Micelles, self-assembling nanosized colloidal particles with a hydrophobic core and hydrophilic shell are currently successfully used as pharmaceutical carriers for water-insoluble drugs and demonstrate a series of attractive properties as drug carriers. Among the micelle-forming compounds, amphiphilic copolymers, i.e., polymers consisting of hydrophobic block and hydrophilic block, are gaining an increasing attention. Polymeric micelles possess high stability both in vitro and in vivo and good biocompatibility, and can solubilize a broad variety of poorly soluble pharmaceuticals many of these drug-loaded micelles are currently at different stages of preclinical and clinical trials. Among polymeric micelles, a special group is formed by lipid-core micelles, i.e., micelles formed by conjugates of soluble copolymers with lipids (such as polyethylene glycol-phosphatidyl ethanolamine conjugate, PEG-PE). Polymeric micelles, including lipid-core micelles, carrying various reporter (contrast) groups may become the imaging agents of choice in different imaging modalities. All these micelles can also be used as targeted drug delivery systems. The targeting can be achieved via the enhanced permeability and retention (EPR) effect (into the areas with the compromised vasculature), by making micelles of stimuli-responsive amphiphilic block-copolymers, or by attaching specific targeting ligand molecules to the micelle surface. Immunomicelles prepared by coupling monoclonal antibody molecules to p-nitrophenylcarbonyl groups on the water-exposed termini of the micelle corona-forming blocks demonstrate high binding specificity and targetability. This review will discuss some recent trends in using micelles as pharmaceutical carriers.

Micellar nanocarriers: pharmaceutical perspectives.

Of the thousands of novel compounds that a drug discovery project team invents and that bind to the therapeutic target, typically only a fraction of these have sufficient ADME/Tox properties to become a drug product. Understanding ADME/Tox is critical for all drug researchers, owing to its increasing importance in advancing high quality candidates to clinical studies and the processes of drug discovery. If the properties are weak, the candidate will have a high risk of failure or be less desirable as a drug product. This book is a tool and resource for scientists engaged in, or preparing for, the selection and optimization process. The authors describe how properties affect in vivo pharmacological activity and impact in vitro assays. Individual drug-like properties are discussed from a practical point of view, such as solubility, permeability and metabolic stability, with regard to fundamental understanding, applications of property data in drug discovery and examples of structural modifications that have achieved improved property performance. The authors also review various methods for the screening (high throughput), diagnosis (medium throughput) and in-depth (low throughput) analysis of drug properties. * Serves as an essential working handbook aimed at scientists and students in medicinal chemistry * Provides practical, step-by-step guidance on property fundamentals, effects, structure-property relationships, and structure modification strategies * Discusses improvements in pharmacokinetics from a practical chemist's standpoint

Drug-Like Properties: Concepts, Structure Design and Methods from ADME to Toxicity Optimization

The use of various pharmaceutical nanocarriers has become one of the most important areas of nanomedicine. Ideally, such carriers should be specifically delivered (targeted) to the pathological area to provide the maximum therapeutic efficacy. Among the many potential targets for such nanocarriers, tumors have been most often investigated. This review attempts to summarize currently available information regarding targeted pharmaceutical nanocarriers for cancer therapy and imaging. Certain issues related to some popular pharmaceutical nanocarriers, such as liposomes and polymeric micelles, are addressed, as are different ways to target tumors via specific ligands and via the stimuli sensitivity of the carriers. The importance of intracellular targeting of drug- and DNA-loaded pharmaceutical nanocarriers is specifically discussed, including intracellular delivery with cell-penetrating peptides.

Targeted pharmaceutical nanocarriers for cancer therapy and imaging

The success of anti-cancer therapies largely depends on the ability of the therapeutics to reach their designated cellular and intracellular target sites, while minimizing accumulation and action at non-specific sites. Surface modification of nanoparticulate carriers with poly(ethylene glycol) (PEG)/poly(ethylene oxide) (PEO) has emerged as a strategy to enhance solubility of hydrophobic drugs, prolong circulation time, minimize non-specific uptake, and allow for specific tumor-targeting through the enhanced permeability and retention effect. Furthermore, PEG/PEO modification has emerged as a platform for incorporation of active targeting ligands, thereby providing the drug and gene carriers with specific tumor-targeting properties through a flexible tether. This review focuses on the recent developments surrounding such PEG/PEO-surface modification of polymeric nanocarriers to promote tumor-targeting capabilities, thereby enhancing efficacy of anti-cancer therapeutic strategies.

Poly(ethylene glycol)-modified Nanocarriers for Tumor-targeted and Intracellular Delivery

http://daigangbio.cn/uploadfile/20140213/20140213150024315.pdf

Enhanced anti-tumor efficacy by co-delivery of doxorubicin and paclitaxel with amphiphilic methoxy PEG-PLGA copolymer nanoparticles.

Paclitaxel-loaded mixed polymeric micelles consisting of poly(ethylene glycol)-distearoyl phosphoethanolamine conjugates (PEG-PE), solid triglycerides (ST), and cationic Lipofectin® lipids (LL) have been prepared. Micelles with the optimized composition (PEG-PE/ST/LL/paclitaxel=12/12/2/1 by weight) had an average micelle size of about 100 nm, and zeta-potential of about −6 mV. Micelles were stable and did not release paclitaxel when stored at 4°C in the darkness (just 2.9% of paclitaxel have been lost after 4 months with the particle size remaining unchanged). The release of paclitaxel from such micelles at room temperature was also insignificant. However, at 37°C, approx. 16% of paclitaxel was released from PEG-PE/ST/LL/paclitaxel micelles in 72 h, probably, because of phase transition in the ST-containing micelle core. In vitro anticancer effects of PEG-PE/ST/LL/paclitaxel and control micelles were evaluated using human mammary adenocarcinoma (BT-20) and human ovarian carcinoma (A2780) cell lines. Pacli...

Polymeric micelles for delivery of poorly soluble drugs: preparation and anticancer activity in vitro of paclitaxel incorporated into mixed micelles based on poly(ethylene glycol)-lipid conjugate and positively charged lipids.

Junping Wang

Papers

Polymeric micelles for delivery of poorly soluble drugs: preparation and anticancer activity in vitro of paclitaxel incorporated into mixed micelles based on poly(ethylene glycol)-lipid conjugate and positively charged lipids.

Polymeric Micelles as Targetable Pharmaceutical Carriers