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Advanced Drug Delivery Reviews (v.63, #3)
EPR effect based drug design and clinical outlook for enhanced cancer chemotherapy
by Hiroshi Maeda (Theme Editor); Yasuhiro Matsumura (Theme Editor) (pp. 129-130).
Tumor delivery of macromolecular drugs based on the EPR effect by Vladimir Torchilin (pp. 131-135).
Enhanced permeability and retention (EPR) effect is the physiology-based principal mechanism of tumor accumulation of large molecules and small particles. This specific issue of Advanced Drug Delivery Reviews is summing up multiple data on the EPR effect-based drug design and clinical outcome. In this commentary, the role of the EPR effect in the intratumoral delivery of protein and peptide drugs, macromolecular drugs and drug-loaded long-circulating pharmaceutical nanocarriers is briefly discussed together with some additional opportunities for drug delivery arising from the initial EPR effect-mediated accumulation of drug-containing macromolecular systems in tumors.
Keywords: Tumors; Drug delivery; EPR effect; Protein drugs; Peptide drugs; Polymeric drugs; Pharmaceutical nanocarriers; Tumor targeting; Intracellular drug delivery
The EPR effect: Unique features of tumor blood vessels for drug delivery, factors involved, and limitations and augmentation of the effect by Jun Fang; Hideaki Nakamura; Hiroshi Maeda (pp. 136-151).
The enhanced permeability and retention (EPR) effect is a unique phenomenon of solid tumors related to their anatomical and pathophysiological differences from normal tissues. For example, angiogenesis leads to high vascular density in solid tumors, large gaps exist between endothelial cells in tumor blood vessels, and tumor tissues show selective extravasation and retention of macromolecular drugs. This EPR effect served as a basis for development of macromolecular anticancer therapy. We demonstrated methods to enhance this effect artificially in clinical settings. Of great importance was increasing systolic blood pressure via slow angiotensin II infusion. Another strategy involved utilization of NO-releasing agents such as topical nitroglycerin, which releases nitrite. Nitrite is converted to NO more selectively in the tumor tissues, which leads to a significantly increased EPR effect and enhanced antitumor drug effects as well. This review discusses molecular mechanisms of factors related to the EPR effect, the unique anatomy of tumor vessels, limitations and techniques to avoid such limitations, augmenting tumor drug delivery, and experimental and clinical findings.
Keywords: Abbreviations; NO; nitric oxide; SMA; styrene maleic acid copolymer; NCS; neocarzinostatin; CT; computed tomography; AUC; area under the concentration–time curve; IgG; immunoglobulin G; HPMA; N; -(2-hydroxypropyl)methacrylamide; α; 2; -M; α; 2; -macroglobulin; XO; xanthine oxidase; RES; reticuloendothelial system; VEGF; vascular endothelial growth factor; SEM; scanning electron microscope; AT-II; angiotensin II; iNOS; inducible nitric oxide synthase; ONOO; −; peroxynitrite; VPF; vascular permeability factor; PG; prostaglandin; SBTI; soybean trypsin inhibitor; cPTIO; carboxy-2-phenyl-4,4,5,5-tetramethylimidazoline-1-oxyl-oxide; O; 2; −; •; superoxide anion radical; MMP; matrix metalloproteinase; NG; nitroglycerin; COX; cyclooxygenase; ACE; angiotensin-converting enzyme; HCC; hepatocellular carcinoma; ISDN; isosorbide dinitrate; pO; 2; partial oxygen pressureDrug targeting; Angiogenesis; Solid tumors; Macromolecular anticancer therapy; Nitroglycerin; Tumor vasculature; Cancer chemotherapy; Angiotensin II-induced hypertension
A multifunctional envelope type nano device (MEND) for gene delivery to tumours based on the EPR effect: A strategy for overcoming the PEG dilemma by Hiroto Hatakeyama; Hidetaka Akita; Hideyoshi Harashima (pp. 152-160).
Gene and nucleic acid therapy are expected to play a major role in the next generation of medicine. We recently developed a multifunctional envelope-type nano device (MEND) for use as a novel non-viral gene delivery system. Poly(ethylene glycol) (PEG)ylation is a useful method for achieving a longer circulation time for delivery of the MEND to a tumour via the enhanced permeability and retention (EPR) effect. However, PEGylation strongly inhibits cellular uptake and endosomal escape, which results in significant loss of activity for the delivery system. For successful gene delivery for cancer treatment, the crucial issue associated with the use of PEG, the ‘PEG dilemma’ must be addressed. In this review, we describe the development and applications of MEND, and discuss strategies for overcoming the PEG dilemma, based on the manipulation of intracellular trafficking of cellular uptake and endosomal release using functional devices such as specific ligands, cleavable PEG systems and endosomal fusogenic/disruptic peptides.
Keywords: Gene delivery; MEND; PEG dilemma; Tumour targeting; Target ligand; PEG cleavage; Membrane fusion
Intracellular targeting delivery of liposomal drugs to solid tumors based on EPR effects by Kazuo Maruyama (pp. 161-169).
The success of an effective drug delivery system using liposomes for solid tumor targeting based on EPR effects is highly dependent on both size ranging from 100-200nm in diameter and prolonged circulation half-life in the blood. A major development was the synthesis of PEG-liposomes with a prolonged circulation time in the blood. Active targeting of immunoliposomes to the solid tumor tissue can be achieved by the Fab' fragment which is better than whole IgG in terms of designing PEG-immunoliposomes with prolonged circulation. For intracellular targeting delivery to solid tumors based on EPR effects, transferrin-PEG-liposomes can stay in blood circulation for a long time and extravasate into the extravascular of tumor tissue by the EPR effect as PEG-liposomes. The extravasated transferrin-PEG-liposomes can maintain anti cancer drugs in interstitial space for a longer period, and deliver them into the cytoplasm of tumor cells via transferrin receptor-mediated endocytosis. Transferrin-PEG-liposomes improve the safety and efficacy of anti cancer drug by both passive targeting by prolonged circulation and active targeting by transferrin.
Keywords: Liposome; PEG-liposome; Transferrin; Boron neutron-capture therapy (BNCT); Oxaliplatin; Passive targeting; Intracellular targeting; Fab' fragment
PLGA nanoparticles containing various anticancer agents and tumour delivery by EPR effect by Sarbari Acharya; Sanjeeb K. Sahoo (pp. 170-183).
As mortality due to cancer continues to rise, advances in nanotechnology have significantly become an effective approach for achieving efficient drug targeting to tumour tissues by circumventing all the shortcomings of conventional chemotherapy. During the past decade, the importance of polymeric drug-delivery systems in oncology has grown exponentially. In this context, poly(lactic- co-glycolic acid) (PLGA) is a widely used polymer for fabricating ‘nanoparticles’ because of biocompatibility, long-standing track record in biomedical applications and well-documented utility for sustained drug release, and hence has been the centre of focus for developing drug-loaded nanoparticles for cancer therapy. Such PLGA nanoparticles have also been used to develop proteins and peptides for nanomedicine, and nanovaccines, as well as a nanoparticle-based drug- and gene-delivery system for cancer therapy, and nanoantigens and growth factors. These drug-loaded nanoparticles extravasate through the tumour vasculature, delivering their payload into the cells by the enhanced permeability and retention (EPR) effect, thereby increasing their therapeutic effect. Ongoing research about drug-loaded nanoparticles and their delivery by the EPR effect to the tumour tissues has been elucidated in this review with clarity.
Keywords: Chemotherapy; Nanotechnology; Drug Delivery; Drug-loaded nanoparticles; EPR Effects
Preclinical and clinical studies of NK012, an SN-38-incorporating polymeric micelles, which is designed based on EPR effect by Yasuhiro Matsumura (pp. 184-192).
Polymeric micelles are ideally suited to exploit the EPR effect, and they have been used for the delivery of a range of anticancer drugs in preclinical and clinical studies.NK012 is an SN-38-loaded polymeric micelle constructed in an aqueous milieu by the self-assembly of an amphiphilic block copolymer, PEG–PGlu(SN-38). The antitumor activity was evaluated in several orthotopic tumor models including glioma, renal cancer, stomach cancer, and pancreatic cancer. Two independent phase I clinical trials were conducted in Japan and the USA.In the preclinical studies, it was demonstrated that NK012 exerted significantly more potent antitumor activity with no intestinal toxicity against various orthotopic human tumor xenografts than CPT-11. In clinical trials, predominant toxicity was neutropenia. Non-hematologic toxicity, especially diarrhea, was mostly Grade 1 or 2 during study treatments. Total 8 partial responses were obtained.According to data of preclinical studies, NK012 showing enhanced distribution with prolonged SN-38 release may be ideal for cancer treatment because the antitumor activity of SN-38 is time dependent. Clinical studies showed that NK012 was well tolerated and had antitumor activity including partial responses and several occurrences of prolonged stable disease across a variety of advanced refractory cancers. Phase II studies are ongoing in patients with colorectal cancer in Japan and in patients with triple negative breast cancer and small cell lung cancer in the USA.
Keywords: Drug delivery system; EPR effect; NK012; SN-38; Clinical trial