(Fig. 2) [15], was the first polymeric drug conjugate to reach clinical trials [16]. It
demonstrated enhanced antitumor efficacy and proved that polymer–drug conjugation decreased dose-limiting toxicities, setting a novel standpoint in pharmaceutical
science. Another successful polymeric drug that resembles Ringsdorf’s model was
developed by Hiroshi Maeda and his group by combining poly(styrene-co-maleic
acid/anhydride) and neocarzinostatin (SMANCS) [17–19]. Even though the molecular weight of SMANCS is only 16 kDA, its blood half-life is extended by
reversibly binding to serum albumin [18], which increases its size to over the
glomerular excretion of kidneys. During early preclinical studies, Maeda, together
with Yasuhiro Matsumura, observed that SMANCS and several other macromolecules selectively accumulated in solid tumors, which they attributed to the tumors’
hypervasculature, i.e., the enhanced permeability of tumor vasculature to macromolecules and the retention of those macromolecules due to impaired lymphatic
drainage [19]. They called these phenomena the enhanced permeability and retention (EPR) effect (Fig. 3) [18], and it has become one of the foundations of tumortargeted polymeric drugs.
Another milestone in the development of polymer–drug conjugates also
occurred in the 1970s and 1980s, when Frank F. Davis and Abraham Abuchowski
modified proteins with poly(ethylene glycol) (PEG) with the aim of extending their
half-life in blood and controlling immunogenicity [20–22]. The unique physicochemical properties of PEG, including its neutral charge, nontoxicity, high flexibility, and degree of hydration, demonstrated to be essential for improving several
aspects of the modified proteins in vivo, including solubility, reduced interaction
with plasma proteins and phagocyte uptake, prolonged blood circulation, reduced
immunogenicity, increased stability, and protection from proteolytic degradation
[20–22]. The first clinically approved PEG–protein conjugates were PEG–enzymes,
followed by PEG–interferons and PEG–granulocyte colony-stimulating factor,
which demonstrated that PEG modification decreased dosage frequency without
compromising efficacy, and also reduced toxicity [20]. In addition, PEG was also
used for modifying the surface of liposomes for drug delivery, prolonging their
circulation in blood and reducing unspecific distribution [23, 24]. Thus, PEG
conjugation is widespread as a safe and efficient method for protecting bioactive
molecules and surfaces, and the term “PEGylation” has become a common word for
describing this strategy.
When PEG, or other hydrophilic polymer, is conjugated to hydrophobic macromolecules, the resulting block copolymers can self-assemble in aqueous environment into various nanoscaled structures, having a hydrophobic center surrounded
by a PEG shell. Macromolecular self-assembly occurs spontaneously in nature
through intermolecular forces, and is essential for the performance of structural
proteins, bioactivity of proteins, and complex biological processes [25]. Moreover,
various natural carriers, such as viruses or casein micelles, are self-assembled
structures of polypeptides, and their supramolecular structures precisely modulate
their interaction with the biological environment for controlled delivery of their
cargo. The mechanisms of self-assembly, the structural conformation, and the
functions of natural supramolecular structures are programmed at the molecular
252
H. Cabral and K. Kataoka
demonstrated enhanced antitumor efficacy and proved that polymer–drug conjugation decreased dose-limiting toxicities, setting a novel standpoint in pharmaceutical
science. Another successful polymeric drug that resembles Ringsdorf’s model was
developed by Hiroshi Maeda and his group by combining poly(styrene-co-maleic
acid/anhydride) and neocarzinostatin (SMANCS) [17–19]. Even though the molecular weight of SMANCS is only 16 kDA, its blood half-life is extended by
reversibly binding to serum albumin [18], which increases its size to over the
glomerular excretion of kidneys. During early preclinical studies, Maeda, together
with Yasuhiro Matsumura, observed that SMANCS and several other macromolecules selectively accumulated in solid tumors, which they attributed to the tumors’
hypervasculature, i.e., the enhanced permeability of tumor vasculature to macromolecules and the retention of those macromolecules due to impaired lymphatic
drainage [19]. They called these phenomena the enhanced permeability and retention (EPR) effect (Fig. 3) [18], and it has become one of the foundations of tumortargeted polymeric drugs.
Another milestone in the development of polymer–drug conjugates also
occurred in the 1970s and 1980s, when Frank F. Davis and Abraham Abuchowski
modified proteins with poly(ethylene glycol) (PEG) with the aim of extending their
half-life in blood and controlling immunogenicity [20–22]. The unique physicochemical properties of PEG, including its neutral charge, nontoxicity, high flexibility, and degree of hydration, demonstrated to be essential for improving several
aspects of the modified proteins in vivo, including solubility, reduced interaction
with plasma proteins and phagocyte uptake, prolonged blood circulation, reduced
immunogenicity, increased stability, and protection from proteolytic degradation
[20–22]. The first clinically approved PEG–protein conjugates were PEG–enzymes,
followed by PEG–interferons and PEG–granulocyte colony-stimulating factor,
which demonstrated that PEG modification decreased dosage frequency without
compromising efficacy, and also reduced toxicity [20]. In addition, PEG was also
used for modifying the surface of liposomes for drug delivery, prolonging their
circulation in blood and reducing unspecific distribution [23, 24]. Thus, PEG
conjugation is widespread as a safe and efficient method for protecting bioactive
molecules and surfaces, and the term “PEGylation” has become a common word for
describing this strategy.
When PEG, or other hydrophilic polymer, is conjugated to hydrophobic macromolecules, the resulting block copolymers can self-assemble in aqueous environment into various nanoscaled structures, having a hydrophobic center surrounded
by a PEG shell. Macromolecular self-assembly occurs spontaneously in nature
through intermolecular forces, and is essential for the performance of structural
proteins, bioactivity of proteins, and complex biological processes [25]. Moreover,
various natural carriers, such as viruses or casein micelles, are self-assembled
structures of polypeptides, and their supramolecular structures precisely modulate
their interaction with the biological environment for controlled delivery of their
cargo. The mechanisms of self-assembly, the structural conformation, and the
functions of natural supramolecular structures are programmed at the molecular
252
H. Cabral and K. Kataoka