Polymeric micelle for tumor pH and folate-mediated targeting.

Novel pH-sensitive polymeric mixed micelles composed of poly(L-histidine) (polyHis; M(w) 5000)/PEG (M(n) 2000) and poly(L-lactic acid) (PLLA) (M(n) 3000)/PEG (M(n) 2000) block copolymers with or without folate conjugation were prepared by diafiltration. The micelles were investigated for pH-dependent drug release, folate receptor-mediated internalization and cytotoxicity using MCF-7 cells in vitro. The polyHis/PEG micelles showed accelerated adriamycin release as the pH decreased from 8.0. When the cumulative release for 24 h was plotted as a function of pH, the gradual transition in release rate appeared in a pH range from 8.0 to 6.8. In order to tailor the triggering pH of the polymeric micelles to the more acidic extracellular pH of tumors, while improving the micelle stability at pH 7.4, the PLLA/PEG block copolymer was blended with polyHis/PEG to form mixed micelles. Blending shifted the triggering pH to a lower value. Depending on the amount of PLLA/PEG, the mixed micelles were destabilized in the pH range of 7.2-6.6 (triggering pH for adriamycin release). When the mixed micelles were conjugated with folic acid, the in vitro results demonstrated that the micelles were more effective in tumor cell kill due to accelerated drug release and folate receptor-mediated tumor uptake. In addition, after internalization polyHis was found to be effective for cytosolic ADR delivery by virtue of fusogenic activity. This approach is expected to be useful for treatment of solid tumors in vivo.     

Polyion complex micelles for photodynamic therapy: incorporation of dendritic photosensitizer excitable at long wavelength relevant to improved tissue-penetrating property.

A polymeric micelle (DPcZn/m) system, which is formed via an electrostatic interaction of anionic dendrimer phthalocyanine (DPcZn) and poly(ethylene glycol)-poly(l-lysine) block copolymers (PEG-b-PLL), was prepared for use as an effective photosensitizer for photodynamic therapy. DPcZn/m exhibited strong Q band absorption around 650 nm, a useful wavelength for high tissue penetration. Dynamic light scattering studies indicated that the DPcZn/m system has a relevant size of 50 nm for intravenous administration. Under light irradiation, either DPcZn or DPcZn/m exhibited efficient consumption of dissolved oxygen in a medium to generate reactive oxygen species and an irradiation-time-dependent increase in photocytotoxicity. The photodynamic efficacy of the DPcZn was drastically improved by the incorporation into the polymeric micelles, typically exhibiting more than two orders of magnitude higher photocytotoxicity compared with the free DPcZn at 60-min photoirradiation.     

A polymeric micelle MRI contrast agent with changeable relaxivity.

Polymeric micelles were formed from cationic polymers (polyallylamine or protamine) and anionic block copolymers (poly(ethylene glycol)-b-poly(aspartic acid) derivative) that bound Gd ions providing high contrasts in Magnetic Resonance Imaging (MRI) by shortening the T(1) longitudinal relaxation time of protons of water. The Gd-binding block copolymer alone showed high relaxivity (T(1)-shortening ability) values from 10 to 11 mol(-1) s(-1), while the polymeric micelles exhibited low relaxivity values from 2.1 to 3.6 mol(-1) s(-1). These findings point to the feasibility of a novel MRI contrast agent that selectively provides high contrasts at solid tumor sites owing to a dissociation of the micelle structures, while selective delivery to the tumor sites is achieved in the polymeric micelle form.     

Tumor pH-responsive flower-like micelles of poly(l-lactic acid)-b-poly(ethylene glycol)-b-poly(l-histidine)

Polymeric micelles were constructed from poly(l-lactic acid) (PLA; M_n 3K)-b-poly(ethylene glycol) (PEG; M_n 2K)-b-poly(l-histidine) (polyHis; M_n 5K) as a tumor pH-specific anticancer drug carrier. Micelles (particle diameter: ∼ 80 nm; critical micelle concentration (CMC): 2 μg/ml) formed by dialysis of the polymer solution in dimethylsulfoxide (DMSO) against pH 8.0 aqueous solution, are assumed to have a flower-like assembly of PLA and polyHis blocks in the core and PEG block as the shell. The pH-sensitivity of the micelles originates from the deformation of the micellar core due to the ionization of polyHis at a slightly acidic pH. However, the co-presence of pH-insensitive lipophilic PLA block in the core prevented disintegration of the micelles and caused swelling/aggregation. A fluorescence probe study showed that the polarity of pyrene retained in the micelles increased as pH was decreased from 7.4 to 6.6, indicating a change to a more hydrophilic environment in the micelles. Considering that the size increased up to 580 nm at pH 6.6 from 80 nm at pH 7.4 and that the transmittance of micellar solution increased with decreasing pH, the micelles were not dissociated but rather swollen/aggregated. Interestingly, the subsequent decline of pyrene polarity below pH 6.6 suggested re-self-assembly of the block copolymers, most likely forming a PLA block core while polyHis block relocation to the surface. Consequently, these pH-dependent physical changes of the PLA-b-PEG-b-polyHis micelles provide a mechanism for triggered drug release from the micelles triggered by the small change in pH (pH 7.2–6.5).     

Characterization of physical entrapment and chemical conjugation of adriamycin in polymeric micelles and their design for in vivo delivery to a solid tumor

An anticancer drug adriamycin (ADR) was incorporated into polymeric micelles forming from poly(ethylene glycol)-poly(aspartic acid) block copolymer by chemical conjugation and physical entrapment. Structural stability of the polymeric micelles was found to be dependent on both the contents of chemically conjugated and physically entrapped ADR. The polymeric micelle with high contents of the chemically conjugated ADR and the physically entrapped ADR expressed very high in vivo antitumor activity against murine C 26 tumor, while the polymeric micelle with only the chemically conjugated ADR showed negligible in vivo activity. This indicates that the physically entrapped ADR played a major role in antitumor activity in vivo. For the polymeric micelle with the high ADR contents, it was found that a dimer of adriamycin molecules formed and that this dimer was physically entrapped in the inner core of the micelle as well as intact ADR.     

Structure and design of polymeric surfactant-based drug delivery systems.

The review concentrates on the use of polymeric micelles as pharmaceutical carriers. Micellization of biologically active substances is a general phenomenon that increases the bioavailability of lipophilic drugs and nutrients. Currently used low-molecular-weight pharmaceutical surfactants have low toxicity and high solubilization power towards poorly soluble pharmaceuticals. However, micelles made of such surfactants usually have relatively high critical micelle concentration (CMC) and are unstable upon strong dilution (for example, with the blood volume upon intravenous administration). On the other hand, amphiphilic block co-polymers are also known to form spherical micelles in solution. These micelles have very high solubilization capacity and rather low CMC value that makes them very stable in vivo. Amphiphilic block co-polymers suitable for micelle preparation are described and various types of polymeric micelles are considered as well as mechanisms of their formation, factors influencing their stability and disintegration, their loading capacity towards various poorly soluble pharmaceuticals, and their therapeutic potential. The basic mechanisms underlying micelle longevity and steric protection in vivo are considered with a special emphasis on long circulating drug delivery systems. Advantages and disadvantages of micelles when compared with other drug delivery systems are considered. New polymer-lipid amphiphilic compounds such as diacyillipid-polyethylene glycol, are described and discussed. These compounds are very attractive from a practical point of view, since they easily micellize yielding extremely stable micelles with very high loading capacity. Micelle passive accumulation in the areas with leaky vasculature (tumors, infarct zones) is discussed as an important physiology-based mechanism of drug delivery into certain target zones. Targeted polymeric micelles prepared by using thermo- or pH-sensitive components or by attaching specific targeted moieties (such as antibodies) to their outer surface are described as well as their preparation and some in vivo properties. The fast growing field of diagnostic micelles is analyzed. Polymeric micelles are considered loaded with various agents for gamma, magnetic resonance, and computed tomography imaging. Their in vitro and in vivo properties are discussed and the results of the initial animal experiments are presented.     

Enhanced antitumor effect of camptothecin loaded in long-circulating polymeric micelles.

A water-insoluble antitumor agent, camptothecin (CPT) was successfully incorporated into polymeric micelles formed from poly(ethylene glycol)-poly(benzyl aspartate) block copolymers (CPT-loaded polymeric micelles). Antitumor effects and biodistribution of CPT-loaded micelles were evaluated in mice subcutaneously transplanted by colon 26 tumor cells. Tumor growth was significantly inhibited after a single i.v. injection of CPT-loaded polymeric micelles at doses of either 15 or 30 mg/kg. Efficacy of a single high-dose injection was comparable to low dose multiple injections. CPT loaded in polymeric micelles showed prolonged blood circulation and higher accumulation in tumors compared with CPT in solution. Polymeric micelle systems offer a stable and effective platform for cancer chemotherapy with CPT.     

Long-circulating poly(ethylene glycol)-poly(D,L-lactide) block copolymer micelles with modulated surface charge.

Reactive polymeric micelles consisting of an alpha-acetal-poly(ethylene glycol)-poly(D,L-lactide) block copolymer (acetal-PEG-PDLLA) with a narrow size distribution were prepared in this study to conjugate small peptidyl ligands, tyrosine (Tyr) and tyrosyl-glutamic acid (Tyr-Glu), through reductive amination after converting the alpha-acetal group to an aldehyde group, allowing modulation of the surface charge of the micelles from neutral (Tyr-) to anionic (Tyr-Glu-). Both of these micelles showed a significantly long circulating time in the blood compartment with 25% of injected dose still circulating even at 24 h. Further, an appreciably lowered uptake into the liver and spleen was demonstrated for the anionic Tyr-Glu-conjugated PEG-PDLLA micelle compared with a neutral Tyr-conjugated micelle, suggesting a substantial role of the slight anionic charge on the micelle surface in avoiding non-specific organ uptake. Stability of the micelle form in the blood compartment was directly observed for the Tyr-PEG-PDLLA micelle by a gel filtration assay of a plasma sample collected from the micelle-injected mice at 24 h. These results demonstrated that a surface-modulated PEG-PDLLA micelle with a suitable size and a narrowly distributed nature has promising potential as a long-circulating carrier system with desirable biocompatibility and biofunctionality.     

TAT peptide-based micelle system for potential active targeting of anti-cancer agents to acidic solid tumors.

A novel drug targeting system for acidic solid tumors has been developed based on ultra pH-sensitive polymer and cell penetrating TAT. The delivery system consisted of two components: 1) A polymeric micelle that has a hydrophobic core made of poly(l-lactic acid) (PLLA) and a hydrophilic shell consisting of polyethylene glycol (PEG) conjugated to TAT (TAT micelle), 2) an ultra pH-sensitive diblock copolymer of poly(methacryloyl sulfadimethoxine) (PSD) and PEG (PSD-b-PEG). The anionic PSD is complexed with cationic TAT of the micelles to achieve the final carrier, which could systemically shield the micelles and expose them at slightly acidic tumor pH. TAT micelles had particle sizes between 20 and 45 nm and their critical micelle concentrations were 3.5 mg/l to 5.5 mg/l. The TAT micelles, upon mixing with pH-sensitive PSD-b-PEG, showed a slight increase in particle size between pH 8.0 and 6.8 (60-90 nm), indicating complexation. As the pH was decreased (pH 6.6 to 6.0) two populations were observed, one that of normal TAT micelles (45 nm) and the other of aggregated hydrophobic PSD-b-PEG. Zeta potential measurements showed similar trend substantiating the shielding/deshielding process. Flow cytometry and confocal microscopy showed significantly higher uptake of TAT micelles at pH 6.6 compared to pH 7.4 indicating shielding at normal pH and deshielding at tumor pH. The confocal microscopy indicated that the TAT not only translocates into the cells but is also seen on the surface of the nucleus. These results strongly indicate that the above micelles would be able to target any hydrophobic drug near the nucleus.     

Doxorubicin-loaded poly(ethylene glycol)-poly(beta-benzyl-L-aspartate) copolymer micelles: their pharmaceutical characteristics and biological significance.

Doxorubicin (DOX) was physically loaded into micelles prepared from poly(ethylene glycol)-poly(beta-benzyl-L-aspartate) block copolymer (PEG-PBLA) by an o/w emulsion method with a substantial drug loading level (15 to 20 w/w%). DOX-loaded micelles were narrowly distributed in size with diameters of approximately 50-70 nm. Dimer derivatives of DOX as well as DOX itself were revealed to be entrapped in the micelle, the former seems to improve micelle stability due to its low water solubility and possible interaction with benzyl residues of PBLA segments through pi-pi stacking. Release of DOX compounds from the micelles proceeded in two stages: an initial rapid release was followed by a stage of slow and long-lasting release of DOX. Acceleration of DOX release can be obtained by lowering the surrounding pH from 7.4 to 5.0, suggesting a pH-sensitive release of DOX from the micelles. A remarkable improvement in blood circulation of DOX was achieved by use of PEG-PBLA micelle as a carrier presumably due to the reduced reticuloendothelial system uptake of the micelles through a steric stabilization mechanism. Finally, DOX loaded in the micelle showed a considerably higher antitumor activity compared to free DOX against mouse C26 tumor by i.v. injection, indicating a promising feature for PEG-PBLA micelle as a long-circulating carrier system useful in modulated drug delivery.     

Preparation and biological properties of dichloro(1,2-diaminocyclohexane)platinum(II) (DACHPt)-loaded polymeric micelles.

Block copolymer micelles, containing dichloro(1,2-diaminocyclohexane)platinum(II) (DACHPt), the oxaliplatin parent complex, were prepared through polymer-metal complex formation of DACHPt with poly(ethylene glycol)-poly(glutamic acid) block copolymer [PEG-P(Glu)] in distilled water. By dynamic light scattering (DLS) measurement, the micelle size was determined to be 40 nm with narrow distribution. The release of platinum complexes from the micelle core was measured in phosphate buffer saline (pH 7.4) at 37 degrees C. DACHPt-loaded micelle showed a sustained release rate of platinum after an induction period of 12 h. In the same conditions, the kinetic stability of DACHPt-loaded micelle was measured. The micelle was found to be very stable, keeping the initial size, for 240 h. Against murine colon adenocarcinoma 26 (C-26) cells, DACHPt-loaded micelle exhibited considerable in vitro cytotoxicity, lower than oxaliplatin but increasing with exposure time as a result of the release of platinum complexes from the micelle. In vivo biodistribution assay performed on tumor-bearing mice demonstrated that the micelle showed prolonged blood circulation due to its high stability and high tumor accumulation for a prolonged time.     

pH-responsive polymeric micelle based on PEG-poly(β-amino ester)/(amido amine) as intelligent vehicle for magnetic resonance imaging in detection of cerebral ischemic area

A series of pH-responsive polymeric micelles is developed to act as intelligent carriers to deliver iron oxide (Fe₃O₄) nanoparticles and respond rapidly to an acidic stimuli environment for magnetic resonance imaging (MRI). The polymeric micelle can be self-assembled at physiological pH by a block copolymer, consisting of a hydrophilic methoxy poly(ethylene glycol) (PEG) and a pH-responsive poly(β-amino ester)/(amido amine) block. Consequently, the Fe₃O₄ nanoparticles can be well encapsulated into polymeric micelles due to the hydrophobic interaction, shielded by a PEG coronal shell. In an acidic environment, however, the pH-responsive component, which has ionizable tert-amino groups on its backbone, can become protonated to be soluble and release the hydrophobic Fe₃O₄ nanoparticles. The Fe₃O₄-loaded polymeric micelle was measured by dynamic light scattering (DLS), superconducting quantum interference device (SQUID) and a 3.0 T MRI scanner. To assess the ability of this MRI probe as a pH-triggered agent, we utilize a disease rat model of cerebral ischemia that produces acidic tissue due to its pathologic condition. We found gradual accumulation of Fe₃O₄ nanoparticles in the brain ischemic area, indicating that the pH-triggered MRI probe may be effective for targeting the acidic environment and diagnostic imaging of pathologic tissue.     

Thermosensitive and biodegradable polymeric micelles for paclitaxel delivery.

The preparation, release and in vitro cytotoxicity of a novel polymeric micellar formulation of paclitaxel (PTX) were investigated. The micelles consisted of an AB block copolymer of poly(N-(2-hydroxypropyl) methacrylamide lactate) and poly(ethylene glycol) (pHPMAmDL-b-PEG). Taking advantage of the thermosensitivity of pHPMAmDL-b-PEG, the loading was done by simply mixing of a small volume of a concentrated PTX solution in ethanol and an aqueous polymer solution and subsequent heating of the resulting solution above the critical micelle temperature of the polymer. PTX could be almost quantitatively loaded in the micelles up to 2 mg/mL. By dynamic light scattering and cryo-transmission electron microscopy, it was shown that PTX-loaded micelles have a mean size around 60 nm with narrow size distribution. At pH 8.8 and 37 degrees C, PTX-loaded micelles destabilized within 10 h due to the hydrolysis of the lactic acid side group of the pHPMAmDL. Because the hydrolysis of the lactic acid side groups is first order in hydroxyl ion concentration, the micelles were stable for about 200 h at physiological conditions. The presence of serum proteins did not have an adverse effect on the stability of the micelles during at least 15 h. Interestingly, the dissolution kinetics of pHPMAmDL-b-PEG micelles was retarded by incorporation of PTX, indicating a strong interaction between PTX and the pHPMAmDL block. The PTX-loaded micelles showed a release of the incorporated 70% of PTX during 20 h at 37 degrees C and at pH 7.4. PTX-loaded pHPMAmDL-b-PEG micelles showed comparable in vitro cytotoxicity against B16F10 cells compared to the Taxol standard formulation containing Cremophor EL, while pHPMAmDL-b-PEG micelles without PTX were far less toxic than the Cremophor EL vehicle. Confocal laser-scanning microscopy (CLSM) and fluorescence activated cell sorting (FACS) analysis of fluorescently labelled micelles showed that pHPMAmDL-b-PEG micelles were internalized by the B16F10 cells. The present results suggest that pHPMAmDL-b-PEG block copolymer micelles are a promising delivery system for the parenteral administration of PTX.     

Hydrotropic agents for study of in vitro paclitaxel release from polymeric micelles.

A new experimental method for in vitro release studies of poorly soluble drugs from polymeric micelle systems was developed using a hydrotropic agent, sodium salicylate. It is difficult to maintain a good sink condition for poorly water-soluble drugs, such as paclitaxel (PTX), because of their low aqueous solubility. In this study, a good sink condition for PTX was achieved by using aqueous sodium salicylate solution which solubilized more than 10 times the total amount of PTX incorporated in polymeric micelles. Sodium salicylate at 1 M concentration increased the aqueous PTX solubility by 100 times without destroying the micellar structure of poly(ethylene glycol)-block-poly(phenylalanine) (PEG-b-PPhe) copolymer. PTX was continuously released from PEG-b-PPhe micelles in the hydrotropic release medium. The hydrotropic solution presents a simple method for studying in vitro release behavior of poorly soluble drugs from polymeric micelles in aqueous media.     

Micellar carriers based on block copolymers of poly(epsilon-caprolactone) and poly(ethylene glycol) for doxorubicin delivery.

Diblock copolymers of poly(epsilon-caprolactone) (PCL) and monomethoxy poly(ethylene glycol) (MPEG) with various compositions were synthesized. The amphiphilic block copolymers self-assembled into nanoscopic micelles and their hydrophobic cores encapsulated doxorubicin (DOX) in aqueous solutions. The micelle diameter increased from 22.9 to 104.9 nm with the increasing PCL block length (2.5-24.7 kDa) in the copolymer composition. Hemolytic studies showed that free DOX caused 11% hemolysis at 200 microg ml(-1), while no hemolysis was detected with DOX-loaded micelles at the same drug concentration. An in vitro study at 37 degrees C demonstrated that DOX-release from micelles at pH 5.0 was much faster than that at pH 7.4. Confocal laser scanning microscopy (CLSM) demonstrated that DOX-loaded micelles accumulated mostly in cytoplasm instead of cell nuclei, in contrast to free DOX. Consistent with the in vitro release and CLSM results, a cytotoxicity study demonstrated that DOX-loaded micelles exhibited time-delayed cytotoxicity in human MCF-7 breast cancer cells.     

Amphiphilic triblock copolymer poly(p-dioxanone-co-L-lactide)-block-poly(ethylene glycol), enhancement of gene expression and inhibition of lung metastasis by aerosol delivery

We describe the development of an aerosol system for topical gene delivery to the lungs of C57BL/6 mice. This system is based on the combination of the commercial cationic lipid Lipofectin with a novel amphiphilic triblock copolymer, poly(p-dioxanone-co-L-lactide)-block-poly(ethylene glycol) (PPDO/PLLA-b-PEG, and abbreviated in the text as polymeric micelles). After optimizing conditions for DNA delivery to the lungs of mice using the combination of polymeric micelles with Lipofectin and LacZ DNA, we used the Lipofectin/polymeric micelle system to deliver the tumor suppressor gene PTEN to the lungs of C57BL/6 mice bearing the B16-F10 melanoma. Lipofectin/PTEN/polymeric micelles significantly improved gene expression of PTEN in the lungs of mice with no evidence of cell toxicity or acute inflammation. Importantly, lung metastasis, as measured by lung weight, was significantly reduced (P<0.001), as were total tumor foci in the lungs (P<0.001) and size of individual tumor nodules in animals treated with Lipofectin/PTEN/polymeric micelles compared with control animals. Survival time was also extended. These results suggest that the Lipofectin/polymeric micelle system is appropriate for enhancing gene delivery in vivo and that it can be applied as a non-invasive gene therapy for lung cancer.     

Folate-conjugated methoxy poly(ethylene glycol)/poly(epsilon-caprolactone) amphiphilic block copolymeric micelles for tumor-targeted drug delivery.

Amphiphilic block copolymers composed of methoxy poly(ethylene glycol) (MPEG) and poly(epsilon-caprolactone) (PCL) were synthesized and then conjugated with folic acid to produce a folate-receptor-targeted drug carrier for tumor-specific drug delivery. Folate-conjugated MPEG/PCL micelles containing the anticancer drug paclitaxel were prepared by micelle formation in aqueous medium. The size of the folate-conjugated MPEG/PCL micelles formed was about 50-130 nm, depending on the molecular weight of block copolymers, and was maintained at less than 150 nm even after loading with paclitaxel. The in vitro release profile of the paclitaxel from the MPEG/PCL micelles exhibited no initial burst release and showed sustained release. Paclitaxel-loaded folate-conjugated MPEG/PCL micelles (PFOL50) exhibited much higher cytotoxicity for cancer cells, such as MCF-7 and HeLa cells, than MPEG/PCL micelles without the folate group (PMEP50). Confocal image analysis revealed that fluorescent paclitaxel-loaded PFOL50 micelles were endocytosed into MCF-7 cells through the interaction with overexpressed folate receptors on the surface of the cancer cells.     

Molecular design of biodegradable polymeric micelles for temperature-responsive drug release.

We designed thermo-responsive and biodegradable polymeric micelles for an ideal drug delivery system whose target sites are where external stimuli selectively release drugs from the polymeric micelles. The thermo-responsive micelles formed from block copolymers that were composed both of a hydrophobic block and a thermo-responsive block. Poly(N-isopropylacrylamide-co-N,N-dimethylacrylamide) showing a lower critical solution temperature (LCST) around 40 degrees C was synthesized for the thermo-responsive block, while biodegradable poly(D,L-lactide), poly(epsilon-caprolactone), or poly(D,L-lactide-co-epsilon-caprolactone) was used for the hydrophobic block. By changing both the block lengths of the poly(D,L-lactide)-containing block copolymers, physical parameters such as micelle diameter and critical micelle concentration were varied. On the other hand, the choice of the hydrophobic block was revealed to be critical in relation to both on the thermo-responsive release of the incorporated anti-cancer drug, doxorubicin, and the temperature-dependent change of the hydrophobicity of the micelles' inner core. One polymeric micelle composition successfully exhibited rapid and thermo-responsive drug release while possessing a biodegradable character.     

Hydrotropic polymer micelles as versatile vehicles for delivery of poorly water-soluble drugs

Polymer micelles have been used widely for delivery of poorly water-soluble drugs. Such drug delivery, however, has been based primarily on hydrophobic interactions. For better drug loading and improved stability, hydrotropic polymer micelles were used. To develop a versatile polymer micelle for solubilizing various poorly soluble drugs, two different hydrotropic agents were examined. The solubilizing properties of two hydrotropic agents, N,N-diethylnicotinamide (DENA) and N,N-dimethylbenzamide (DMBA), in polymeric form were investigated for their ability to solubilize five drugs with low aqueous solubility covering a wide range of hydrophobicity and molecular structures. The hydrotropes were covalently linked to the hydrophobic block of a block copolymer that also had a hydrophilic poly(ethylene glycol) (PEG) block.The solubilizing capacity of the polymeric hydrotropes was compared with that of the non polymeric hydrotropes, as well as of two conventional (non hydrotropic) copolymer systems. The solubilizing capacity of polymeric hydrotropes reflects combined effects of the micellar solubilization by the hydrophobic micelle core and hydrotropic solubilization. Because of the highly localized configuration, hydrotropes in the polymeric form are more powerful solubilizers than in the monomeric (non-polymeric) solution. It is possible to produce 1 ~ 3 orders of magnitude increase in solubility with polymeric hydrotropes at the 1% (w/v) level. Of the two hydrotropic polymeric systems in this study, the DENA-based system is highly specific, whereas the DMBA-based system is a general solubilizer of hydrophobic drugs. An additional advantage of polymeric hydrotropes over the non-polymeric form is absence of high concentrations of free hydrotropes in the formulation. Solubilization vehicles based on polymeric hydrotropes are expected to provide a new and versatile means of preparing formulations for various poorly soluble drugs and drug candidates without using organic solvents. This advantage is accompanied with the inherent controlled release property of the hydrotropic polymer micelles, making them ideal for pharmaceutical formulations used in drug candidate screening and toxicology studies.