Biomedical Engineering Reference
In-Depth Information
administered via the tail vein to tumor-bearing mice [138]. In vivo antitumor activity results
showed that polymer-drug conjugates effectively suppressed tumor growth and reduced
the toxicity against animal body when compared with commercial doxorubicin hydro-
chloride injection. Additionally, pH-sensitiveness of the cis -aconityl spacers may facilitate
the targeting and release of anticancer drugs to tumor sites where the pH condition is
weak acid (pH 5-6).
6.6.3.2 Active Targeting: RME
Passive targeting of drugs to tumor sites through the EPR effect does not always guarantee
successful therapy if the drug does not reach the target site of the tumor cell such as the
cell membrane, cytosol, or nucleus. A more effective mechanism needs to be developed so
that the therapeutic medicine is able to reach the molecular targets. RME is a highly spe-
cific process happening in the human body. During the process, cells take in only certain
molecules, the specificities of which are determined by receptors on the cell's membrane.
This internalization of extraneous molecules can be utilized to achieve active targeting.
Compared to most normal cells, human cancer cells frequently overexpress some spe-
cific antigens or receptors on their surfaces, which can be utilized as targets in nanomedi-
cine. Active targeting can be achieved by chemical modification of nanosized drug carriers
with ligands that precisely recognize and specifically interact with receptors on the tar-
geted tissue. For improving therapeutic effects on cancer treatment, therapeutic agents are
frequently entrapped physically in the nanosized carrier where the ligands are chemically
conjugated through covalent bonds. The merits of this system for delivering drugs include
the following: (1) the physically entrapped drugs can preserve its activity; (2) a relatively
large payload of drugs can be loaded into the hydrophobic cores of the carriers exceeding
their intrinsic water solubility; (3) the targeting moieties on the carriers can be precisely
tuned to increase the probability of binding to the target cells; and (4) owing to the small
size of the carrier system, it can effectively infiltrate across- the inflamed leaky disease
vasculature but not at the normal vasculature [144].
Folate-conjugated stearic acid-grafted chitosan (Fa-CSOSA) was synthesized by the EDC-
mediated coupling reaction [148]. It can be used as an active targeting carrier, because folic
acid (folate) is a low-molecular-weight vitamin whose receptor (folate receptor) is frequently
overexpressed in many human cancer cells, including malignancies of the ovary, brain,
kidney, breast, myeloid cells, and lungs. In the meantime, folate is always highly restricted
by most normal cells [149]. The anticancer drug paclitaxel was physically encapsulated into
the hydrophobic domains of nanosized Fa-CSOSA micelles by a dialysis method. The inter-
nalization of Fa-CSOSA micelles by RME was faster and greatly improved in the folate
receptor overexpressing cell line, compared with the folate receptor-deficient cell line [148].
Recently, Sahu et al. [150] synthesized folate-carboxymethyl chitosan (Fa-CMCS) conju-
gates using 2,2′-(ethylenedioxy)-bis-ethylamine as the coupling agent. They used Fa-CMCS
nanoparticles as an active targeting carrier to deliver doxorubicin, which was physically
encapsulated into the nanoparticles. An in vitro study indicated that nanoparticles are
more effectively targeting cancerous cells than normal cells because of the folate receptor
overexpressing on the cancerous cell membrane. More importantly, they proposed that the
basis of their research lies in the pH-sensitiveness of nanoparticles. According to them,
nanoparticles can be taken up by cells via an endocytosis process. As the endocytic
pathway begins near the physiological pH of 7.4, drops to a lower pH of 5.5-6.0 in endo-
somes, and approaches pH 4.5-5.0 in lysosomes, polymeric nanoparticles that are respon-
sive to pH can be designed to selectively release their payload in tumor tissue or within
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