Synthesis and therapeutic effect of styrene–maleic acid copolymer‐conjugated pirarubicin

Abstract

Previously, we prepared a pirarubicin (THP)-encapsulated micellar drug using styrene–maleic acid copolymer (SMA) as the drug carrier, in which active THP was non-covalently encapsulated. We have now developed covalently conjugated SMA-THP (SMA-THP conjugate) for further investigation toward clinical development, because covalently linked polymer–drug conjugates are known to be more stable in circulation than drug-encapsulated micelles. The SMA-THP conjugate also formed micelles and showed albumin binding capacity in aqueous solution, which suggested that this conjugate behaved as a macromolecule during blood circulation. Consequently, SMA-THP conjugate showed significantly prolonged circulation time compared to free THP and high tumor-targeting efficiency by the enhanced permeability and retention (EPR) effect. As a result, remarkable antitumor effect was achieved against two types of tumors in mice without apparent adverse effects. Significantly, metastatic lung tumor also showed the EPR effect, and this conjugate reduced metastatic tumor in the lung almost completely at 30 mg/kg once i.v. (less than one-fifth of the maximum tolerable dose). Although SMA-THP conjugate per se has little cytotoxicity in vitro (1/100 of free drug THP), tumor-targeted accumulation by the EPR effect ensures sufficient drug concentrations in tumor to produce an antitumor effect, whereas toxicity to normal tissues is much less. These findings suggest the potential of SMA-THP conjugate as a highly favorable candidate for anticancer nanomedicine with good stability and tumor-targeting properties in vivo.

HPMA Copolymer-Conjugated Pirarubicin in Multimodal Treatment of a Patient with Stage IV Prostate Cancer and Extensive Lung and Bone Metastases

“…injection by virtue of the enhanced permeability and retention (EPR) effect 1 of solid tumors, as described elsewhere [2][3][4][5][6][7]. In addition to accumulating in primary tumors, it accumulates in metastatic tumors [3][4][5][8][9][10][11]. We also showed that P-THP released active free pirarubicin more in the mildly acidic pH (near 6) of tumor tissue than in the pH of normal tissue (7.4) [2].…”

Cancer nanomedicine: progress, challenges and opportunities

“…A newly developed system of polymeric micelles formulated from polymer–drug conjugates has shown promising therapeutic efficacy in a mouse model of colon cancer with lung metastasis 202 , and in a pilot study of one patient with castration-resistant prostate cancer with lung and bone metastases 203 . Comparatively little effort has been devoted to exploiting nanotechnology to modify the premetastatic microenvironmental niche and suppress tumour growth.…”

Amphiphilic core cross-linked star polymers as water-soluble, biocompatible and biodegradable unimolecular carriers for hydrophobic drugs

“…This is a similar order of magnitude to the non-degradable, amphiphilic CCS polymer recently developed by us, which was synthesised via a combination of atom transfer radical polymerisation (ATRP) and copper-catalysed azide-alkyne cycloaddition (CuAAC) in a grafting-to-approach. 48,59,62,63 The slow intracellular uptake of the drug once liberated from these conjugate limits their anti-tumor efficacy. The attachment of pendant pyrene groups favours π-π interaction with pirarubicin affording loading capabilities of ca.…”