The enhanced permeability retention effect: a new paradigm for drug targeting in infection

Abstract

Multidrug-resistant, Gram-negative infection is a major global determinant of morbidity, mortality and cost of care. The advent of nanomedicine has enabled tailored engineering of macromolecular constructs, permitting increasingly selective targeting, alteration of volume of distribution and activity/toxicity. Macromolecules tend to passively and preferentially accumulate at sites of enhanced vascular permeability and are then retained. This enhanced permeability and retention (EPR) effect, whilst recognized as a major breakthrough in anti-tumoral targeting, has not yet been fully exploited in infection. Shared pathophysiological pathways in both cancer and infection are evident and a number of novel nanomedicines have shown promise in selective, passive, size-mediated targeting to infection. This review describes the similarities and parallels in pathophysiological pathways at molecular, cellular and circulatory levels between inflammation/infection and cancer therapy, where use of this principle has been established.

Biofilm formation and antimicrobial resistance in Klebsiella pneumoniae isolated from patients visiting a tertiary care center of Nepal

“…pneumoniae produces a number of virulence factors that contribute to pathogenesis, including a thick polysaccharide capsule, fimbrial and non-fimbrial adhesins and siderophores [4]. Moreover, pathogenicity and chronicity of K. pneumoniae infections are increased by its biofilm forming ability [5]. The biofilm is an assembly of microbial cells that are irreversibly associated with a surface and enclosed in an exopolysaccharide matrix [6].…”

Development and Validation of an In Vitro Pharmacokinetic/Pharmacodynamic Model To Test the Antibacterial Efficacy of Antibiotic Polymer Conjugates

“…The conjugate unmasking by ␣-amylase was shown to be time dependent, meaning that in clinical use, administration of an initial dose of conventional antibiotic may be required when treating acute disease. In addition to improving the therapeutic efficacy of nanoformulated drugs, incorporating antibiotics into nano-sized structures also converts conventional small-molecule antibiotics into macromolecules, which may benefit from passive size-based targeting and accumulation at sites of inflammation/ infection via the enhanced permeability and retention (EPR) effect (4,41). A potential limitation of this model is its inability to replicate the potential benefits of the EPR effect, representing an avenue for future development.…”

“…The sealed beaker was incubated as described previously. Samples (150 l) were extracted from each compartment at various intervals (0, 4,8,12,24,36, and 48 h) using sterile, medical-grade, singleuse vascular catheters and immediately frozen on dry ice and stored at Ϫ20°C prior to analysis. Protein content was determined using a standard BCA assay, and the antimicrobial susceptibility of E. coli NCTC 10418 isolates was assessed using an MIC assay (see below).…”

“…The adoption of these approaches as antimicrobial therapies has seen the preclinical development of novel agents, including antibiotic-bearing nanoparticles, liposomes, dendrimers, and polymer therapeutics (3,4). These agents may offer potential benefits over conventional systemic delivery in minimizing toxicity and overcoming drug resistance by affording selective targeting of systemically delivered antibiotics to sites of infection and inflammation, thus maximizing local bioavailability of the chemotherapeutic agent (3,5).…”

“…These agents may offer potential benefits over conventional systemic delivery in minimizing toxicity and overcoming drug resistance by affording selective targeting of systemically delivered antibiotics to sites of infection and inflammation, thus maximizing local bioavailability of the chemotherapeutic agent (3,5). The employment of polymer therapeutics, in which an antibiotic is covalently attached to a water-soluble polymer, may afford a number of important practical advantages, including increased solubility and bioavailability, decreased toxicity, and a chemically modifiable controlled-release system that can be truly customized (2,4,6).…”