as the blood–brain barrier or the dense stromal tissue of the pancreas [38,39]. The use of
encapsulated forms of a drug can improve the pharmacodynamics and pharmacokinetic properties
of the substance [40]. Nanoparticles have advantages over conventional anti-tumor drugs because
they can be multi-functionally designed to pinpoint several targets in the tumor microenvironment.
Nanomedicine appears as a very promising field in cancer therapy, as demonstrated by the large
number of publications that refer to successful in vitro and preclinical proofs of concept.
Figure 1. Types of nanoparticles commonly used for biomedical applications.
Nanotechnology provides different strategies to relieve intra-tumor hypoxia (Table 1). Some
approaches are directed towards tissue re-oxygenation, either through in situ oxygen supply or by
promoting intra-tumor H2O2 decomposition. Another therapeutic approach is the administration of
HIF-1 blockers. Nanomaterials have been designed to silence the gene expression of HIF-1 by antisense
oligonucleotides or by interference RNA (RNAi). Likewise, the encapsulated form of several HIF-1
signal-interfering drugs present some benefits with respect to the free drug, minimizing toxicity and/or
improving its pharmacokinetic behavior.
Molecules 2020, 25, 715 5 of 25
Table 1. Nanotechnology strategies against hypoxia.
Categories Cargo Type of Nanoparticle Mode of Action Ref.
O2 carriers
Perfluorocarbonand derivatives
Perfluorocarbon
Perfluorooctane
Perfluorohexane
Perfluorocarbon
PLGA-PEG emulsion
Hollow microparticles
Liposomes
Hollow Bi2Se3 NPs
Rapid release of O2 by hydrolysis
[41]
[42]
[43]
[44]
Ultrasound-based carrier Oxygen Microbubbles Ultrasound controlled release and imaging
by ultrasonography [45]
H2O2 catalysis platforms
MnO2
Catalase
UPCNPs
Liposomes Decomposition of H2O2 into O2 and H2O [ [46 47] ]
Inhibitors of HIF-1 signaling
Camptothecin
Topotecan
HIF-1 siRNA
HIF-1 ASO
Cyclodextrin-based polymer
Liposomes
PEGylated “-polylysine
copolymer
Liposomes
Topoisomerase I inhibition
Topoisomerase I inhibition
Reduction of HIF-1 levels
Reduction of HIF-1 levels
[48]
[49]
[50]
[51]
Abbreviations: PLGA, Poly(lactic-co-glycolic acid); PEG, Polyethylene glycol; US, ultrasound; UPCNPs, up-conversion nanoparticles; ASO, antisense oligonucleotide.
Molecules 2020, 25, 715 6 of 25
As with conventional drugs, the flow of nanomedicines into the tumor may be negatively
influenced by the hypoxia of the tumor microenvironment despite the existence of the enhanced
permeability and retention effect (EPR). EPR exists in solid tumors as a consequence of the abnormalities
in their vasculature, which lead to a selective extravasation of nanometric molecules in tumors, where
they may reach a much higher concentration than in normal tissues [52]. Nanomedicine has taken
advantage of this unique phenomenon, but the extreme hypoxic condition in the central region of a
large tumor mass can limit the EPR effect, and be a barrier for the entrance of NPs. Several methods
have been reported to enhance EPR, such as hyperthermia to mediate vascular permeabilization in solid
tumors [53,54], ultrasound-induced cavitation to modify tumor tissue [55,56], the application of nitric
oxide (NO)-releasing agents to expand blood vessels [57] or the administration of anti-hypertensives
to normalize blood flow [58]. Some of these methods have been implemented from the field of
nanomedicine to minimize side effects. Thus, different types of responsive-nanoparticles were
designed to produce tumor heating after photostimulation, magnetism, radiofrequency waves or
ultrasound [59]. Regarding NO, nanotechnology devices could facilitate its therapeutic use, which is
limited by its short half-life, instability during storage, and potential toxicity [60].
Lessons from the undesired consequences of blocking angiogenesis in tumor progression led
to the hypothesis that normalization of the tumor vasculature is a better therapeutic option than its
destruction [61]. Vessel normalization would transform the abnormal phenotype of tumor vessels into
a phenotype which resembles the normal functional vessels by repairing the basement membrane and
increasing the rate of pericyte coverage and, consequently, decreasing the vessel leakage. Correcting
the abnormalities in tumor vessels would prevent a further increase in harmful intra-tumor hypoxia
levels, allowing medication delivery which is dependent on efficient blood flow. Normalization of
tumor vasculature is also seen as necessary to improve NPs’ delivery [62]. In clinical practice, low doses
of anti-angiogenic treatments attempt to achieve a balance of anti- and pro-angiogenic factors to make
tumor vessels into a more normal phenotype. Moreover, the normalization of the aberrant vasculature
of the tumor can present added advantages. Treatment with low doses of anti-VEGFR2 antibody
resulted in a less immunosuppressive tumor microenvironment by the polarization of tumor-associated
macrophages, and recruitment and activation of CD8+ T lymphocytes in a murine breast cancer
model [63]. The infiltration of CD8+ T cells in tumor was associated with a better prognosis in various
types of cancer. Unfortunately, vascular normalization does not have an easy application in clinical
settings because it is a transitory state, and is referred to as the “normalization window”. It lasts 1–2
days and, in this period, the cytotoxic effects of anti-tumor drugs are markedly increased. Therefore,
it becomes critical to adjust the timing of the cytotoxic treatments to take advantage of this vascular
normalization window.
From the field of nanomedicine, attempts have also been made to design particles to promote the
normalization of tumor vasculature, such as gold nanoparticles used to provide human recombinant
endostatin (rhES) in tumors by EPR to facilitate transient vessel normalization and improve antitumor
therapeutic efficacy [64]. Another approach is the combination of an anti-angiogenesis treatment and
chemotherapy in the same nanomedicine formulation. The cytotoxic drug paclitaxel (PTX) is loaded
into lipid-derivative conjugates (LGCs) made of anti-angiogenic agents such as a low molecular weight
heparin and gemcitabine to simultaneously restore the tumor vasculature and deliver the cytotoxic
drug [65]. Despite promising results obtained at the preclinical level, there is no clinical experience
with any of these nanoplatforms.
Decades of research have yielded only a few anticancer nanomedicines currently in clinical use [66].
Some formulations are hypoxia-limiting drugs such as DaunoXome or liposomal daunorubicine, a
chemotherapeutic drug of the anthracycline family used in Kaposi sarcoma, and Onivyde or liposomal
irinotecan, a topoisomerase I inhibitor used for the treatment of pancreatic cancer [67,68]. These
nanomedicines improve the safety profile of the drugs, but, as with other nanopharmaceuticals, the
efficacy shown in preclinical experiments is not achieved at clinical level.
Molecules 2020, 25, 715 7 of 25
6. The Limits of Nanomedicine in Clinical Applications
It is a fact that the clinical translation of nanomedicine for the treatment of cancer remains a great
challenge. Regardless of the important contributions of nanotechnology to oncology in minimizing the
toxic side effects of drugs, overall survival of patients has not improved. Several relevant questions
must be addressed in order to improve the applicability of nanomedicine formulations to treat cancer,
and this requires the understanding of the complexity and heterogeneity of human tumors and a
deeper insight into nano–bio interactions.
For NPs to have clinical translation potential, there is a need to evaluate their safety and toxicity in
humans and determine how large-scale manufacturing processes can introduce changes in this profile.
Although the safety of many materials has been proven, as the complexity of nanoparticles increases
by the use of synthetic compositions or by the addition of ligands or coatings, the in vivo behavior
and the toxicological profile must be evaluated. The main safety concerns derive from direct cell
toxicity, nanoparticles aggregation, long-term accumulation, hemolytic effects, and/or immunogenic
behavior [69]. Toxicological evaluation of nanoparticles is based on an understanding of their in vivo
distribution, metabolism and excretion [70].
To take advantage of nanomedicine, it is vital to optimize nanomaterial properties such as
drug-loading capacity and/or capability of sustained release of the cargo in vivo, among others.
Furthermore, it is essential to minimize the location of nanoparticles in healthy tissues and improve
their delivery to the target organ. Increasing the efficiency in the delivery of nanoparticles to the tumor
is considered the main goal in order to achieve real benefit [71].
The use of nanomedicine in cancer therapy has been supported by the existence of the EPR
phenomenon; however, only a small percentage of systemically injected NPs accumulate in tumors (a
median of 0.7% according to a wide meta-analysis study based on preclinical data) [72]. EPR seems
to be an overestimated effect, as its understanding is based on the high EPR existing in fast-growing
subcutaneous tumor xenografts in mice models. However, non-invasive imaging techniques applied
to a small number of patients to determine the penetration and accumulation of nanoparticles in tumor,
revealed that EPR is not a uniformly extended effect in solid tumors in humans [67]. Variability in
vascular permeability, blood velocity, interstitial blood pressure, oncotic pressure, and complexity of
the tumor stroma influence the movement of nanoparticles into and out of the tumor [73]. Additionally,
physicochemical properties of nanoparticles, principally size and shape, also affect NPs extravasation
and accumulation. In order to predict tumor susceptibility to EPR, and therefore, to benefit from the
use of nanomedicine, some attempts have been made to characterize EPR-related genes, proteins or cell
biomarkers (reviewed in [74]). Several studies have suggested the value of stratifying subpopulations
of cancer patients according to their EPR relevance, in order to define the “right patients” to be treated
by nanomedicine strategies in an analogous manner, as is being done in the development of other
anti-cancer strategies [67].
As an alternative to passive accumulation, active targeting of nanoparticles is proposed in order
to improve their tumor retention and to favor their uptake by the target cells. This strategy relies on
the interaction between ligands conjugated onto the surface of nanoparticles (e.g., antibodies, peptides
or carbohydrates) and their target. Target substrates can be surface receptors expressed by tumor cells
or by other cells in the tumor microenvironment, secreted molecules, or even the physicochemical
environment in the tumor. An additional advantage of actively targeted NPs could lie in their capacity
to target disseminated locations throughout the body, such as metastatic lesions or hematological
cancers where EPR does not exist [75]. However, several problems have made the use of ligand-targeted
approaches at the clinical level, so far, negligible. These problems are the accessibility and expression
of the target, the anatomical and physiological barriers to NPs delivery, as well as the lack of real
knowledge about the toxicities of these complex formulations [70].
The targeting of nanoparticles to tumors, whether active or passive, must overcome physiological
barriers to reach the tumor site once systemically administered. Whatever increases circulating lifetime
by reducing clearance means an improvement in efficacy. The clearance of NPs by kidneys and their
Molecules 2020, 25, 715 8 of 25
sequestration by reticuloendothelial organs are the main barriers affecting their bio-distribution, and
therefore must be considered at the design stage. Renal elimination of nanoparticles is determined
by their size, charge, shape and surface composition [76]. Recognition of NPs by immune cells and
retention by the reticuloendothelial organs, such as liver, spleen or bone marrow, constitute the other
major obstacles to the success of nanoparticle delivery, since they lead to premature elimination from the
bloodstream. Having interacted with biological fluids, nanoparticles are exposed to active biomolecules,
and diverse serum proteins non-specifically adhere onto their surface, forming a protein corona. There
is an evident impact of protein corona in the fate and biological effects of nanoparticles [77,78].
Several surface-coating molecules such as polyethylene glycol (PEG) have been used to provide
“stealth” properties to NPs during circulation [79]. Nonetheless, complement-related responses to PEG
result in mild to severe hypersensitivity reactions in some susceptible individuals [80]. In addition,
PEG-specific antibodies have been detected after the repeated administration of PEG-coated liposomes
in the same animal [81]. These immunological responses may lead to altered pharmacokinetics and
subsequent loss of efficacy of the treatment, and to potentially serious toxicities including anaphylaxis.
7. Biological Carriers to Deliver NPs
Anti-angiogenic treatments have revealed the relevance of the tumor microenvironment in the
progression of the tumor. In the battle against cancer, it is mandatory to attack simultaneously on
various fronts. Then, targeting tumor cells, normalizing tumor vasculature and overcoming hypoxia,
among others, are vital to control the growth of solid tumors and to prevent metastasis. Nanomedicine
appears as a valuable tool to achieve these goals, having the opportunity to design polyvalent NPs.
Unfortunately, physiological barriers decrease NPs circulating lifetime and hinder their delivery to
the tumor site. Additionally, the hypoxic region of the tumor constitutes an insuperable barrier
resulting in an inefficient distribution of the NPs, and, as a consequence, a non-uniform release of
drugs into the tumor. Furthermore, the potential toxicity of NPs, owing to their composition and/or
to the nano-bio interactions, can compromise the feasibility of their use [82]. It is necessary to find
solutions to overcome these problems without forgetting the great heterogeneity of human tumors.
The encapsulation of nanoparticles into cell- or cell membrane-based systems can enable these issues
to be addressed to some extent.
Mesenchymal stem cells (MSCs), exosomes and plasma membrane coating are biocompatible
candidates to transport NPs to the tumor site, given their stability, non-cytotoxic effects, high drug
carrying capacity, and low- or no-immunogenic profile. In addition to the load of anticancer drugs,
these biological carriers can be engineered to express therapeutic peptides and proteins, and to transport
RNAs or imaging agents, this enabling a more synergistic approach to anticancer therapy. As discussed
below, mesenchymal stem cells and their exosomes have tumor tropism because tumor hypoxia is a
potent mediator directing MSCs’ migration [83]. Although the use of these encapsulated formulas is in
initial stages, they appear as a potential way to reach the impenetrable hypoxic core of solid tumors.
7.1. Mesenchymal Stem Cells as Carriers to Deliver NPs
The use of stem cells as cellular vehicles of drug-loaded nanoparticles seems to be a very promising
strategy for targeting tumor tissues [84]. Different types of stem cells could be used as cellular vehicles,
such as embryonic stem cells, adult stem cells or induced pluripotent stem cells. Within the adult
stem cell group, the mesenchymal stem/stromal cells (MSCs) are the most common cell type used,
given their several advantages (Table 2), such as their availability, easy isolation, non-immunogenicity
and immunomodulatory properties [85]. MSCs have been isolated from many sources, such as bone
marrow [86], adipose tissue [87], umbilical cord tissue [88], amniotic fluid [89] and placenta [90]. From
a clinical point of view, MSCs are the first choice of stem cells for use in cancer therapies. It is well
known that MSCs specifically migrate, home and survive in tumor sites without being incorporated
into normal tissue [91,92]. MSCs can migrate towards a tumor, since these cells respond to tissue
damage, hypoxia and inflammation, as found in tumor microenvironments (Table 2). This tropism
Molecules 2020, 25, 715 9 of 25
property makes MSCs a promising strategy for drug delivery systems in cancer therapy [91,93,94].
MSCs home to tumor stroma because of their attraction to several growth factors, cytokines and
proteases existing in the tumors [95]. Exploring this tropism of MSCs toward tumor sites to deliver
gene therapy, drugs or nanoparticles to the tumors is a promising strategy in cancer therapy (Figure 2).
Figure 2. Mesenchymal stem cell (MSC)-based strategies for targeted-cancer therapy. MSCs can be used
an anti-cancer agents due to their tumor-tropic properties, and their anti-proliferative, pro-apoptotic
or anti-angiogenic properties (naïve MSCs). MSCs can be genetically modified to express suicide or
anti-tumor genes. MSCs can incorporate small molecules of anti-tumor agents and they have been used
as cellular vehicles of NPs. In addition, MSC-derived exosomes can be used as drug-delivery tools.
Molecules 2020, 25, 715 10 of 25
Table 2. Advantages and disadvantages of the different cell-based delivery systems.
Cell-Based Strategy Advantages Disadvantages
MSCs
Easy isolation from accessible sources
Easy culture in vitro
No immunogenicity
Tissue regeneration capacity
Tumor tropism
Migration ability into the site of damage
Homing capacity
Uncertain tumorigenic effect
High retention in lungs after systemic administration
Possible occlusion of microvessels after systemic administration
Repeated injection may result in production of alloantibodies
EXOSOMES
High stability in physiological and pathological conditions
Unlikely to be immunogenic
Small and relatively homogeneous size
Intracellular delivery of cargo by fusion of membranes
Able to cross natural barriers such as blood–brain barrier
Autologous use allowing personalized medicine
Need of standardized protocols for isolation and purification
Need of adequate characterization of cell of origin
Undesired effects due to exosome components themselves
Lack of standardized mass production protocols
PLASMA
MEMBRANE-COATING
Provide biocompatibility to nanoparticles
Immune escape and longer circulation lifetime
High versatility
Easy functionalization
Need of techniques for large-scale cell culture
Need of high-yield methods for membrane derivation
Lack of knowledge about all membrane components
Molecules 2020, 25, 715 11 of 25
There are other advantages in using MSCs in cancer therapy, such as the fact that they can be
genetically modified to serve as a vehicle for cancer gene therapy, with little or no impact on their
biology [96]. There are many reports showing that MSCs engineered to express anti-proliferative [97],
pro-apoptotic [98] or anti-angiogenesis [93] agents were successfully used for the treatment of
several types of tumors (reviewed in [96]). In addition, naïve MSCs have anti-proliferative [91,99],
pro-apoptotic [100] or anti-angiogenic [93] properties and have a low risk of malignant transformation
after transplantation in vivo due to their limited proliferation capacity [90,101]. Although some studies
have proven that MSCs have pro-tumorigenic effects, increasing tumor growth and metastasis [102], it
is generally agreed that MSCs can be manipulated with anticancer genes to be used in cancer therapies
(Figure 2). The use of viral and non-viral vectors for genetic modifications to MSCs has several
drawbacks, such as transient gene expression and low transfection efficiency, along with a high risk of
cell transformation [103].
MSCs can also incorporate small molecules of anti-tumor agents, such as paclitaxel or doxorubicin,
and carry them to tumor sites (Figure 2). However, this strategy has some downsides such as the
low loading capacity and the rapid diffusional clearance of the molecules out of cells. Additionally,
anti-cancer drugs may have some cytotoxic effects on MSCs and result in their loss before arrival
at tumor sites. The effects of chemotherapeutics on MSCs have been quite controversial, from a
reduction in proliferation and apoptosis, to resistance while retaining proliferation and differentiation
potential (reviewed in [104]). MSCs are resistant to the cytotoxic effects of paclitaxel via the inhibition
of their proliferation, inhibition of apoptosis and induction of quiescence [105]. However, paclitaxel
exposure does not up-regulate the expression of the trans-membrane pump P-glycoprotein 1 in MSCs,
a mechanism by which cancer cells resist paclitaxel treatment [106]. Doxorrubicin at clinically used
doses induces premature senescence of MSCs in vitro [107]. These senescent MSCs are functional
but not proliferative, and are protected from doxorubicin-induced tumor transformation. The effect
of doxorubicin on MSCs in vivo is contradictory, from resistance to reduced proliferation rates and
apoptosis [104], and this may be due to the ex vivo culture conditions of MSCs and duration of
treatments. Hence, long-term in vitro and in vivo studies are necessary to understand the mechanisms
behind the influence of chemotherapy on MSCs.
The encapsulation of chemotherapy drugs into NPs increases the drug-loading capacity of MSCs
while reducing potential toxic effects on MSCs (Figure 2). In case of toxicity, the incorporation of
controlled release or stimuli-responsive nanoparticles may avoid the loss of MSCs during the process
of migration and tumor homing, as well as ensuring that a therapeutic dose of the anti-cancer agent
is released at the tumor site [108,109]. MSCs loaded with ultrasound-responsive mesoporous silica
NPs selectively released the cargo when the stimulus was applied, both, in vivo and in vitro [35].
When loaded with doxorubicin, these NPs caused death to mammary cancer cells in vitro after
ultrasound exposition. This stimuli-response strategy would significantly reduce undesired side
effects of anticancer treatments. Although progress has been made in the design of NPs to introduce
anti-cancer drugs to be transported by MSCs, this combined system MSC/NP is still in its initial
stages. It has been reported that the type of NP and its size, as well as its concentration, incubation
time, and the presence or absence of serum in the culture medium, could interact with and alter the
physical and phenotypical properties of MSCs [33]. However, other studies suggested that MSCs
loaded with NPs preserved their morphology, proliferation, migration and homing capacity [35,84,110].
Mesoporous silica nanoparticles did not inhibit the tumor-tropic capacity of MSCs and, when loaded
with doxorubicin-NPs, showed in vitro and in vivo migration towards tumors and in vitro induction
of cancer cell death. [110]. It is an important goal to achieve clinical efficacy while ensuring safety by
using small amounts of nanomaterials. MSCs loaded with carbon nanotube-doxorubicin presented
migratory capacity, active targeting and long-term apoptosis of lung cancer cells in vitro and in vivo
with extremely low doses of the anti-cancer nano-drug, with no side effects [111]. The sustained release
of paclitaxel encapsulated into PLGA nanoparticles does not affect the functional capacities of MSCs
Molecules 2020, 25, 715 12 of 25
or their tumor tropism and increases survival of tumor-bearing rats while decreasing glioma tumor
tissue [112].
The main advantage of using MSCs is their ability to infiltrate uniformly into tumor tissue and
this ability will improve the intra-tumor distribution of anti-cancer drugs [113]. Paclitaxel-loaded
poly(lactic-co-glycolic acid) (PLGA) NPs had little effect on MSC viability, did not affect their migration
and differentiation potential, and presented a dose-dependent cytotoxicity against lung cancer cells
in vitro and in vivo [114]. In vivo, the paclitaxel-NPs-MSCs platform accumulated in lung tumors and
produced higher tumor growth inhibition and survival compared to injected paclitaxel encapsulated in
NPs [115]. Another study using MSCs with paclitaxel-loaded PLGA NPs in a rat model of orthotopic
glioma showed similar results [112]. Achieving a high payload capacity is critical to getting therapeutic
drug concentrations to the tumor site. Covalent conjugation or the physical association of NPs to
MSCs’ surface can significantly increase the cargo besides the drug-NPs loaded by endocytosis. Such
nanoengineered MSCs demonstrated greater tumor inhibition and increased in vivo survival with
reduced systemic toxicity when compared to free or NP-encapsulated drugs in a variety of tumors
(reviewed in [103]). In addition to anti-cancer drugs, NPs could also serve as carriers of bioactive
molecules such as DNA, mRNA or siRNA into MSCs (Figure 2). Gene transfection of MSCs with
plasmids encoding cytosine deaminase and uracil phosphoribosyl transferase suicide genes was
successfully attained using a polyethylenimine (PEI) coating of mesoporous silica nanoparticles [116].
These PEI-plasmid-NPs induced cell death to breast cancer cells without producing any significant
toxicity to the vehicle MSCs [116]. This approach will provide a double therapeutic effect after
transplantation, migration and homing to tumor sites of the PEI-NPs-engineered-MSCs; one effect
will be from the plasmid transported outside the NP and another from the drug transported inside
the NP [35]. This Trojan-horse strategy could significantly improve the efficacy of NP-MSC-based
anti-cancer therapy.
Nanoparticle-based anti-angiogenesis systems have been developed and studied in preclinical
models. The anti-angiogenic properties of several types of NPs such as gold nanoparticles, silica and
silicate-based nanoparticles, diamond nanoparticles, nanoceria nanoparticles, silver nanoparticles
and copper nanoparticles, have been reported [82,117]. Encapsulation of these NPs in MSCs would
overcome some of the limitations and side effects, and selectively target the tumor site, enhancing
the anti-angiogenic properties of the NPs. On the other hand, the use of anti-angiogenic factors onto
biocompatible nanoparticles has recently attracted great interest. Paclitaxel inhibits tumor growth
using both a direct inhibition of tumor cell proliferation and an inhibition of angiogenesis [118].
However, paclitaxel develops hematologic toxicities (i.e., leukopenia and neutropenia) and liver
damage. MSCs loaded with paclitaxel-PLGA nanoparticles showed a selective accumulation into the
lungs of tumor-bearing mice with respect to non-tumor mice. This system presented a maintained
concentration of paclitaxel in plasma for longer, and developed a deposition of paclitaxel in the
lungs with a significantly lower “off-target” deposition in liver and spleen. In addition, the effect of
these nano-engineered MSCs was a reduced proliferation of tumor cells, reduced angiogenesis, and
increased apoptosis in the tumor tissue, and a less severe leukopenia because of the very low dose of
paclitaxel [115]. The encapsulation of bevacizumab onto mesoporous silica nanoparticles is another
promising drug delivery system for improving anti-angiogenic therapy [119]. Since mesoporous silica
nanoparticles are well tolerated by MSCs [110], the use of this this system will be an effective treatment
in tumor therapies.
MSCs have high tropism for the hypoxic microenvironment of tumors [83], and it has been
described that the hypoxic preconditioning of MSCs improves the migration and homing of MSCs [120].
Hypoxic preconditioning of MSCs loaded with PEG-superparamagnetic iron oxide NPs increased their
migration toward gliomas and their trafficking across the blood–brain barrier. This study showed
the role of hypoxia in the migration and homing abilities of MSCs and the use of an innovative
systemic MSCs-based cell therapy for the treatment of aggressive tumors [121]. The migration of MSC
is regulated by several cytokine/receptor pairs. Chemokine receptor-4 (CXCR-4) and its interaction
Molecules 2020, 25, 715 13 of 25
with stromal cell-derived factor SDF-1 secreted on the surface of tumor cells is the most important
set involved in MSCs tumor tropism [122]. The use of biodegradable polymeric nanoparticles to
overexpress CXCR-4 in human adipose MSCs enhanced cell migration velocity and increased their
co-localization within the hypoxic area of the tumor [123]. Human MSCs loaded with iron oxide-NPs
showed an overexpression of epidermal growth factor receptor (EGFR) that resulted in an improved
migration of the MSCs towards hypoxic area of the tumor [124]. In addition, iron oxide NPs improved
the homing and anti-inflammatory abilities of MSCs without modifying their properties [125]. These
results suggest that NP-engineered MSCs could serve as vehicles to deliver therapeutic agents into
hypoxic areas of tumors to overcome drug-resistance.
Once the cells are transplanted in vivo, it is important to monitor the long-term fate of MSCs,
their migratory capacity and their biodistribution, as well as their tumor penetration capacity.
The conjugation of different types of nanoparticles to MSCs have successfully demonstrated
feasibility of tracking the migration and intratumor localization of MSCs by non-invasive imaging
techniques used in preclinical and clinical settings, such as magnetic resonance imaging (MRI),
computed tomography (CT), ultrasound, optical imaging, positron emission tomography (PET)
and single-photon emission computed tomography (SPECT). Adipose-derived MSCs loaded with
mesoporous silica-coated manganese oxide NPs were efficiently monitored by MRI imaging over long
periods after transplantation [126]. Adipose-derived MSCs can be also monitored by non-invasive
CT imaging in vivo after labelling by PEG-coated gold NPs [127]. These gold NPs were visible at
the transplantation site for as long as four weeks with no loss in signal. The authors were able to
quantify the number of visualized cells as a function of the CT value obtained. These results are
very important to quantify the migratory and homing abilities of MSCs into tumor sites. Migratory
capacity and tumor tropism toward malignant glioblastoma of both bone marrow and placenta-derived
MSCs was demonstrated by in vivo MRI tracking after labeling with superparamagnetic iron oxide
(PEG-SPIO)-NPs [121,128]. Although several nanoparticles have been designed for diagnostic and
in vivo imaging, the optimal type of formulation for cell tracking in vivo does not, as yet, exist [129].
Further studies are necessary to use nanoparticles for diagnostic and imaging purposes in the field
of oncology. The main challenges to be overcome are biocompatibility and an improvement in the
synthesis process. This approach would allow the in vivo tracking and biodistribution of MSCs as
carriers of therapeutic agents and would provide information about tumor-targeted accumulation,
drug release and long-term drug efficacy. Such information could contribute to a model of personalized
medicine and patient individualization.
Although there are several clinical trials with MSCs to treat several pathologies, their use in
humans may cause some concerns owing to their potential to promote tumor growth, angiogenesis
and fibrinogenesis [93]. There are other studies showing the anti-tumor and anti-angiogenic properties
of MSCs [103], but whether MSCs facilitate or inhibit tumor growth remains controversial (Table 2).
Therefore, a deeper understanding of the molecular and cellular interactions between MSCs and the
tumor microenvironment is required.
7.2. Exosomes as Carriers to Deliver NPs
Exosomes have recently emerged as possible natural carriers of therapeutic agents for cancer
therapy. These are small extracellular vesicles (30–150 nm in diameter) released from cells after the fusion
of an intermediate endocytic compartment, the multivesicular body (MVB), with the plasma membrane.
Exosomes are secreted by most eukaryotic cells and have been recognized as important messengers in
cell-to-cell communication through the transfer of macromolecules such as lipids, proteins, and nucleic
acids (mRNAs, tRNAs, long, noncoding RNA, microRNAs and mitochondrial DNA). Exosomes have
been implicated in physiological processes but also in diseases such as neurodegenerative diseases [130],
heart failure [131], liver disease [132], or cancer [133]. The proteomic and RNA content of exosomes
from different cellular sources has been analyzed (www.exocarta.org) [134]. In addition to several
conserved proteins that are common to most exosomes regardless of their origin, such as tetraspanins
Molecules 2020, 25, 715 14 of 25
(CD9, CD63 and CD81) and heat shock proteins (HSP60, HSP70 and HSP90), among others, exosomes
express tissue-specific proteins which reflect their originating parental cell [135]. Recently, it has
been shown that exosomes have intrinsic homing capabilities similar to their original cells [136] and
recapitulate their biological activity so that, in some cases, exosomes may be an alternative to cell
therapy, avoiding the adverse effects of intravenous administration of cells.
The therapeutic properties of exosomes in clinical use can rely on three components: vesicle,
load and/or surface decors. Exosomes are “natural nanoparticles” delivering an array of proteins and
nucleic acids, and they can also be engineered to improve tumor recognition and killing properties
in order to increase the effectiveness of cancer therapy [137]. The efficient encapsulation of different
types of nanoparticles into exosomes for therapeutic and diagnostic purposes in cancer is also
possible [138–140]. Compared to synthetic nanomaterials, a first advantage of the use of exosomes is
their innate biocompatibility so they may be less immunogenic or cytotoxic (Table 2). Exosomes are
large enough to avoid being cleared rapidly by kidneys and, in some cases, small enough to escape the
capture of the mononuclear phagocyte system and to take advantage of the EPR effect accumulating
in tumors. Exosomes are formed by a lipid bilayer delimiting an aqueous core, and this allows the
upload of drugs of both, hydrophobic and hydrophilic natures, thus increasing their versatility [141].
Some concerns in the scalable production of exosomes for clinical use are the establishment of optimal
culture conditions, product purity, batch uniformity and storage conditions (Table 2), among others, to
ensure that the exosome-based product meets the expected quality and efficiency [142]. The relevant
issues are the optimal dose, the timing of administration, and the route of injection to achieve maximal
efficacy and minimize adverse effects [143]. The fate of exosomes can be monitored in vivo by labeling
them with NPs that are detected by non-invasive imaging techniques such as magnetic resonance
imaging (MRI), computed tomography (CT) or magnetic particle imaging (MPI) [144,145]. These
techniques have advantages and disadvantages according to their sensitivity, specificity, penetration,
radiation and spatial resolution. Further developments need to be investigated to obtain more efficient,
biocompatible and quantifiable exosome labeling and imaging techniques with the aim of translating
exosome therapy to the clinic [144,146].
Although many types of cells in the body produce exosomes, MSCs are one of the most prolific
(Figure 2), and, therefore, are more suitable for the mass production of exosomes for drug delivery [147].
Clinical trials of MSC-derived exosomes that are currently in progress focus on gene delivery,
regenerative medicine, and immunomodulation [136]. As expected, MSC-derived exosomes have
intrinsic homing capabilities similar to those of MSCs and, in the treatment of cancer, can penetrate the
tumor site [148]. In a similar way, hypoxia could also be a target for MSC-derived exosomes. Very
interestingly, in hypoxia studies it has been published that hypoxic cancer cells avidly uptake exosomes,
which have been produced in hypoxic conditions [149]. Culturing MSCs in hypoxic conditions would
not only produce hypoxia-conditioned exosomes but also lead to an increase in exosome production,
as described [150]. The effects of native MSCs-derived exosomes in cancer remain controversial and
further analysis is required. Observed pro-tumor or anti-tumor effects are supposed to rely on cell
culture conditions, on the methods to promote vesicle formation and on the tumor model used [151].
Although a cancer suppression ability by MSCs native exosomes from adipose tissue has been reported
in vitro [152] and in vivo [153], genetic modification is the commonly used strategy in MSCs-derived
exosome-based cancer therapy through transfection of diverse miRNAs or siRNAs. These genetically
modified exosomes have provided the reduced viability of cancer cell lines, growth inhibition of tumor
xenografts and/or prolonged survival in mice cancer models (reviewed in [137]). On the other hand,
active drugs can be incorporated into exosomes from primed MSCs, resulting in in vitro antitumor
effects [154].
7.3. Cell Membrane-Coated Nanoparticles
Another strategy to deliver nanomedicines into tumors is the use of cell membrane-coated
NPs [155]. These systems use the plasma membrane of different types of cells, such as red blood
Molecules 2020, 25, 715 15 of 25
cells [156], leukocytes [157], macrophages [158], platelets [159], stem cells [160], bacterial [161] or
cancer cells, [162] to coat the NPs. Depending on its origin, the membrane could provide different
in vivo biological behavior to these cell membrane-based NPs. For example, blood and immune
cell membranes could be responsible for an extended systemic circulation and for avoiding immune
clearance, while the cancer cell membrane will provide tumor targeting (Table 2). In addition, using the
fusion of cell membranes from different sources, the hybrid cell membrane-based NPs obtain multiple
functionalities [163].
The nanoparticle used in the core would be designed according to its future application, such as
anti-cancer drug delivery, tissue imaging or photothermal therapy [163,164]. It has been proven that
these membrane-coated NPs accumulate preferentially at tumor sites, improving their efficacy while
reducing their toxicity [163]. A macrophage-biomimetic drug delivery system with anti-angiogenesis
properties was developed by coating PLGA-NPs with macrophage membrane [165]. PLGA-NPs were
loaded with saikosaponin D, a compound which exhibits potential anticancer therapeutic properties.
The authors showed that these cell-membrane engineered NPs effectively inhibited tumor growth
and metastasis of breast cancer in vitro and in vivo through the inhibition of angiogenesis. Polymeric
NPs loaded with the anticancer drug paclitaxel were coated with red blood cell (RBC) membranes.
This RBC-biomimetic drug delivery system significantly inhibited tumor growth and suppressed
lung metastasis [166]. Although the angiogenesis inhibition by paclitaxel was not evaluated, these
RBC-mimetic NPs seem to be an efficient system for cancer therapy.
To overcome tumor hypoxia and improve the therapeutic effects of anti-cancer treatments, several
attempts based in membrane-camouflage have been made. Platelet membranes as nanocarriers were
co-loaded with tungsten oxide (W18O49) nanoparticles and metformin (PM-W18O49-Met NPs) to treat
lymphoma tumors. In this system, metformin reduced tumor oxygen consumption to alleviate tumor
hypoxia, enhancing the therapeutic effects of W18O49 mediated by reactive oxygen species (ROS)
and heat generation [167]. PM-W18O49-Met NPs significantly inhibited tumor growth and induced
apoptosis in lymphoma tumors in vitro and in vivo. Platelet membranes provide immune evasion and
active adhesion to tumor cells mediated by the interaction of platelet P-selectin with ligands expressed
on tumor cells [168]. Other approaches used RBCs as the source of biomimetic membranes. RBCs are
one of the most abundant cell types in the body and, as indicated above, their use as biomimetics
provides immune escape and a long blood circulation time for NPs. In addition, enzymatically active
catalase in the RBC membrane [169] could metabolize tumor endogenous H2O2 and ameliorate tumor
hypoxia. PLGA-NPs coated with RBC membranes were engineered to co-deliver the chemotherapeutic
agent curcumin, and the hypoxia-activated molecule, tirapazamine [170]. These drug-loaded and
coated NPs induced apoptosis via the generation of reactive oxygen species and consequent DNA
damage, suggesting the potential of the present system to circumventing hypoxic solid tumors. In
another approach, the membrane from red blood cells was used to encapsulate nanoparticles consisting
of perfluorocarbon inside PLGA [171]. This nanomimetic approach could provide an efficient supply
of oxygen to the tumor site. Recently, encapsulated Ag2S quantum dots in RBC membranes have
been used as a sonosensitizer to generate ROS under ultrasonic stimulation [172]. This design takes
advantage of ultrasound to promote tumor blood flow, improving hypoxic conditions and enhancing
the sonotherapic effect of the system. In combination with oral anti-tumor drugs, this approach
significantly increased survival of tumor-bearing mice.
Although encouraging results have been found using cell membrane-coated nanoparticles to treat
tumor angiogenesis and hypoxia, this field needs further lines of investigation such as improvement of
the production process to increase the yield and decrease the batch-to-batch variability (Table 2), as
well as a better knowledge of the proteins present in cell membranes to avoid unexpected adverse
immune reactions.
Molecules 2020, 25, 715 16 of 25
8. Conclusions
In cancer therapy, new targets are needed, and the microenvironment provides a wide range of
elements to be targeted. Anti-angiogenic therapies proved lesser benefit than expected and revealed
the relevance of overcoming intra-tumor hypoxia. Hypoxia is a characteristic abnormality of tumor
responsible for the resistance towards conventional cancer therapies. Correction of hypoxia levels and
abnormalities in tumor vessels may improve medication administration and the outcome of treatments.
Taking into account the results reviewed in this article, the most effective strategy in cancer therapy
appears to be the simultaneous targeting of several processes, such as those involved in tumor cell
proliferation, tumor angiogenesis and tumor hypoxia. Therefore, to obtain real clinical benefits it is
necessary to design combined treatments.
Nanotechnology emerges as a fundamental tool in the design of multifunctional anticancer agents.
Nanoparticles will offer an improvement with regard to drug cargo, and targeting and reducing toxicity,
as compared to traditional chemotherapeutic agents. However, NPs present several problems such as
poor penetration inside the tumor and rapid clearance by the reticuloendothelial system.
The use of MSCs as vectors for the delivery of anticancer agents is a very promising strategy due to
their tropism for the tumor microenvironment. Moreover, they are easily available, non-immunogenic
and can be manipulated in vitro. To date, there are several studies suggesting that unmodified MSCs
can exhibit both anti- and pro-tumor properties. Further research is needed to understand the biological
differences between MSCs obtained from different sources and to standardize the culture conditions in
order to improve the safe use of this approach. Two different strategies can be used to combine MSCs
and NPs. Firstly, MSCs are engineered by loading NPs with anti-cancer drugs to be released into tumor
sites. Secondly, drug-loaded NPs are genetically engineered by a gene vector to produce antitumor
proteins and later introduced into MSCs. This system acts as a “Trojan Horse” to deliver two different
therapeutic agents to targeted sites. Besides the challenges of biocompatibility and improvement in the
synthesis process of NPs, further studies are necessary to unravel the role of MSCs in facilitating or
inhibiting tumor growth. Therefore, the use of the MSC/NP system needs additional study before it
can be used clinically in humans.
MSC-derived exosomes can be an alternative to the use of MSCs. Exosomes are endogenous
nanoparticles delivering biomolecules and can also be engineered to be used in cancer therapy.
However, the anti- or pro-tumor properties of native MSCs have also been observed in isolated
exosomes. More studies are needed to evaluate MSCs exosomes’ migration and homing abilities.
Overall, future studies should be carried out to understand exosomes’ and NPs’ interaction, in vivo
biodistribution and interrelation with the tumor microenvironment.
The newest strategy is to use membranes from different types of cells to protect the NPs, but this
approach needs further development.
Although nanomedicine-related technologies need additional improvements, it is reasonable to
assume that the best approach to treat cancer in the future is to combine anti-tumor, anti-angiogenic
and anti-hypoxic agents. These treatments could be administered simultaneously by targeting delivery
methods such as NPs, NP-loaded MSCs, exosome-natural NPs, NP-loaded exosomes and NP-loaded
membranes for a more selective and effective method of treatment.
Author Contributions: All authors have read and agreed to the published version of the manuscript.
Funding: This work was funded by projects PI15/01803 and PI18/01278 (Instituto de Salud Carlos III, Ministry
of Economy, Industry and Competitiveness, and cofunded by the European Regional Development Fund) and
Fundacion Francisco Soria Melguizo.
Acknowledgments: The authors are very grateful to Ian Ure for the English editing of this review article.
Conflicts of Interest: The authors declare no conflict of interest.
Molecules 2020, 25, 715 17 of 25
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