Sharper image: A newly developed polysaccharide/drug conjugate (see picture) responds to changes in pH value and was shown to penetrate HeLa tumors in mice as determined by fluorescence imaging. It has the potential to be used in photodynamic therapy, thereby targeting the tumor while having no detrimental effects on the surrounding tissue.

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).

An optimized, pH-sensitive mixed micelle system conjugated with folic acid was prepared to challenge multidrug resistance (MDR) in cancers. The micelles were composed of poly(histidine (His)-co-phenylalanine (Phe))-b-poly(ethylene glycol) (PEG) and poly(L-lactic acid) (PLLA)-b-PEG-folate. Core-forming, pH-sensitive hydrophobic blocks of poly(His-co-Phe) of varying composition were synthesized. The composition-dependent pK values of poly(His-co-Phe) (Mn=5,000−5,500 Da) were examined. The size and critical micelle concentration were evaluated as a function of pH. The pH sensitivity of the micelles was roughly controlled by the copolymer composition, and its fine tuning to early endosomal pH was achieved by blending PLLA(3K)-b-PEG (2K)-folate, especially in the presence of a basic anticancer drug, doxorubicin (DOX).To prove the efficacy of the micellar system, in vitro tests including cell viability, folate receptormediated endocytosis, and endosomolytic acitivity were conducted against both wild-type (A2780) and DOX-resistant ovarian carcinoma cell lines (A2780/DOX R ). From the physicochemical properties and in vitro results, a mixed micelle system composed of poly(His-co-Phe (16 mole%))-b-PEG (80 wt%) and PLLA-b-PEG-folate (20 wt%) was selected to target early endosomal pH. DOXloaded (ca. 20 wt%) micelles effectively killed both wild-type sensitive and MDR cancer cell lines through an instantaneous high dose of DOX in the cytosol, resulting from active internalization, accelerated DOX release triggered by endosomal pH, and a disruption of endosomal pH.

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Rabies virus-inspired silica-coated gold nanorods are fabricated by mimicking size, shape, surface glycoprotein property and in vivo behavior of the rabies virus. These nanorods not only resemble the appearance of the actual rabies virus but also travel into the brain through the neuronal pathway bypassing the blood-brain barrier, and moreover respond to near-infrared laser (808 nm) irradiation, emit heat, and effectively suppress brain tumors.

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