Recent Progress in Polymer Therapeutics as Nanomedicines - Harnessing Biomaterials in Nanomedicine: Preparation, Toxicity, and Applications - page 96

Camptothecin (CPT) is a potent anti-neoplastic agent with
activity against a broad range of cancer types. Unmodified CPT has
low solubility, high levels of protein binding, and rapid activation
through lactone ring hydrolysis [119]. CPT was recently conjugated
to the polymeric backbone Fleximer (poly[1-hydroxymethylene
hydroxymethyl formal]), which is also called PHF. This polymeric
prodrug derivative of CPT, named XMT-1001, is a hydrophilic,
biodegradable 40-70 kDa conjugate. Release of CPT from
intravenously administered XMT-1001 involves a dual-phase release
mechanism, in which CPT is first released in plasma as the lipophilic
prodrugs CPT-SI (a succinimidoglycinate derivative) and CPT-SA
(a succinamidoyl glycinate derivative), which are then hydrolyzed
in tissues to release the lactone active form of CPT. The release of
prodrugs to the blood is thought to lower bladder toxicity, due to
lower levels of active CPT in the urine. XMT-1001 showed enhanced
efficacy and safety in animal models and is currently undergoing
phase I clinical trials in cancer patients [119]. Another conjugated
form of CPT is CRLX-101 (former name IT-101). CRLX-101 is a
conjugate of CPT based on a cyclodextrin polymer. CPT is attached to
the polymer at the 20-OH position, which inhibits the ring opening
of CPT, so it remains in its active lactone form [120]. CRLX-101 is
currently undergoing clinical trials for various types of cancers. So
far evidence of function with low side eff ects was found [121].
Another anti-neoplastic approach is anti-angiogenic therapy,
first proposed in 1971 by Judah Folkman [122]. This approach has
been since extensively developed, and it is well accepted now that
the process of angiogenesis has a strategic role in cancer [123].
The microvasculature endothelial cells, recruited by a tumor, have
become an important second target in cancer therapy. However, the
vast majority of the anti-angiogenic agents are low-molecular-weight
compounds exhibiting poor pharmacokinetic profile with short half-
life in the bloodstream and high overall clearance rate [10].
In preclinical studies, caplostatin, an HPMA copolymer conjugate
of the anti-angiogenic agent TNP-470, which is a low-molecular-
weight analog of fumagillin, has been shown to eff ectively inhibit
tumor progression, and no drug-related toxicities were observed
[39, 41]. Another anti-angiogenic approach involves specific targeting
to tumor endothelial of chemotherapeutics. Polyak et al. used a PEG-
DOX conjugate with an RGD peptidomimetic targeting moiety. This
conjugate targets endothelial and tumor cells overexpressing α v β 3
integrin, thus dual targeting is achieved [52].