Recent Progress in Polymer Therapeutics as Nanomedicines - Harnessing Biomaterials in Nanomedicine: Preparation, Toxicity, and Applications - page 95

Paclitaxel is a drug commonly used for the treatment of
advanced breast, prostate, and ovarian cancers. It is a very potent
cytotoxic drug, although it is hydrophobic and causes side eff ects
such as neutropenia, neuropathies, and hypersensitivity (due to the
solubilizing Cremophor EL). Paclitaxel was conjugated with high
loadings to PGA (paclitaxel poliglumex, OPAXIO; Cell Therapeutics,
Inc.) Although paclitaxel is conjugated to PGA via an ester bond,
the polymer backbone is generally stable in the circulation [111].
OPAXIO is currently being evaluated in phase III clinical trials against
particularly non-small-cell lung cancer, ovarian cancer as a single
agent or in combination therapy with carboplatin. Retrospective
analysis of clinical data suggests that OPAXIO's anti-tumor activity
may be modulated by estrogen levels. Recent in vivo studies indicate
that OPAXIO metabolism by some cancer cells is enhanced in the
presence of estrogen, which leads to increased levels of paclitaxel in
tumor tissue and greater anti-tumor eff ects [112-115].
Cisplatin is another major chemotherapeutic drug, used in
combination with a wide range of other drugs in treatment of
various cancers. Its use is restricted due to severe dose-limiting
side eff ects, such as nephrotoxicity, neurotoxicity, ototoxicity, and
myelosuppression, which arise from the indiscriminate uptake of
the drug into all rapidly dividing cells and the body's attempt to
excrete the drug through the kidneys. In addition, the limited doses
enable the tumor to develop resistance to the treatment. Therefore,
the improvement of platinum-based anti-cancer drugs either by
reduced side eff ects or by overcoming the resistance to this drug
is the goal of many studies [116]. Many low-molecular-weight
derivatives have been suggested, and some got clinically approved
(carboplatin, oxaliplatin). Two HPMA copolymer-platinum
conjugates were clinically assessed by Access Pharmaceuticals,
namely AP5280 and AP5346. In these two conjugates, the diamine
or a diaminocyclohexane (DACH) moiety is bound to a dicarboxylate
ligand that is coupled to the polymer. Although phase I clinical trial
of AP5280 was promising [117], they chose to focus on AP5346, now
named ProLindac TM . ProLindac phase II has been completed with
the results of excellent tolerability and equivalent efficacy, if not
superior to oxaliplatin. Recently, a combination study of ProLindac
with paclitaxel has been started in the second-line treatment of pre-
treated advanced ovarian cancer [118].