pH-sensitive polymeric cisplatin-ion complex with styrene-maleic acid copolymer exhibits tumor-selective drug delivery and antitumor activity as a result of the enhanced permeability and retention effect

Abstract

Cisplatin (CDDP) is widely used to treat various cancers. However, its distribution to normal tissues causes serious adverse effects. For this study, we synthesized a complex of styrene-maleic acid copolymer (SMA) and CDDP (SMA-CDDP), which formed polymeric micelles, to achieve tumor-selective drug delivery based on the enhanced permeability and retention (EPR) effect. SMA-CDDP is obtained by regulating the pH of the reaction solution of SMA and CDDP. The mean SMA-CDDP particle size was 102.5 nm in PBS according to electrophoretic light scattering, and the CDDP content was 20.1% (w/w). The release rate of free CDDP derivatives from the SMA-CDDP complex at physiological pH was quite slow (0.75%/day), whereas it was much faster at pH 5.5 (4.4%/day). SMA-CDDP thus had weaker in vitro toxicity at pH 7.4 but higher cytotoxicity at pH 5.5. In vivo pharmacokinetic studies showed a 5-fold higher tumor concentration of SMA-CDDP than of free CDDP. SMA-CDDP had more effective antitumor potential but lower toxicity than did free CDDP in mice after i.v. administration. Administration of parental free CDDP at 4 mg/kg×3 caused a weight loss of more than 5%; SMA-CDDP at 60 mg/kg (CDDP equivalent)×3 caused no significant weight change but markedly suppressed S-180 tumor growth. These findings together suggested using micelles of the SMA-CDDP complex as a cancer chemotherapeutic agent because of beneficial properties-tumor-selective accumulation and relatively rapid drug release at the acidic pH of the tumor-which resulted in superior antitumor effects and fewer side effects compared with free CDDP.

A Novel Multimodal NIR-II Nanoprobe for the Detection of Metastatic Lymph Nodes and Targeting Chemo-Photothermal Therapy in Oral Squamous Cell Carcinoma

“…As reported, HA is an ideal DDS [Drug Delivery System] that can be combined with CDDP via ionic interactions between Pt 2+ of CDDP and carboxylic acid of HA 56-59. We used AAS to confirm the successful encapsulation of CDDP by measuring the concentration of CDDP in an HT@CDDP-containing PBS solution.…”

EPR-Effect Enhancers Strongly Potentiate Tumor-Targeted Delivery of Nanomedicines to Advanced Cancers: Further Extension to Enhancement of the Therapeutic Effect

“…SMA (molecular size 5500-6500 Da) was obtained from KJ Chemicals, Tokyo, Japan. Smaplatin ® , with a particle size of 100.2 nm as described previously [36]; SGB-complex, with a diameter of 12-15 nm, containing about 16-18% (w/w) glucosamine; and 7-8% (w/w) boric acid was synthesized by Maeda's group [37]. P-HPMA-conjugated zinc protoporphyrin (PZP) [38] was developed previously for PDT.…”

“…The three nanomedicines used were PZP, SGB-complex, and Smaplatin ® . Table S1 summarizes their characteristics [36][37][38]. We first determined tumor delivery of PZP by means of fluorescence spectroscopy.…”

“…We report here our utilization of these vascular mediators in combination with three macromolecular drugs to increase delivery of the drugs to tumors and thereby improve therapeutic efficacy in advanced C26 tumors in mice. These three drugs tested are the fol-lowing: a complex of SMA encapsulated cisplatin (registered name Smaplatin ® ), in which cisplatin is used in cancer chemotherapy [36]; SMA glucosamine-conjugated boric acid complex (SGB-complex) that was designed for boron neutron capture therapy (BNCT) [37]; and poly(N-(2-hydroxypropyl methacrylamide) (P-HPMA) copolymer-conjugated zinc protoporphyrin (PZP), used for photodynamic therapy (PDT) [38]. Our data showed about two-to four-fold enhancement of therapeutic outcome for all these drugs.…”

Cisplatin delivery vehicles based on stabilized polymeric aggregates comprising poly(acrylic acid) chains

“…42 In a recent study, polymeric micelles derived from the styrenemaleic acid copolymer and cisplatin demonstrated a marked antitumor effect against S-180 solid tumors and less cytotoxicity than the free drug due to tumor-selective drug delivery based on the enhanced permeability and retention (EPR) effect. 43 On that basis, considering the results obtained for SPA-Pt conjugates, it could be expected that the latter would exhibit prolongеd blood circulation, protecting the drug from undesired deactivation and achieving selective accumulation in tumor tissue. To address this objective, in vivo experiments are envisaged.…”