Nanomaterials: Versatile Drug Carriers for Nanomedicine
269
There are three general categories for specific targeting in cancer—(i) uncontrolled
cell proliferation targeting, (ii) tumor cell targeting, and (iii) angiogenesis-associated
targeting. Various proangiogenic factors are responsible for the chemical stimulation of the angiogenesis, such as basic fibroblast growth factor (bFGF) and vascular
endothelial growth factor (VEGF). These are the critical factors for a complex biological mechanism that is essential for life and also for the growth of solid tumors. Thus,
it has become necessary to target angiogenesis in cancer therapeutics [49, 50]. Therefore, targeting angiogenic factors with the usage of drugs will cause tumors to cease
from developing new blood vessels.
Cancer cells can also be targeted with the help of cell proliferation markers.
The markers used are ordinary to the cancer cells. But specific cancer cells overexpress these markers, which are mainly transferrin receptors, folate receptors, and
human epidermal receptors (HER). Nanoparticles are embedded with monoclonal
antibodies to target overexpressed receptors for cell proliferation [51]. FDA has
approved the treatment of monoclonal antibodies in some of the cancers. A humanized monoclonal antibody, Trastuzumab, is used against HER-2, overly expressed in
positive breast cancer. A trastuzumab-conjugated nanoparticle can target specifically
HER-2 positive cells, which have been demonstrated in several in vitro case studies
using divergent cell lines [52] and also in some in vivo studies [53]. Trastuzumabconjugated super magnetic iron oxide NPs serve as an MRI contrast agent to detect
HER-2 positive tumors and can be easily identified by magnetic relaxometry [54].
This can be used for diagnostics of early breast cancer. Apart from this, trastuzumab
is used as the delivery of chemotherapeutic drugs to cancer cells [52].
A serum glycoprotein, transferrin (TfR), transports iron into cells through the
bloodstream via binding to the cell surface transferrin receptor. This results in
receptor-mediated endocytosis and, thus, internalization of the iron [55]. The upregulation of the transferrin receptors is found to be 100-folds higher in metastatic
and drug-resistant malignant cells than that of the normal cells. Doxorubicin-loaded
liposomal nano-carriers using TfR as targeting ligand is an intracellular drug delivery
system [56]. The TfR-conjugated liposome NPs have resulted in being efficient drug
delivery cargo into the neoplastic cells. These NPs bind specifically to the TfR receptors and thus internalized via a receptor-dependent endocytotic pathway, which helps
it to bypass P-glycoprotein-mediated drug efflux to overcome the MDR [57].
Several studies have used transferrin to target cancer cells using paclitaxel-loaded
polymeric PLGA NPs. TfR-conjugated PLGA NPs loaded with aromatase inhibitor
were evaluated in vitro against SKBR-3 breast cancer cells. This resulted in enhanced
activity of aromatase inhibitor of the TfR receptor-targeted NPs than that of the
nontargeted NPs due to the TfR-mediated uptake [58]. This has achieved the highest
accumulation of the nanoconjugates at the tumor sites with in significant reduction
in weight of the tumor in the in vivo S180 murine sarcoma model [59].
A liposomal formulation of mifamurtide (MEPACT) is aimed to target the delivery
of the drug to macrophages and monocytes, which are present in the spleen, liver, and
lungs. Mifamurtide is a synthetic derivative of muramyl peptide used as a chemotherapeutic adjuvant. It majorly stimulated monocytes and macrophages to enhance
tumoricidal effects. The liposomal encapsulation helps to enhance the tumoricidal
269
There are three general categories for specific targeting in cancer—(i) uncontrolled
cell proliferation targeting, (ii) tumor cell targeting, and (iii) angiogenesis-associated
targeting. Various proangiogenic factors are responsible for the chemical stimulation of the angiogenesis, such as basic fibroblast growth factor (bFGF) and vascular
endothelial growth factor (VEGF). These are the critical factors for a complex biological mechanism that is essential for life and also for the growth of solid tumors. Thus,
it has become necessary to target angiogenesis in cancer therapeutics [49, 50]. Therefore, targeting angiogenic factors with the usage of drugs will cause tumors to cease
from developing new blood vessels.
Cancer cells can also be targeted with the help of cell proliferation markers.
The markers used are ordinary to the cancer cells. But specific cancer cells overexpress these markers, which are mainly transferrin receptors, folate receptors, and
human epidermal receptors (HER). Nanoparticles are embedded with monoclonal
antibodies to target overexpressed receptors for cell proliferation [51]. FDA has
approved the treatment of monoclonal antibodies in some of the cancers. A humanized monoclonal antibody, Trastuzumab, is used against HER-2, overly expressed in
positive breast cancer. A trastuzumab-conjugated nanoparticle can target specifically
HER-2 positive cells, which have been demonstrated in several in vitro case studies
using divergent cell lines [52] and also in some in vivo studies [53]. Trastuzumabconjugated super magnetic iron oxide NPs serve as an MRI contrast agent to detect
HER-2 positive tumors and can be easily identified by magnetic relaxometry [54].
This can be used for diagnostics of early breast cancer. Apart from this, trastuzumab
is used as the delivery of chemotherapeutic drugs to cancer cells [52].
A serum glycoprotein, transferrin (TfR), transports iron into cells through the
bloodstream via binding to the cell surface transferrin receptor. This results in
receptor-mediated endocytosis and, thus, internalization of the iron [55]. The upregulation of the transferrin receptors is found to be 100-folds higher in metastatic
and drug-resistant malignant cells than that of the normal cells. Doxorubicin-loaded
liposomal nano-carriers using TfR as targeting ligand is an intracellular drug delivery
system [56]. The TfR-conjugated liposome NPs have resulted in being efficient drug
delivery cargo into the neoplastic cells. These NPs bind specifically to the TfR receptors and thus internalized via a receptor-dependent endocytotic pathway, which helps
it to bypass P-glycoprotein-mediated drug efflux to overcome the MDR [57].
Several studies have used transferrin to target cancer cells using paclitaxel-loaded
polymeric PLGA NPs. TfR-conjugated PLGA NPs loaded with aromatase inhibitor
were evaluated in vitro against SKBR-3 breast cancer cells. This resulted in enhanced
activity of aromatase inhibitor of the TfR receptor-targeted NPs than that of the
nontargeted NPs due to the TfR-mediated uptake [58]. This has achieved the highest
accumulation of the nanoconjugates at the tumor sites with in significant reduction
in weight of the tumor in the in vivo S180 murine sarcoma model [59].
A liposomal formulation of mifamurtide (MEPACT) is aimed to target the delivery
of the drug to macrophages and monocytes, which are present in the spleen, liver, and
lungs. Mifamurtide is a synthetic derivative of muramyl peptide used as a chemotherapeutic adjuvant. It majorly stimulated monocytes and macrophages to enhance
tumoricidal effects. The liposomal encapsulation helps to enhance the tumoricidal