Recent Progress in Polymer Therapeutics as Nanomedicines - Harnessing Biomaterials in Nanomedicine: Preparation, Toxicity, and Applications - page 84

it a versatile carrier in polymer therapeutics. PEG is commercially
available with either one or two attachment points. It can be produced
as a linear or branched polymer. The functional hydroxyl group at
the chain termini can be conjugated with drugs or other functional
groups. The lack of multivalency is one of the limitations of this
polymer; it limits the loading capacity and the potential use of PEG as
a backbone. To overcome this limitation, additional reactive groups
can be added by reaction of the OH - groups with multifunctional
compounds, such as glutamic acid dendron [27]. While PEG is
mostly common in the field of polymer-protein conjugates, it is also
extensively used in the polymer therapeutics field in general, as a
drug carrier or as stabilizing and as immunogenicity reducer.
HPMA copolymers are one of the most studied platforms for
polymer-drug conjugates; they have been studied extensively over
the last 30 years [17]. Most of HPMA polymer-drug conjugates were
developed for the treatment of cancer, with a special focus on the
site-specific delivery of anti-cancer drugs. HPMA is water soluble,
neutral, biocompatible, and non-immunogenic. HPMA copolymer
conjugated to DOX via a peptidyl linker Gly-Phe-Leu-Gly was the first
synthetic polymer-based anti-cancer conjugate to enter clinical trial
in 1994 [28] (i.e., PK1) and has been the breakthrough that led to the
exponential growth of interest in the field of polymer therapeutics.
Although PK1 is a promising cancer treatment, the polymer is not
biodegradable; so there are issues as to how it is metabolized and
cleared from the body. Since then, five other anti-cancer compounds
and two gamma camera imaging agents conjugated to HPMA
copolymer have been evaluated clinically [16].
In recent years, living free radical polymerization methods,
including atom transfer radical polymerization (ATRP) and reversible
addition-fragmentation chain transfer (RAFT), have been used for
the synthesis of HPMA copolymers with narrow molecular weight
distributions. Matyjaszewski's laboratory was the first to report on
polymerization of HPMA by ATRP method [29, 30]. It was reported
that the polymerization was difficult to control and the yield was low
in some cases. McCormick and coworkers were the first to report
on the polymerization of HPMA using the RAFT method [31]. They
presented conditions that facilitate the direct controlled RAFT
polymerization of this copolymer. This living polymerization method
allows the addition of further amounts of monomers during the