Biomedical Engineering Reference
In-Depth Information
Polymer-drug conjugates are formed through side-chain grafting of drugs
to polymer chains, allowing them to deliver high doses of chemotherapeutic
drugs. These agents bear numerous functional groups that are available for
covalent binding to a variety of biochemically active groups, which direct
them to malignant tumors where they can deliver functional drugs acting
on several tumor targets [102]. Nanoconjugates that carry more than one
functional group provide the capability to simultaneously inhibit several tu-
mor pathways, deliver optimal drug concentrations to the site of treatment,
and reduce adverse effects on healthy tissue. Nanoconjugate polymers are
generally synthesized around a polymer with pendant functional groups like
-OH, -COOH, or -NH2. Nanoconjugates are also smaller in size, less
immunogenic and chemically more stable in plasma. Prolindac (AP5346)
is composed of a HPMA backbone copolymer with platinum grafted to
the side chains through a pH-sensitive chelator designed for drug release
in the tumor environment. Preclinical data demonstrates superior efficacy
of the polymer-drug conjugates, using multiple cancer models including a
M5076 sarcoma platinum-resistant tumor xenograft mice model, multiple
colon xenograft models, L1210 leukemia, and 0157 hybridoma models
[103]. Polyamino acids grafted with drugs on the side chains are another
class of polymer-drug conjugates that have demonstrated high drug load-
ing and efficacy [104]. In the case of polyglutamate-glycine-campthotecin
(CT-2106), degradable linkers have allowed drug loadings ranging from 5%
to 50% [105]. Nanoconjugates can overcome drawbacks of conventional
chemotherapy such as drug resistance and toxicity by specifically targeting
tumor cells, activating cancer cell uptake, and bypassing multidrug resis-
tance transporters. Meanwhile, Xyotax, a similar polymer-drug conjugate
(polyglutamate-paclitaxel), is used in several clinical trials including prostate
cancer, metastatic breast cancer, neck cancer, and metastatic colorectal can-
cer. The clinical data shows an improvement in median survival in Xyotax
patients compared with the control group. One benefit of the treatment was
the reduction of multiple side effects including neurotoxicity [106].
5.2 Micelle nanoparticles
Micelles nanoparticles (MNPs) are amphiphilic spherical structures com-
posed of a hydrophobic core and a hydrophilic shell. The hydrophobic part
is the inner core of the block copolymer which encapsulates the poorly
water-soluble drug, whereas the outer hydrophilic shell or corona of the
block protects the drug from the aqueous environment and stabilizes the
MNPs against recognition in vivo by the RES. The core can sometimes be
made up of a water-soluble polymer that is rendered hydrophobic by the
chemical conjugation of a water-insoluble drug, and by complexation of the
two oppositely charged polyions. The polymer always contains a nonionic
water-soluble segment and an ionic segment that can be neutralized by an
oppositely charged surfactant to form a hydrophobic core. The electrostatic
