Improving Drug Potency and Efficacy by Nanocarrier-Mediated Subcellular Targeting

Abstract

Nanocarrier-mediated drug targeting is an emerging strategy for cancer therapy and is being used, for example, with chemotherapeutic agents for ovarian cancer. Nanocarriers are selectively accumulated in tumors as a result of their enhanced permeability and retention of macromolecules, thereby enhancing the antitumor activity of the nanocarrier-associated drugs. We investigated the real-time subcellular fate of polymeric micelles incorporating (1,2-diaminocyclohexane) platinum(II) (DACHPt/m), the parent complex of oxaliplatin, in tumor tissues by fluorescence-based assessment of their kinetic stability. These observations revealed that DACHPt/m was extravasated from blood vessels to the tumor tissue and dissociated inside each cell. Furthermore, DACHPt/m selectively dissociated within late endosomes, enhancing drug delivery to the nearby nucleus relative to free oxaliplatin, likely by circumvention of the cytoplasmic detoxification systems such as metallothionein and methionine synthase. Thus, these drug-loaded micelles exhibited higher antitumor activity than did oxaliplatin alone, even against oxaliplatin-resistant tumors. These findings suggest that nanocarriers targeting subcellular compartments may have considerable benefits in clinical applications.

Targeted therapy of spontaneous murine pancreatic tumors by polymeric micelles prolongs survival and prevents peritoneal metastasis

“…DACHPt/m are prepared by polymermetal complexation between DACHPt and the carboxylic groups of biocompatible and biodegradable poly(ethylene glycol)-b-poly (glutamic acid) [PEG-b-P(Glu)] copolymers ( Fig. 1) (23)(24)(25)(26)(27), while the active drug is released from the micelles as a result of the ligand substitution with the chloride in the medium. Because DACHPt/m presents sustained drug release and concomitant micelle dissociation with an induction period of ∼8 h in the extracellular environment, the micelles can circulate stably in the bloodstream in a micelle form with minimal drug release and gradually release the drug after accumulating in solid tumors (25).…”

“…Because DACHPt/m presents sustained drug release and concomitant micelle dissociation with an induction period of ∼8 h in the extracellular environment, the micelles can circulate stably in the bloodstream in a micelle form with minimal drug release and gradually release the drug after accumulating in solid tumors (25). Thus, DACHPt/m have shown remarkably higher antitumor activity than the clinically approved DACH-containing platinum drug, that is, oxaliplatin, reducing the growth rate of several xenografted tumor models, such as human cervical cancer (24), human colon cancer (25), human pancreatic cancer (26), and human gastric cancer (27), due to their prolonged blood circulation and enhanced tumor accumulation.…”

Stimuli-responsive clustered nanoparticles for improved tumor penetration and therapeutic efficacy

“…These obstacles existing in the body could considerably prevent nanomedicine from reaching its targets in a sufficient drug concentration (7,8). To overcome these barriers, a variety of strategies have been envisioned (9)(10)(11)(12)(13)(14)(15)(16)(17)(18). Despite great advances, these strategies have mainly focused on one or a few biological barriers and led to suboptimal therapeutic effect.…”

Functionalized milk-protein-coated magnetic nanoparticles for MRI-monitored targeted therapy of pancreatic cancer

“…5,[7][8][9][10][11][12] These studies demonstrated promising strategies to use nanotechnology for delivery of cancer therapeutics, but also suggested that new strategies are needed for developing stable nanocarriers with prolonged circulation time and target-specific delivery and for lowering the drug resistance of cancer cells. [13][14][15] In addition, noninvasive monitoring of drug delivery to the tumor site is desirable to optimize delivery in order to improve the treatment efficacy. 16 Herein, we report a new targeted drug delivery nanosystem based on milk protein (casein [CN])-coated magnetic iron oxide (CNIO) nanoparticles, composed of a cancer cell targeting moiety that is the amino-terminal fragment (ATF) of urokinase plasminogen activator with an affinity to urokinase plasminogen activator receptor (uPAR), and the anticancer agent or CDDP for pancreatic cancer treatment.…”