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Smart Drug Delivery Systems – Futuristic Window in Cancer Therapy
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Figure 5.
Internal structure of nanoliposome and its preparation.
Figure 6.
Entrapment of anticancer drug loaded nanoliposome by active and passive targeting.
Nanomedicine for Targeted Drug Delivery in Cancer Chemotherapy
DOI: http://ITexLi.114066
Clinical products Formulation Indication Company Year
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Nanolipid vesicles
Onivyde Liposomal
irinotecan
Visudyne Liposomal
verteporfin
DaunoXome Liposomal
daunorubicin
AmBisome Liposomal
amphotericin B
Myocet Liposomal
doxorubicin
Doxil/Caelyx Liposomal
doxorubicin
Marqibo Liposomal
vincristine
Inorganic and metallic nanoparticles
GastroMARKumirem SPION coated
with silicone
INFed Iron dextran
(low MW)
Feridex/endorem SPION coated
with dextran
Venofer Iron sucrose Iron deficiency in chronic
NanoTherm Iron oxide Glioblastoma MagForce 2010
Pancreatic cancer Merrimack 2015
Macular degeneration, wet
age-related, myopia, and
ocular histoplasmosis
AIDS-related Kaposi’s
sarcoma
Fungal/protozoal infections Gilead Sciences —
Combination therapy
with cyclophosphamide in
metastatic breast cancer
Ovarian, breast cancer,
Kaposi’s sarcoma, and
multiple myeloma
Acute lymphoblastic
leukemia
Imaging agent AMAG
Iron deficiency in chronic
kidney disease (CKD)
Imaging agent AMAG
kidney disease (CKD)
Bausch and
Lomb
Galen 1996
Elan
Pharmaceuticals
Janssen 1995–
Talon
Therapeutics
Inc.
Pharmaceuticals
Sanofi Aventis 1957
Pharmaceuticals
Luitpold
Pharmaceuticals
2000
2000
2008
2012
2001–
2004
2000
Table 1.
List of lipid-based nanolipid vesicles, and inorganic (metallic) nanoparticles approved by the FDA.
. Polymeric nanoparticles
Polymeric nanoparticles (PNPs) are colloidal nature with submicron range of
10–1000nm in size. Drugs are incorporated within the nanoparticles or attached to
the surface of them to forma nanosphere or nanocapsule achieves sustained release to
malignant cells for targeted action (Figure and Table ) [31, 34]. Generally biodegradable polymers are poly(lactic-co-glycolic acid) (PLGA), polylactic acid (PLA),
poly(amino acids), poly(q-caprolactone) (PCL) and herbal polymers consist albumin, alginate, chitosan, and gelatin are used. Cytotoxic drugs such as doxorubicin,
cisplatin or other anticancer can be loaded drug in polymeric nanoparticles for cancer
chemotherapy which prevent toxic or unwanted effects [35]. Due to leaky blood
vessels anticancer drug loaded nanoparticles easily penetrate the malignant cells at
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Figure 7.
Internal structure of polymeric nanoparticle include nanocapsule and nanosphere.
the targeted sites and accumulate via passive targeting [36]. Monoclonal antibodies
are used for specific targeting ability. To further modify the therapeutic efficacy
of anticancer drugs (mAbs) is conjugated or tagged with the surface of polymeric
nanoparticles used for active targeting of malignant cells in cancer chemotherapy.
For the treatment of breast cancer cells with positive expression of human epidermal
growth factor receptor 2 Trastuzumab (Herceptin i.e. HER2) is may be used [37].
. Protein-based nanoparticles
In the field of nanomedicine for cancer treatment, protein has been constructed
as nanocarriers for chemotherapy. They are three-dimensional structure and have
several advantages such as good biocompatibility, biodegradability and low toxicity. Proteins designed as nanodevices mainly include albumin, transferrin, ferritin,
low-density lipoprotein, high density lipoprotein etc. [38]. Protein based nanoparticle
delivers anticancer drugs has been widely studied and shown good clinical application
prospects [39]. Albumin-bound paclitaxel are the most classic compound for proteinbased nanoparticles. Paclitaxel was incorporated into albumin via hydrophobic interaction and then formation of albumin bound paclitaxel nanoparticles with a diameter
range of 130nm, which is traded as Abraxane (celgene) [40]. Nowadays Abraxane
has become one of the best-selling protein-based nanoparticles for cancer chemotherapy. Amine, thiol and carboxyl groups which are the binding sites of albumin can
be combined with anticancer drugs by non-covalent interactions such as hydrophobic
and electrostatic interactions [41]. Protein-based nanoparticles specifically respond
to stimuli in the malignant cells and deliver the drug to the tumor region, enabling
targeted therapy (
Iron homeostasis-related proteins such as transferrin and ferritin, are another class
of proteins are commonly used as protein based nanoparticles shown excellent performance in receptor-mediated active targeted delivery [43]. Transferrin is the main
iron-containing hydrophilic transporter in plasma mainly formed by hepatocytes in
Figure ) [42].
Nanomedicine for Targeted Drug Delivery in Cancer Chemotherapy
DOI: http://ITexLi.114066
Figure 8.
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Protein based nanoparticle and its application.
the human body, and also responsible for transporting iron in hepatocytes to cells
in other tissues [44]. Transferrin are constructed of single chain glycoprotein and is
divided into two evolutionary lobes, namely C-lobe (343 amino acids) and N-lobe
(336 amino acids) which are connected to each other by a short spacer [45].
Transferrin mediates iron uptake by binding with the transferrin receptor (TfR)
which is glycoprotein including TfR1 and TfR2 are the major protein receptor for
iron metabolism in vivo. TfR is expressed in both in normal as well as cancer tissues.
Research studies have confirmed that the expression rate of TfR in cancer cells is
nearly 100 times higher than that of normal cells. Neoplastic cells rapidly grow and
iron demand is greatly enhanced during DNA synthesis, differentiation and for
regeneration also [44]. TfR expression is therefore enhanced in malignant cells in
order to adapt to the increased iron requirement and maintain rapid cell division.
Transferrin nanoparticles can be widely applicable for tumor diagnosis for its active
transport capability and beneficial for targeted delivery of therapeutic agents.
Transferrin-templated copper nanoclusters-doxorubicin NPs were fabricatedfor
targeted drug delivery and bioimaging. Transferrin can also be used alone as ligand to
provide active tumor targeting capabilities of drug delivery systems.
. Viral nanoparticles
In the field of nanoparticles and biomedicine viruses may be used to develop
technologies particularly in tissue targeting and drug delivery. Viral nanoparticles are
significant in their protection of nucleic acids due to the stability of capsid [46]. This
physical feature enhances the resistance of VNPs to both temperature and pH levels
while allowing the VNPs to remain stable in different types of solvents [47]. Various
VNP platforms have been constructed, such as bacteriophages and icosahedral plant
viruses as well as rod-shaped plant viruses and filamentous phages [48]. The adaptability of this binding drug moiety can occur via adsorption, encapsulation and
covalent attachment (Figure ) [49]. Cargo molecules may be incorporated through
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Figure 9.
Viral nanoparticle and its application.
interactions with the interior architecture of the capsid and their highly systemic and
repetitive surfaces provide multiple sites for the covalent attachment of site specific
residues [50]. Imaging agents and therapeutic drugs can chemically linked to reactive
functional groups such as thiol for specific delivery. This method has been validated
through the use of virus-like protein cage architecture used to attach and release the
anticancer drugs such as doxorubicin [51].
. Mesoporous silica nanoparticles
Large amount of anticancer drugs can be incorporated mesoporous silica nanoparticles (MSN) and their accumulation in tumor tissues has been observed via passive targeting [52]. Silica nanoparticles having a porous architecture, in their physical structure
and they are beneficial for biomedical and nanomedicine applications. Prolongation of
circulation, drug availability and biodistribution of therapeutic drugs may modify after
PEGylation processes which can promote escape from the reticuloendothelial system
(RES) [53]. Mesoporous silica nanoparticles (MSNs) are preferably studied for targeted
drug delivery, diagnosis, bio sensing and cellular uptake in the field of biomedical
application. Mon disperse spherical nanoparticles (SNP) with diameter ranges of
20–200nm were employed to study size, dose and cell type-dependent cytotoxicity in
A549 and Hep G2 epithelial cells and NIH/3T3fibroblastasca nanoparticles having pore
diameters ranging from 2 to 50nm with narrow pore size distribution and having good
chemical and thermal stability. Convenient surface functionalization of these nanocarriers through chemical modification of the active targeting mechanism and several
attractive features such as good biocompatibility, large specific surface area, high loading capacity of these devices many anticancer drugs, including doxorubicin, methotrexate, paclitaxel have been loaded and delivered effectively via MSN (Figure )
[54]. MSNs are preferably studied for targeted drug delivery, diagnosis, bio sensing and
cellular uptake in the modern field of cancer chemotherapies. Mon disperse spherical
nanoparticles (SNP) with diameter ranges of 20–200nm were employed to study the
size, dose and cell type-dependent cytotoxicity in A549 and Hep G2 epithelial cells and
NIH/3T3fibroblastas [55]. The extension mechanism of SNP cytotoxicity (such as cell
viability, oxidative stress, cellular uptake, membrane disruption were found to be not
Nanomedicine for Targeted Drug Delivery in Cancer Chemotherapy
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Figure 10.
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Schematic diagram of mesoporous nanoparticle and its application.
only size and dose dependent but also highly cell type dependent. Generally, 60nm size
of SNPs was preferentially endocytosed by cells and high doses, because a disproportionate decrease cell bioavailability [56].
. Polymeric nanogels
Above the critical micelle concentration (CMC) polymer-based micelles and
vesicles maintain their structure. They lose the function as drug carriers with the
dissociation of their self-assembled nanostructures into single polymer chains below
the CMC. To overcome this problem the employment of chemically or physically
crosslinked polymer network to obtain nanogels which is effective approach to obtain
more stable nanocarriers in different biological conditions [57].
Nanogels are the three dimensional hydrophilic networks with three-dimensional
(3D) porous structures which are cross-linked hydrogel nano-size devices ranges from
20 to 200nm. These are either co-polymerized or monomers and ionic or non-ionic.
Nanogels are physically or chemically crosslinked polymer networks that are swell in
a good solvent [58]. Due to their nano size nanogel showed the prolonged serum halflife period and escape renal clearance. These devices have tendency to imbibe water or
physiological fluid in large amount, without changing in internal network structure.
By incorporating of ligands molecules into nanogels can be applicable for targeted
delivery in cancer chemotherapy [57]. These nano devices shows better thermodynamic stability, relatively low viscosity, and also form elevated capacity of the solubilization. These nanocarriers have the capability of undergoing vigorous sterilization
techniques. Nanogels possess a hydrophilic nature which limits good encapsulation
property of hydrophobic drugs. Nanogels can entrap anticancer drugs and the biological molecules and also employed in protein and gene delivery [59]. For this reason,
suitable structure engineering of the polymer was taken to permit high encapsulation
efficiency. Therefore, nanogels provided novel strategy of drug delivery for poorly
soluble drugs which does not only improve their solubility and stability but increasing
the opportunity of their cellular uptake than the free drug. They show high biocompatibility as well as better biodegradability compare to other nanodevices. Because of
their extremely small size in nature they enhanced permeation capability. Nanogels
permits both passive and active drug targeting for cancer chemotherapy [58].
Polymer-based nanogels are three-dimensional network consisting of chemically or
physically crosslinked polymer containing both hydrophilic (polar) and hydrophobic
monomers. They form semisolid states (hydrogels) when dispersed in aqueous media,
which may be swollen by a large amount of water [59]. The needs of application of
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Clinical products Formulation Indication Company Year
Genexol-PM mPEG-PLA micelle loaded
Cimzia/
certolizumabpegol
Adynovate Polymer-protein conjugate
Eligard Leuprolide acetate and
Renagel Poly(allylamine
Estrasorb Micellarestradiol Menopausal
with paclitaxel
PEGylated antibody
fragment (certolizumab)
(PEGylated factor VIII)
polymer PLGA (poly(DL-
lactide-co-glycolide)
hydrochloride)
Table 2.
List of relevant (polymer-based and lipid-based) organic and inorganic (and metallic) nanomedicines approved
by the FDA.
Metastatic breast
cancer
Crohn’s disease
Rheumatoid/
psoriatic arthritis
Ankylosing
spondylitis
Hemophilia Baxalta 2015
Prostate cancer Tolmar 2002
Chronic kidney
disease
therapy
Samyang
Corporation
UCB 2008–2013
Sanofi 2000
Novavax 2003
South
Korea
2007
Figure 11.
Anticancer drug loaded polymeric nanogel and its application.
hydrogels tuned to match the properties of hydrogels. By the choice of specific polymers (molecular structure and segment length), the crosslinking mechanism, and the
eventual presence of acidic (or basic) polymer moieties, whose protonation can be
easily controlled with the pH or salt concentration (Table ) [60]. The composition
of polymeric nanogel i.e. hydrogels depends on the specific biomedical application
Nanomedicine for Targeted Drug Delivery in Cancer Chemotherapy
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and may require specific properties such as biocompatibility, transport mechanical
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properties, chemical stability and the ability to respond to microenvironment changes.
Another crucial factor for hydrogel performance is the nature of the involved (chemical or physical) crosslink interaction, as it influences many of the network properties
like swelling, elastic modulus, and transport properties (Figure
) [61].
. Micelles-based delivery systems or micellar nanoparticles
Micellar nanoparticles are commonly made up with an amphiphilic block of copoly
mers which is the main component of micelles. Micellar characteristics are based on the
properties and hydrophilic nature of copolymers, in buffered media. Their structure
made up to form a nano-sized shell or core structure. Because of their nature of biodegradability and biocompatibility, copolymers are commonly used owing to their ability
to entrap hydrophobic drugs. For lipophilic drug component, the hydrophobic cavity of
micelles acts as a reservoir and outer hydrophilic shell maintain the stability of micelle
in an aqueous environment, and these features form micelles for intravenous administration [62]. Drug molecules can be incorporated into micelles by using two methods,
one method is chemical covalent attachment and another one is physical encapsulation. PEG is generally used as a hydrophilic shell; shells with hydrophobic domains
include PLA, PLGA, polystyrene, poly(cyanoacrylate), poly(vinylpyrrolidone), and
polycaprolactone. Above the critical micelle concentration, micellar nanoparticles
are collected from self-assembly of amphiphilic block copolymers in aqueous media
(Figure
) [63]. The core, consisting of hydrophilic shell maintains steric stability
and aqueous solubility to the micellar structure whereas the hydrophobic domain, acts
as a reservoir and protects the drug from being dissolved. Recently, the first formulation was designed paclitaxel loaded polymeric micelles, known as Genexol-PM, are
cremophor-free polymeric micelle [64]. Paclitaxel loaded in micelle was fabricated with
steering ligands which is another type of micelles has been undergone a clinical trial
therapeutic agents and for imaging also. These results are applicable for conventional
amid numerous models of the micellar preparation (Table
). In the modern field of
nanotechnology for cancer treatment, a research group designed the novel nanodevices
polymeric micelles incorporated with of ursolic acid- (UA-PMs). Undissolvable drugs,
such as docetaxel and paclitaxel, can be covered with a water-solute layer to modify
their hydrophilicity and improve their bioavailability in this modern technology. The
hydrophilic shell maintains lengthens and protection circulation in vivo, influencing the
enhanced permeability and retention effect [65].
-
Figure 12.
Schematic diagram of micellar nanoparticles.
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. Nanosponge
Nanosponges are can be defined as hydrophilic, water-insoluble, and supramolecular nano devices with three-dimensional (3D) hyper-reticulated nanoporous
structures which exhibit significant stability over a wide range of temperatures and
pH levels. These nanodevices have high entrapment efficiency, are widely engineered
for cancer therapy and drug delivery purposes [66]. They are applicable for cancer
treatment for their property, such as high biocompatibility, biodegradability, and low
cytotoxicity, making them suitable for biomedical applications also.
For instance, cyclodextrin-based nanosponges have excellent potential for the
production of inclusion and non-inclusion complexes with a variety of drugs/active
with low bioavailability [67]. In inclusion complex nanosponges, the drug forms an
inclusion complex with the cyclodextrin molecule. However, in non-inclusive complex
nanosponges, the drug molecule becomes entrapped or imbibed into their porous
nanostructures. Among nanosponges, cyclodextrin-based structures have been widely
explored for drug delivery, remediation, sensing, and catalytic applications [68].
The use of anticancer drug loaded nanosponge that can improve the therapeutic
efficacy and could increase drug concentration at the tumor site, reducing the side
effects during chemotherapy. In particular, cyclodextrin-based nanosponges (NS)
have been proposed for cancer nanotherapeutic development.
The fabrication of self-catabolic DNAzyme nanosponges, in bioinspired for
controllable drug delivery behaviors and suitable gene silencing functions have been
reported which is a novel and smart nanosystem for biomedical commitments [67].
Ethylcellulose nanosponges were designed via an ultrasonic-assisted emulsion by
solvent evaporation method for targeted drug delivery of withaferin-A for cancer chemotherapy. Ribociclib loaded nanosponges revealed maximum drug release and exhibited
high cytotoxic effects in MCF-7 and MDA-MB-231 breast cancer cell lines [69].
Glutathione-responsive β cyclodextrin nanosponges (GSH-NSs) were designed
with improve the solubilization of Reveratrol, which is natural polyphenolic compound obtained from various natural sources used for targeting to the cancer cells
without any harmful effect of normal cells (Figure ) [68].
. DNA based nanoparticles and gene therapy
DNA which plays an important role in the pathological as well as physiological
action of the organisms and also act as an important carrier of the genetic information in the organisms. DNA based nanoparticles have significant merits with excellent
Figure 13.
Internal structure of nanosponge and its application.
Nanomedicine for Targeted Drug Delivery in Cancer Chemotherapy
DOI: http://ITexLi.114066
biocompatibility and biodegradability for sequence programming. DNA based
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nanoparticles or nanodevices can load several anticancer drugs and applicable for targeted drug delivery to malignant cells with the assistance of functional elements. These
types of devices improving the cellular uptake and stimuli responsive of drug release.
At present days, DNA based nanodevices have successfully achieved effective delivery
of chemotherapeutic drugs such as doxorubicin, daunorubicin, platinum etc. [69].
Scientists have begun to treat various complicated diseases by site gradient by gene
manipulation technologies such as gene silencing and gene editing by site gradient,
which can form stable complexes with mRNA to achieve high loading rates such as
ionisable lipid NPs, polymer-lipid hybrids nanodevices and biological nanostructures
with high biocompatibility [70].
. Mechanism of action of several anticancer drug loaded
nanoformulations
Among various anticancer drug loaded nanoformulations such as nanoparticles,
nanolipid vesicles, nano micelles, nanotubes achieve therapeutic goal in modern
cancer chemotherapy for its high drug loading capacity and shows effective therapeutic efficacy and due to their smaller size easily can be entrapped or penetrated by
malignant cells for its leaky vasculature of basement membrane [64].
These types of devices are applicable for delivery of antineoplastic drugs to the
target site of specific neoplastic cells, where the active medicament may release in
pre-programmed manner. Grafting with various targeting ligand molecules such as
antibody fragments or may be aptamers by tagging with the surface of nanocarriers,
so that they can easily recognize the malignant cells and entrapped by the neoplastic
cells as a result cellular uptake will be enhance [71].
Translatable phospholipid-mimic OXA prodrug (Oxalipid) clinically synthesized
which could self-assemble to form nanolipid vesicles showed longer blood circulation time, enhanced tumor accumulation, and inhibited the progression of metastatic triple negative breast cancer [72]. Silibinin loaded organic/inorganic hybrid
mesoporous nanoparticles was fabricated could inhibit the invasion of metastatic
breast cancer cells MDA-MB-231 [73]. Doxorbicin (DOX) loaded mesoporous silica
nanoparticles (HMCNs) was constructed which is hollow-structured and after oxidization with concentrated H2SO
and HNO
4
endow HMCNs entering tumor cells, DOX
3
was released in acid lysosomes to inhibit migration, growth and invasion of neoplastic
metastatic cells [74].
The redox-sensitive strategy combining with nanoparticles were constructed
to elevate in tumor cells for antimetastatic treatment was reported. A reductionsensitive amphiphilic block polymer Tween 85-disulfide bond-polyethyleneimine 2K
(TSP), was manufactured which could self-assemble in aqueous nature to deign or
frame micelles for carrying the shRNA silencing NF-κB (shp65) with positive charges.
As a result these are capable for suppress the growth and metastasis of MDA-MB-435
tumors [75].
. Conclusion and future perspectives
We focus on recent advances of anticancer drug loaded nanocarriers for tar-
geted drug delivery in cancer chemotherapy which are novel strategy in the field
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