Super pH-sensitive multifunctional polymeric micelle for tumor pHe specific TAT exposure and multidrug resistance

Abstract

As an alternative to cell specific cancer targeting strategies (which are often afflicted with the heterogeneity of cancer cells as with most biological systems), a novel polymeric micelle constitute of two block copolymers of poly(L-lactic acid)-b-poly(ethylene glycol)-b-poly(L-histidine)-TAT (transactivator of transcription) and poly(L-histidine)-b-poly(ethylene glycol) was developed. The micelle formed via the dialysis method was approximately 95 nm in diameter and contained 15 wt. % of doxorubicin (DOX) by weight. The micelle surface hides TAT during circulation, which has the strong capability to translocate the micelle into cells, and exposes TAT at a slightly acidic tumor extracellular pH to facilitate the internalization process. The micelle core was engineered for disintegration in early endosomal pH of tumor cells, quickly releasing DOX. The ionization process of the block copolymers and ionized polymers assisted in disrupting the endosomal membrane. This processes permitted high DOX concentrations in the cytosol and its target site of the nucleus, thus increasing DOX potency in various wild and multidrug resistant (MDR) cell lines (3.8-8.8 times lower IC 50 than free DOX, depending on cell line). When tested with the xenografted tumors of human ovarian tumor drug-resistant A2780/AD, human breast tumor drug-sensitive MCF-7, human lung tumor A549 and human epidermoid tumor KB in a nude mice model, all tumors significantly regressed in size by three bolus injections at a dose of DOX 10 mg equivalent/kg body per injection of DOX-loaded micelle at three day interval, while minimum weight loss was observed. This approach may replace the need for cell-specific antibodies or targeting ligands, thereby providing a general strategy for solid tumor targeting.

Classification of stimuli–responsive polymers as anticancer drug delivery systems

“…This gradient has been used to design pH-responsive tumor-targeted drug release systems based on pH-sensitive polymers (Vaupel et al, 1989;Stubbs et al, 2000;Lee et al, 2008;Fleige et al, 2012).…”

Development of Worm-like Polymeric Drug Carriers with Multiple Ligands for Targeting Heterogeneous Breast Cancer Cells

“…The DOX concentration was measured using a UV/visible spectrophotometer. [25][26][27][28] Fragmentation of micelles. In order to evaluate the physical scissoring of the worm-like micelles in PBS pH 7.4 (ionic strength = 0.15) under mechanical shaking (100 rev./min) at 37 o C, the micelle solution was extracted at a given time and coated on a slide glass.…”

“…23,24 Herein, we investigated the morphological properties of worm-like micelles with multiple ligands and evaluated their cancer specificity in an in vitro cell uptake test. 27,28 were synthesized as described in detail in our previous studies.…”

Resveratrol down-regulates survivin and induces apoptosis in human multidrug-resistant SPC-A-1/CDDP cells

“…ONCOLOGY REPORTS 23: 279-286, 2010 281 Table I. Effect of resveratrol on SPC-A-1/CDDP cells proliferation (x10 4 ). - (Table III).…”

“…The poor prognosis of this malignancy may be partially based on the pronounced resistance to multiple chemotherapeutic drugs (multidrug resistance, or MDR) that is intrinsically present in most NSCLCs and is acquired during treatment in many SCLCs that are initially drugsensitive (2,3). The intrinsic and acquired resistance of cancer cells to chemotherapeutic agents limits the efficacy of cancer treatment (4). MDR is defined as resistance to multiple structurally and functionally unrelated anticancer drugs that occurs after treatment with a single agent (5,6).…”