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instability, inflammatio n, immunosurveillance evasion, reprogramming of cellular energetics,
and deactivation of growth suppressors [33,34].
In recent years, the deep interest of researchers in the discovery and development of novel
antitumoral compounds was reflected in the massive increase in the number of cancer ther-
apeutics, from 50,000 known compounds in 2006, to 326,000 in 2014 [2]. Moreover, of all the
antitumoral molecules discovered between 1981 and 2014, 49% were natural compounds or
derivatives [35]. Specific mechanisms of action displayed by alkaloids, diterpenes, polyketi-
des, flavonoids, etc., include inhibition of topoisomerase, cell-cycle arrest, ability to bind mi-
crotubules or DNA, and induction of apoptosis [2].
Currently, over 60% of the chemothe rapeutic drugs used in clinic are derived from natural
sources [32]. Some honorable examples include paclitaxel, obtained from Taxus brevifolia,
vincristine and vinblastine, from Catharanthus roseus [2,36], docetaxel, obtained from 10-
deacetylbaccatin from Taxus brevifolia [37], topotecan and irinotecan, from Camptotheca acumi-
nata [38,39], eribulin, derived from Halicondrina B [35] and trabectedin, sourced from the
algae Ecteinascidia turbinata [35]. The clinical applications of paclitaxel (Taxol), one of the
most used chemotherapeutic agents, as a mono- or combined therapy, include the treatment
of metastatic/advanced breast cancer, advanced ovarian cancer, non-small cell lung cancer,
and Kaposi sarcoma [36]. Moreover, chemotherapy drugs can be obtained by modifications
of primary natural compounds. This is the case of irinotecan and topotecan, both derivates of
TABLE 3.1 Examples of different natural compounds or derivatives with relevant biological activities
belonging to the above-mentioned classes.dcont’d
Bioactive Biological activity
Class of natural
compounds References
Rapamycin Immunosuppressant Polyketides [15]
Erythromycin A Antimicrobial [13,15]
Tetracycline Antimicrobial [15]
Lovastatin Antihypercholesterolemic [13,15]
Amphotericin B Antifungal
Doxorubicin Antitumoral [13,15,30]
Daunorubicin Antitumoral [13]
Epirubicin Analgesic [30]
Paclitaxel Anticancer Terpenoids[31][17,18]
Limonene
Menthol Analgesic [31]
Cannabinoids Psychoactive, anxiolytic and anesthetic.
Artemisinin Antimalarial
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camptothecin, a natural compound present in different plant species, but especially
C. acum inata [40]. Camptothecin-derived compounds showed very promising antitumoral ac-
tivity, particularly against colorectal cancer, by interfering with topoisomerase I. However,
these derivatives presented some limitations, i.e., poor water solubility, in vivo instability,
and unpredictable drug-drug interactions [40,41]. To solve these issues, irinotecan and topo-
tecan, water-soluble first-generation analogs of camptothecin, were synthesized [41]. Another
strategy to improve camptothecin applicability in clinic is the use of drug delivery systems,
which are presented further on.
1.2 Natural compounds and infectious diseases
The number of infectious diseases caused by microorganisms is increasing worldwide,
significantly impacting economies and raising severe public health concerns [42]. An
alarming issue regarding infectious diseases is the emergence of drug- or multidrug resistant
microorganisms (i.e., vancomycin-resistant Enterococci and Staphylococcus aureus, methicillin-
resistant S. aureus, multidrug-resistant Gram-negative bacteria, multidrug-resistant Mycobac-
terium tuberculosis)[43e45]. Although antimicrobial-resistant infections are not among the
major causes of death worldwide, these infections are related to prolonged hospitalizations,
increased healthcare, and treatment costs. [44]. On the other hand, the continuous misuse of
antimicrobial agents in developed countries will most likely contribute to a rise in mortality
[46]. Other factors associate d with the increase of these infections include the faster dissem-
ination of microorganisms across the world and the occurrence of spontaneous mutations
[43,44]. Thus, there is the need to discover and/or produce new bioactive compounds with
antimicrobial properties that are effective in the treatment of drug- or multidrug-resistant in-
fectious diseases [47].
Natural products have historically been used for their antimicrobial properties [48,49], and
have shown proof of their high importance for the disco very of novel drugs, comprising the
biggest share of the currently used antibiotics [50]. In fact, out of the nine classes of antibi-
otics, six are sourced naturally (b-lactams, tetracycline, macrolides, glycopeptides, and linco-
samides) [51]. Plant-d erived compounds may intrinsically present antimicrobial properties or
may act synergistically with conventional antimicrobial drugs, restoring their therapeutic ac-
tion, increasing their potency, and overcoming resistance [52]. Alkaloids, a previously pre-
sented class of natural compounds, play a very important role in the treatment of
infectious diseases [52]. Some examples include isoquinolines that inhibit cell division and
disturb the Z-ring; quinolones that function as respiratory inhibitors, reducing O
2
consump-
tion; agelasines that disrupt bacteria homeostasis by inhibiting dioxygenase enzymes; and
squalamine that disrupts the outer and cytoplasmatic membranes [53]. Flavonoids have
also demonstrated antimicrobial properties, which may be related with the formation of com-
plexes with microbial extracellular and membrane proteins [54]. Also, this class of com-
pounds presents a significant antiviral activity, such as apigenin (i.e., herpes simplex virus
type 1 and 2, poliovirus type 2, hepatitis C virus, African swine fever virus); baicalein (i.e.,
human cytomegalovirus, influenza H5N1 and H1N1, influenza H1N1 Tamiflu-resistant vi-
rus, dengue virus); luteolin (i.e., HIV-1, EpsteineBarr virus, Japanese encephalitis virus,
and SARS-CoV); quercetin (i.e., Mengo virus, poliovirus type 1, her pes simplex virus type
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1 and 2, influenza H1N1, H5N2, H7N3, and H9N2, Japanese encephalitis virus, hepatitis C
virus, rhinovirus); naringenin (i.e., hepatitis C virus); and rutin (i.e., HIV-1, dengue virus,
SARS-CoV) [55,56]. In addition, terpenoids are active against Gram-positive bacteria, mainly
due to their lipophilic nature, increasing the fluidity and penetrability of bacterial membranes
[52]. Some examples of terpenoids with antibacterial activity include thymol, carvacrol,
linalool, terpinene-4-ol, oleanolic acid, and menthol [57,58]. Examples of phenylpropanoids
and polyketides with antimicrobial activity are also presented in Table 3.1.
1.3 Anti-inflammatory properties of natural compounds
Inflammation is the body’s response to harmful stimuli (noninfectious or infectious), being
required to maintain normal homeostasis [59,60]. Uncontrolled inflammatory processes are
involved in the pathophysiology and progression of many diseases that account for high
mortality and morbidity rates (i.e., cancer, stroke, diabetes mellitus, heart disease, nonalco-
holic fatty liver disease (NAFLD), autoimmune diseases, and neurodegenerative diseases)
[59,61,62]. Usually, the involvement of inflammation in disease occurrence and progress ion
follows a multistep process: cytokines are secreted upon initiation and progression of the in-
flammatory process, attracting leukocytes; the chemokines and cytokines increase the expres-
sion levels of adhesion properties, promoting the extravasation of circulating inflammatory
cells and directing these cells to the inflammation site. Herein, macrophages play a key
role in many inflammation-mediated diseases, namely cancer and atherosclerosis [62].
Thus, it is important to reduce inflammation to diminish the diseases’ aggressiveness [62].
Currently, different classes of drugs are clini cally available against inflammation, including
nonsteroidal anti-inflammatory drugs (NSAIDs), immunosuppressants, glucocorticoids,
and other biologicals. However, most of them lead to some adverse side effects that might
limit their use [60].
To overcome these limitations, natural compounds of different classes emerge as prom-
ising anti-inflammatory agents. Among these are flavonoids, i.e. , wogonin, kaempferitrin,
fisetin, papyriflavonol A, glabidrin, luteolin, baicalein, puranic, isoflavone, catechin, cyani-
din, apigenin, rutin, chrysin, genistein, and oroxylin A [63e65]; alkaloids, i.e., berberine, che-
lerythrine, warifteine, matrine, oxymatrine, brucine, riparin I and II, ailanthamide,
berbamide, brucine, caulerpin, theacrine, scholaricine, eleagnine, and sanguinarine [63,66];
terpenoids, i.e., pristimerin, isocyperol, ursolic acid, vernomelitensin, onoprodopicrin, arte-
morin, goyazensolide, hawtriwaic acid, erythroivorensin, casearin B, andalusol, pinusolide,
acanthoid acid, triptolide, inflexinol, and tetracyclic iridoid plumericin [63,67,68]; and phenyl-
propanoids, i.e., resveratrol, curcumin, epigallocatechin gallate, verbascoside, teupolioside,
polydatin, dillapiole, dihydrodillapiole, and phenethyl alcohol [69,70].
2. Plant bioactives market and conventional pharmaceutical formulations
Historically, the exploration of bioactives from natural sources has been prompted by the
isolation of morphine, a broadly used alkaloid for pain management, by Friedrich Serturner
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in 1806 [71]. The pharmaceutical industry was also shaped by this discovery, with Heinrich
Merck initiating the commercialization of this opium-based analgesic in 1827 [72].
The World Health Organization (WHO) reveals that there are 20,000 medicinal plants scat-
tered over 91 count ries and, currently, it is estimated that more than 50% of drugs available in
the market are derived natural sources [73,74]. Currently, 75% of drugs used to treat infec-
tious diseases and 60% of anticancer drugs are of plant origin [75]. Synt hetically produced
plant actives were introduced to supply high quantities of bioactives at lower costs. In
1853, salicylic acid was the first plant active being produced through chemical synthesis
[76]. Another example of a semisynthetic plant active is paclitaxel. Naturally, paclitaxel is pre-
sent in the bark of Taxus brevifolia in extremely low concentrations (0.001%e 0.05%), costing
$600,000 to produce 1 kg of this drug [77]. Therefore, a semisynthetic form was produced,
with its manufacturing process approved by the Food and Drug Administration (FDA) in
1994 [77,78]. In this synthesis process, baccatin II and/or deacetylbaccatin II are isolated
from needles and stems harvested from Taxus brevifolia, which are then chemically converted
into paclitaxel [78].
According to the FDA, a natural product with therapeutic potential can be of different na-
tures: unregulated natural materials; FDA-regulated compounds that occur in nature or un-
modified natural materials; chemically modified natural occurring compounds, also referred
to as semisynthetic; and synthetic compounds inspired on plant actives, used as scaffolds
[72]. The market introduction of FDA-approved drugs based on plant actives, highlighted
in Table 3.2, has continuously increased since the 1930s, peaking around the 1990s and
showing a steady decline ever since [72]. Although bioactives from natural sources were
essential for the development of pharmaceutics and the pharmaceutical industry as we
know it, currently less than a quarter (23%) of drugs under investigation in the industry pipe-
line are plant-derived actives [86].
The shift in the industry’s interest to the production of synthetical drugs can be explained
by the difficulties associated with isolating and classifying plant actives [76]. Examples of
such obstacles include the necessity for automated assays for the high throughput screening
of many drug candidates; intense purification to isolate and identify the compound of interest
from a complex mixture [87]. In addition, obtaining the rights of Intellectual Property can be
troublesome, as it is not always possible to patent naturally occurring plant actives [88].
Nevertheless, the number of new drugs reaching the market is discrete, highlighted by the
difference in the number of drugs approved by the FDA in 1990 (45 drugs) and 2010 (21 drugs)
[89,90]. Moreover, of all the drugs introduced to the market between 1981 and 2002, only 36%
were classified as synthetic, with the majority of drugs being naturally occurring or semisyn-
thetic plant actives [89]. Due to this and the overall unmet expectations of chemical synthesis
of novel drugs, the pharmaceutic industry is once again focusing on the development of plant-
based bioactives [76,90]. Although very complex, research of novel plant actives has proven to
originate promising drug candidates [76]. Furthermore, there are still many plant species to be
discovered and screened. With only 20% (60.000) of all known plant species screened for bio-
actives, that originated 135 compounds [89], the pharmaceutic industry believes that the
remaining 80% would lead to the discovery of 700 new drug candidates [89
].
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TABLE 3.2 Commercialized plant-based bioactives, their origin, and indications.
Bioactive Origin Indications References
Amorphine Papaver somniferum Dopamine agonist [79]
Codeine Antitussive [71]
Morphine Opioid analgesic
Papaverine Antispasmodic
Atropine Atropa belladonna Anticholinergic
Tiotropium [79]
Artemisinin Artemisia annua L. Antimalarial [76]
Paclitaxel Taxus brevifolia Anticancer [75,80]
Taxol Taxus baccata
Docetaxel
Vinblastine Catharanthus roseus [80,81]
Vincristine
Vinorelbine
Vindesine
Quinine Cinchona officinalis L. Antimalarial
(
L)-Dopa Mucuna deeringiana Anti-Parkinson
Vincamine Vinca minor Nootropic
Capsaicin Capsicum annum L. & C. minimum Mill Analgesic [76]
Colchicine Colchicum spp. Antigout
Galanthamine Galanthus caucasicus Acetylcholinesterase inhibitor
Masoprocol Larrea tridentata Anticancer
Ephedrine Ephedra sinica Stapf. Alpha/Beta-adrenergic agonists [82]
Aspirin Salix spp. Analgesic, antipyretic [83]
Etoposide Podophyllum peltatum Anticancer
Tricosanthin Tricosanthes kirilowii [84]
Digoxin Digitalis lanata Cardiotonic [72]
Nitisinone Callistemon citrinus Hydroxyphenylpyruvate dioxygenase inhibitor [79]
Silymarin Silybum marianum Liver disease
Caffeine Camellia sinensis L. CNS stimulant [85]
Theobromine Theobroma cacao L. Diuretic, bronchodilator
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3. Limitations of plant bioactives
As mentioned in Table 3.2, a diversity of plant-derived products with pharmacologic prop-
erties has been investigated and successfully approved for clinical use [91,92]. However,
despite their therapeutic potential against a variety of conditions, natural-based compounds
present limitations and are not deprived of toxic side effects (Fig. 3.1)[93e96]. A major aspect
of plant actives is their low solubility, either in water (e.g., carotenoids, phytosterols, caroten-
oids) or in oil (e.g., ʟ-ascorbic acid, polyphenols) [97,98]. The majority of natural compounds
are highly hydrophobic and may display chemical instability (oxidation, hydrolysis) and/or
be susceptible to degradation when exposed to specific conditions (e.g., enzymes, light, oxy-
gen, high temperature, pH variations) [93,94]. These factors lead to a lack in research data
regarding safety, allergic reactions, drug interactions, and mechanism of action, limiting
the successful translation into the clinical setting [99]. Moreover, natural-based products
may present poor pharmacokinetic and biodistribution profiles that result in low concentra-
tion at targe t tissues and, therefore, suboptimal therapeutic outcomes [96].
For instance, the bioactive thymoquinone, obtained from the plant Nigella sativa, is widely
investigated for its potent pharmacological properties, such as antioxidant, anti-inflamma-
tory, hepato- and neuroprotective, antidiabetic, and anticancer [100]. However, the oral
bioavailability of this compound is low due to poor stability in the gastrointestinal tract.
The high hydrophobicity of thymoquinone results in low intestinal permeation and low
oral bioavailability [100,101]. Naringenin, a flavonoid naturally found in citrus and other
fruits, presents various pharmacological properties, including metal chelation, free radical
scavenging, apoptosis induction, anticancer, anti-inflammatory, antibacterial, as well as
neuro- and hepatoprotective [102]. Unfortunately, the bioavailability of this natural com-
pound is also very low due to its hydrophobicity, extensive gastrointestinal degradation, liver
first-pass metabolism, and limited membrane transportation [102]. Considering these factors,
solutions for a successful use of plant-derived compounds as pharmacologically active agents
are mandatory.
FIGURE 3.1 Limitations of plant bioactives.
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4. Innovative pharmaceutical formulations of plant bioactives
As mentioned in Section 2, the industry’s interest in plant actives has reemerged [103]. The
efficacy of plant actives, as well as of other types of compounds, greatly depends on the suc-
cessful targeting of respective molecules and/or receptor, which can be located intra- or
extracellularly [103]. It is well-known that a great majority of commerciali zed drugs present
poor water solubility, low in vivo stability, inability to cross biological membranes and inad-
equate absorp tion due to high molecular size and/or weight, leading to impaired drug effi-
cacy [ 104e106].
In recent years, there have been advances regarding novel and innovative formulations to
deliver plant actives, with some successfully reaching the market [107]. Examples include
mouth-dissolving tablets, mucoadhesive systems, implants, granules, etc. [107,108]. Although
these innovative formulations can control the release of a dr ug, they as mostly used for the
delivery of hyd rophilic drugs and lack target specificity [108]. These limitations can be over-
come by empl oying novel delivery systems.
These systems can precisely deliver the plant active to the target site, minimizing un-
wanted side effects and increasing its bioavailability, allowing for controlled release, and pro-
tecting the compound from premature degradation [105,109]. An ideal drug delivery system
should not only be able to deliver a high payload of certain compounds but also keep it in the
designated therapeutic window [110]. Moreover, the design of these systems should take into
account certain aspects, including the properties of the plant active, route of administration,
targeting ability, biocompatibility, and the mechanism behind the release of the plant active
[103]. Research involving the delivery of plant actives using delivery systems is applied to
different diseases, in particul ar diabetes, cancer, infectious diseases, and neurodegenerative
disorders [95,111].
Different types of drug delivery systems are available, such as vesicular delivery systems
(i.e., liposomes, solid lipid nanoparticles (SLNs), ethosomes, phytosomes, and transfero-
somes); particulate delivery systems (i.e., organi c and inorganic nanoparticles [NPs]); and
biphasic systems (i.e., micro- and nanoemulsions) [103,112]. Vesicular systems have been
described as advantageous over other types of drug delivery systems for controlled drug de-
livery due to many factors, including improved bioavailability of poo rly soluble drugs; deliv-
ery of both hydrophilic and lipophilic drugs; reduced drug toxicity and increased drug
stability; and prolonged blood circulation time of drugs [109,113]. Some vesicular and partic-
ulate delivery systems are part of a group of drug delivery systems known as nanocarriers
[104] and will be further explored in the following sections.
5. Nanotechnology as key strategy to deliver bioactives
Nanotechnology is present in our day-to-day life and has revolutionized many fields,
including medicine and healthcare [114]. In fact, and endorsing its importance, the European
Union (EU) has acknowledged that nanotechnology may achieve significant and innovative
solutions to medical problems (i.e., treatments and diagnosis), awarding it the title of Key
Enabling Technology [114].
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Nanomedicine is the application of nanotechnology to medicine and healthcare, normally
focused on therapeutics, diagnosis, and disease prevention, at the cellular level [115].
Applying nanotechnology to therapeutics has many advantages, namely increased bioavail-
ability, which leads to a reduction in the required dosage, improved transport across biolog-
ical barriers and distribution profile due to targeting abilities, and controlled drug release
[116]. Such advantages have been corroborated in preclinical and clinical trials, in which
drug-loaded nanosystems were shown to improve safety, drug efficacy, and drug accumula-
tion at the target site [117]. The successful clinical application of these nanocar riers for the de-
livery of plant actives is demonstrated by the seve ral commercialized products, as displayed
in Table 3.3.Bydefinition, stated by the European Medicines Agency (EMA), a nano pharma-
ceutical is a system with reproducible properties, with at least on e component at the nano-
scale, designed for clinical applications and that takes advantage of nanoengineering [116].
Most plant activesebased nanopharmace uticals approved for clinical use are for the treat-
ment of cancer, in which nanomedicine has proven to be extremely advantageous [128].
Among the developed drug delivery systems, NPs and nanocarriers have gained tremen-
dous attention [95,104,117,129]. NPs present sizes ranging from 10 to 1000 nm and are usually
made from polymer s or lipids [130]. NPs and nanocarriers are generally able to overcome the
TABLE 3.3 Commercialized formulations of plant bioactives/derivatives using nano-based delivery systems.
Commercial
name Bioactive Nanosystem Applications Outcome References
Abraxane Paclitaxel Albumin
NPs
Breast, non-small cell lung, and
pancreatic cancers
Improved solubility and
delivery to tumor
[118]
Opaxio Polymeric
NPs
Head and neck cancer,
glioblastoma
Controlled release [119,120]
Genexol-PM Polymeric
micelles
Breast and non-small cell lung
cancers
Improved solubility and
safety profile
[120]
Tocosol Nano-
emulsion
Breast cancer Similar to Taxol [121]
Doxil Doxorubicin Liposomes Kaposi sarcoma, ovarian
carcinoma, and multiple
myeloma
Improved safety profile and
delivery to tumor
[122]
Myocet Metastatic breast cancer
DaunoXome Daunorubicin Kaposi sarcoma Improved safety profile and
delivery to tumor
[123]
Marqibo Vincristine Acute lymphoblastic leukemia [124]
Onivyde Irinotecan Pancreatic cancer [125]
DepoDur Morphine Postoperative analgesic Extended release [126]
Avinza Nanocrystal Psychostimulant Extended release; increased
bioavailability; drug loading
[127]
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previously presented physicochemical and pharmacokinetic challenges related to plant ac-
tives [104]. The different nanosystems can be classified into two main groups according to
the nature of the material used for their production. Some examples are depicted in
Fig. 3.2: organic, when polymeric, lipid-based, and dendrimers; or inorganic, such as quan-
tum dots or when composed of carbon, metals, silica; and hybrid, composed of a mixture
of organic and inorganic materials [131,132]. Polymeric NPs and liposomes have been the
most explored among the different types of nanosystems for the delivery of plant actives
and extracts, with several approved nanopharmaceuticals [104,130].
Nanosystems are able to passively accumulate at the target site via the enhanced perme-
ability and retention (EPR) effect and may be actively targeted with tissue- or cell-specific li-
gands or other moieties, bound to the surface (i.e., peptides, small molecules, antibodies,
proteins, nucleic acid aptamers) [133,134].
The EPR effect, first described by Matsumura and Maeda in 1986, is most prevalent in can-
cer and inflammation due to the specific associated microenvironment but is also useful for
passive drug delivery targeting other lesions [135,136]. This phenomenon is dependent on
specific pathophysiological alterations that occur upon certain disorders, i.e., wide fenestra-
tions of blood vessels and poor lymphatic drainage [137,138]. Typically, commercialized
drugs with low-molecular weight freely extravasate out of the blood vessels into healthy tis-
sues. On the other hand, drug-loaded nanosystems remain in circulation [136], only extrav-
asating upon the occurrence of wide fenestrations, such as the ones observed in cancer and
other pathological conditions. Abraxane, an albumin-bound paclitaxel formulation, is
FIGURE 3.2 Representative examples of different types of nanosystems (i.e., inorganic and organic).
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commonly used for cancer chemotherapy, being a popular example of commercialized drug-
loaded nanosystem that accumulates at the target site by passive targeting [138]. This FDA-
approved formulation was a big breakthrough, as it allowed to improve paclitaxel’s
bioavailability and solubility without using Cremophor, a solubilizing agent commonly asso-
ciated with hypersensitivity reactions [139]. Moreover, Abraxane improved paclitaxel’s accu-
mulation at the tumor site, promoted by albumin receptor (gp60)-mediated endothelial
transcytosis [134,139]. Other FDA-approved nanopharmaceuticals that take advantage of
the EPR effect include Myocet, Doxil, DaunoXome, Mariqbo, Onivyde, and Genexol-PM
[140,141]. Although the rate of extravasat ion from blood vessels is slow, and drug leakage
and degradation may occur during systemic circulation, drug targetability toward diseased
sites and subsequent accumulation at therapeutic levels is still improved when compared
to the fre e drug [135].
As aforementioned, active targeting requires the functionalization of an NP or nanocarrier
surface with targeting moieties to enhance the drugs specificity, accumulation, and cell inter-
nalization [140]. The latter can be achieved by targeting internalizing receptors, promoting
the cellular uptake of the nanosystem by receptor-mediated endocytosis [142,143]. While pas-
sive targeting relies on the pathophysiological characteristics of the target tissue, active tar-
geting depends on the biological interactions between the ligand-decorated nanosystem
and the target cells [144]. A vast number of ligands, as well as corresponding targets, have
been studied in vitro and in vivo with promising results [145]. Logically, receptors and/or
targets of interest depend on the disease under investigation. However, some receptors are
common to different diseases and disorders, and thus have gained special attention [146].
Among these are the folate receptor, the vascular endothelial growth factor receptor
(VEGFR), mannose-6-phosphate receptor, matrix metalloprotease, insulin growth factor-1
(IGF-1) receptor, interleukin (IL-1) and IL-2 receptors, low density lipoprotein (LDL)-receptor
family, epidermal growth factor receptor (EGFR), ErbB2, transferrin receptor, vascular cell
adhesion molecule 1 (VCAM-1), and platelet endothelial cell adhesion molecule-1
(PECAM-1) [146e148]. Although active targeting has shown very promising results in pre-
clinical models, so far no targeted nanomedicine has been approved for commercialization
by the regulatory agencies [149].
5.1 Polymeric nanoparticles
Polymeric NPs have ga ined attention due to their versatile properties, i.e., physicochemical
characteristics, biocompatibility, easy functionalization, and biodegradability. They can be
prepared using different methods, such as nanoprecipitation, emulsion-diffusion, double
emulsification, emulsion-coacervation, layer-by-layer, and polymer coating [104,150]. “Poly-
meric NPs” include both polymeric nanocapsules and nanospheres, differing in the way the
drug is delivered. Polymeric nanocapsules are a reservoir system, with the drug dissolved in
an oily core and protected by a polymeric shell. Nanocapsules can deliver both hydrophilic
and lipophilic drugs and, compared to other types of drug delivery systems, their drug
loading is increased [104]. Nanospheres are a matrix system in which the drug is retained
in a continuous polymeric network or adsorbed to the surface of this network [151]. Den-
drimers are also made of polymers, and thus will be included in this section [152].
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