Recent Progress in Polymer Therapeutics as Nanomedicines - Harnessing Biomaterials in Nanomedicine: Preparation, Toxicity, and Applications - page 108

4.7 CombinationTherapy
A great advantage of the polymeric delivery system is the ability to
tailor diff erent compounds with controlled loading percentage on the
polymeric backbone (Figure 4.1). The concomitant targeted delivery
of two agents that act synergistically allows the administration of
lower concentrations of each agent, increasing their combined
anti-tumor efficacy and decreasing their toxicity. This direction has
been explored lately by many. Here we will give a few examples. The
reader is referred to a thorough review about combination therapy
in polymer therapeutics [159].
DOX and the aromatase inhibitor aminoglutethimide (AGM)
were conjugated to HPMA copolymer by Vicent et al. [160].
This conjugate was the first to combine endocrine therapy and
chemotherapy on one polymeric backbone. It exhibited increased
anti-tumor activity in vitro on breast cancer cells. Santucci et al. [161]
conjugated both epirubicin and nitric oxide (NO) agents on PEG.
The combination of these two agents is synergistic. Furthermore,
NO displays cardioprotective action that could counterbalance
the cardiotoxicity induced by epirubicin. The resulting conjugate
induced higher cytotoxic eff ect on Caco-2 cells than free epirubicin.
Moreover, NO presented a protection eff ect against epirubicin-
mediated cardiotoxicity in adult cardiomyocytes [161]. In another
combination study, HPMA copolymer was conjugated to DOX and
anti-inflammatory drug dexamethason through pH-sensitive linker.
The release of the drugs was examined in vitro [162]. Bae et al.
[163] conjugated DOX and a phosphatidylinositol-3 kinase inhibitor
wortmannin (WOR) to poly(ethylene glycol)-poly(aspartate
hydrazide) block copolymers through a hydrazone bond. These
polymer-drug conjugates assembled into less than 100 nm micelles
in which the drug mixing ratios between DOX/WOR were precisely
controlled. Cytotoxicity assay against a human breast cancer MCF-7
cell line showed enhanced cytotoxic activity.
Combining bone-targeting moiety and a drug on a polymeric
backbone is also attracting much attention, aiming to target bone-
related diseases actively. Work done in our laboratory recently
presented two HPMA copolymer conjugates based on the bone-
targeting anti-angiogenic bisphosphonate alendronate. On one
HPMA copolymer paclitaxel and alendronate were conjugated. This
conjugate exhibited a binding capacity to hydroxyapatide, anti-