Biomedical Engineering Reference
In-Depth Information
such as prolonging circulation time, introducing targeting moieties, and modifying the drug-release
profi le [167,203]. As water-soluble blocks, the most widely investigated and used ones are PEO and
PEG, the commonly used nonionic water-soluble polymers. The property of the hydrophobic seg-
ment of PLAA varies from the amino acid that composed the polymer backbone. The multiform
nature of the core-forming PLAA blocks provides a feasible approach to optimize the properties
of the PLAA micelles for encapsulation of various kinds of drugs, peptides, proteins, and genes
in the micelles core for delivery proposes. Because of the existence of reactable functional groups
on the side chain of the amino acids, the PLAA copolymers not only form micelles that encapsule
hydrophobic drugs through the physical hydrophobic interaction, but also form block copolymer-
drug conjugates that aggregate in aqueous phase to form micelles. These micelles are functionally
similar to the biological carriers, namely lipoproteins and viruses. The amino acids originate natu-
rally from living creatures, thus making the micelles based on PLLA core advantageous for safety,
stability, and easy to scale-up.
Block copolymers of PEG and poly(beta-benzyl-l-aspartate) were synthesized (PEG-PBLA)
by Kataoka and coworkers. Anticancer agent DOX was physically encapsulated into the core of the
micelles with a substantial drug-loading level (15-20 w/w%). The size of these DOX-loaded micelles
ranged about 50-70 nm, with narrow size distribution. The DOX was considered to possibly inter-
act with the benzyl residues of PBLA blocks through π-π resonance, to facilitate the stability of the
micelles and the release behaviors. At the beginning of the DOX release, an initial boost was observed.
This was followed by a slow and long-lasting release of DOX. The encapsulation of DOX into the
PEG-PBLA micelle carrier greatly elongated the DOX blood circulation period because of the
reduced reticuloendothelial system uptake of the micelles through a steric stabilization mecha-
nism. Compared with free DOX, the micelle drug delivery system showed a considerably higher
in vivo
antitumor activity in the animal experiment using mouse as the model animal [204,205].
Platinum compounds are potent anticancer agents that are clinically employed in cancer
chemotherapeutics. However, the poor water solubility of these compounds limits their applica-
tion. Some efforts have been made to improve the solubility by encapsulating these compounds in
polymeric micelles [176,196]. Because of the various types of PLAA, the various side chains of
the polymer can be obtained by using different amino acids as the starting material. Some PLLA
with carboxylic side groups were found to form complex with platinum compounds that were stable
enough to aggregate as the core of micelles. Thus, block copolymers of these PLLA with PEG
or other hydrophilic polymer block form the micelles with platinum compounds that act as drug
delivery system.
Cabral et al. reported a block copolymer of PEG-poly(glutamic acid) [PEG-P(Glu)]. A plati-
num compound, dichloro(1,2-diaminocyclohexane)platinum(II) (DACHPt), was mixed with the
copolymer in distilled water to prepare the metal-complex micelles through polymer-metal com-
plex formation. As a result, the micelles sized approximately 40 nm with narrow distribution were
obtained. The initial size of the micelles remained unchanged even after 240 h, suggesting that the
micelles were very stable. DACHPt-loaded micelles showed a sustained release rate of platinum
after an induction period of 12 h. They exhibited considerable
in vitro
cytotoxicity against murine
colon adenocarcinoma 26 (C-26) cells. The cytotoxicity increased with exposure time as a result
of the release of platinum complexes from the micelle.
In vivo
biodistribution assay performed on
tumor-bearing mice demonstrated that the micelle had prolonged blood circulation due to its high-
stability and high-tumor accumulation for a prolonged time [206].
Copolymers of poly(aspartic acid) and PEG were also used to prepare metal-complex micelles
with platinum compounds to achieve the delivery of the metal anticancer agent to the tumor cell.
The pharmacological activity and the pharmacokinetics of a clinical anticancer agent, cisplatin
(CDDP)-loaded polymeric micelles were examined by Nishiyama et al. using PEG-poly(aspartic
acid) block copolymer as the carrier.
In vivo
investigation in Lewis lung carcinoma-bearing
mice revealed that compared with the free CDDP, the micelles exhibited 5.2- and 4.6-fold higher
