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Tumor Discovery Targeted drug delivery systems for the treatment of tumors

such as bone spaces. On the other hand, in regions with the initial stages of tumor growth, there is a significant
a continuous basal membrane, which includes endocrine release of pro-angiogenic factors that contribute to the
glands, nanoparticles may have poorer localization . formation of convoluted, disorganized, and immature
[6]
vessels with indistinct arterioles, venules, and capillaries.
2.2. Organ-level barriers These developed tumor vessels exhibit aberrant cellular
One of the critical barriers at the organ level is the blood- organization and contain numerous factors, including
brain barrier, which is of utmost concern for effectively vascular endothelial factor, tumor-infiltrating leucocytes,
delivering therapeutic agents and nutrients across the protein factor, and tumor necrosis factor. In addition,
blood-brain membrane. The brain capillaries that line the reactive ions such as reactive oxygen, carbon monoxide,
brain exhibit a high degree of polarization and consist nitric oxide, and hydrogen peroxide are present, along
of different luminal and abluminal membranes with with various processes associated with hemoxigenase,
different functional roles . In addition, the presence of matrix metalloproteinase, and inflammation . All of
[7]
[12]
tight junctions in the endothelial cells of brain capillaries these factors play a role in regulating vascular permeability
restricts the diffusion of small hydrophilic molecules, within tumor vessels, as well as in processes related to
resulting in a low rate of transcytosis (poor movement of inflammation, intravasation, and the distribution of tumor
[13]
solutes through transcellular pathways). Several factors cells .
related to nanocarriers influence their ability to transverse Tumor-targeted therapeutics aim to accumulate
the blood-brain barrier, including lipid solubility, surface around the tumor and induce an enhanced permeation
[8]
area, size, polarity, and concentration gradients . and retention effect (EPR), facilitating the increased
2.3. Cellular-level barriers accumulation of bioactive agents at the target site. The
disorganized architecture of tumors, along with leaky
The internalization of nanocarriers, achieved through vasculature and impaired lymphatic drainage, enables
processes such as phagocytosis, pinocytosis, or receptor- enhanced EPR efficiency. A schematic illustration of
mediated endocytosis, represents cellular-level barriers. passive targeting is depicted in Figure 1. Several drug
Cellular endocytosis is a common occurrence in tumor delivery approaches, such as liposomes, nanoparticles,
cells, although it may vary from cell to cell and can be micelles, polymeric nanoparticles, and dendrimers,
affected by extracellular conditions. The functionalization achieve enhanced EPR through passive targeting,
of nanocarriers with ligands plays a crucial role in gradually releasing active ingredients within the tumor
enhancing internalization, cellular uptake, and achieving mass. Numerous passively targeted drug delivery systems
precise targeting with tumors . In addition, the size of from different countries have been successfully employed
[9]
nanocarriers has an impact on cellular uptake and the in clinical use. Examples of such nanocarriers include
internalization process. Smaller particles (<200 nm) can Doxil , DaunoXome , Marqibo , Onivyde (USA),
TM
TM
TM
TM
be internalized through a clathrin-mediated process, Mepact , Myocet (Europe), SMANCS (Japan), and
TM
TM
TM
while larger particles (>200 nm) are taken up via caveolin- Genexol-PM (Korea).
TM
mediated pathways . The presence of surface charges on
[10]
tumor-targeted nanocarriers is also significant, as they 3.2. Active targeting
influence cell binding, signaling, and cell responses. These Active targeting, also referred to as receptor-mediated
surface charges determine the extent and type of protein targeting, capitalizes on the distinctive overexpression
interactions, thus governing cell adhesion.
of specific receptors, such as vascular epithelial growth
3. Molecular principles in tumor-targeted factors, transferrin receptors, and human epidermal
drug delivery systems growth factors within tumor masses. These receptors
serve as recognition for target ligands, including tethered
At present, three approaches are employed in targeted antibodies, linked peptides or proteins, aptamers, affisomes,
drug delivery systems for the management of tumors at and small molecules. The presence of leaky vasculature,
the molecular level. These approaches include passive a disrupted lymphatic system, and a hypoxic or acidic
targeting based on tumor vasculature, active targeting environment within tumors further facilitate the covalent
through molecular binding, and cell-mediated targeting . or non-covalent binding between receptors and ligands,
[11]
essential for the successful execution of active targeting .
[14]
3.1. Passive targeting Figure 2 illustrates the fundamental concept behind
Passive targeting involves the targeting of structural features the internalization of a tumor-targeted drug delivery
associated with the newly formed blood vessels that supply system through active targeting. The epidermal growth
nutrition and metabolic support to the tumor site. During factor receptors (EGFRs) family is incessantly involved

Volume 2 Issue 3 (2023) 3 https://doi.org/10.36922/td.1356