We describe the development of multifunctional polymeric micelles with cancer-targeting capability via alpha(v)beta(3) integrins, controlled drug delivery, and efficient magnetic resonance imaging (MRI) contrast characteristics. Doxorubicin and a cluster of superparamagnetic iron oxide (SPIO) nanoparticles were loaded successfully inside the micelle core. The presence of cRGD on the micelle surface resulted in the cancer-targeted delivery to alpha(v)beta(3)-expressing tumor cells. In vitro MRI and cytotoxicity studies demonstrated the ultrasensitive MRI imaging and alpha(v)beta(3)-specific cytotoxic response of these multifunctional polymeric micelles.

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These nanoconstructs are composed of amphiphilic block copolymers with distinct hydrophobic and hydrophilic segments that can self-assemble into supramolecular core±shell structures (usually 10 to 100 nm) in aqueous solution. The hydrophobic micelle core provides an ideal carrier compartment for hydrophobic agents, and the shell consists of a protective corona that stabilizes the nanoparticles. Many hydrophobic drugs such as paclitaxel and doxorubicin have been successfully loaded inside the micelle core to improve drug solubility and pharmacokinetics. [2,3,6,7] In addition to therapeutic applications, polymeric micelles have also received increasing attention in diagnostic imaging applications. When incorporated into micelles, different types of contrast agents have achieved longer blood half-life, improved biocompatibility, and better contrast.[1]In this communication, we report the development of superparamagnetic polymeric micelles as a new class of magnetic resonance imaging (MRI) probes with remarkably high spin± spin (T 2 ) relaxivity and sensitivity. Superparamagnetic iron oxide (SPIO) nanoparticles such as magnetite (FeO´Fe 2 O 3 ) are known to have a strong effect on T 2 . Better detection sensitivity and slower kidney clearance of SPIO nanoparticles make them advantageous over Gd-based small molecular contrast agents. Currently, most T 2 contrast agents are composed of hydrophilic magnetite nanoparticles dispersed in a dextran matrix. [8,9] In contrast, our micelle design consists of a cluster of hydrophobic magnetite particles encapsulated inside the hydrophobic core of polymeric micelle whose surface is stabilized by a poly(ethylene glycol) (PEG) shell. This unique core±shell composite design has allowed us to achieve an ultrasensitive MRI detection limit of 5.2 lg mL ±1 (~5 nM), a sensitivity that promises to expand the ªtool boxº of MR probes for molecular imaging and image-visible drug-delivery applications.We used an amphiphilic diblock copolymer of poly(e-caprolactone)-b-poly(ethylene glycol) (PCL-b-PEG) for the micelle formation (Fig. 1). This copolymer was synthesized by a ringopening polymerization of e-caprolactone using monomethoxy-terminated PEG (5 kDa; 1 Da .

Conspectus Enormous efforts have been made toward translating nanotechnology into medical practice, including cancer management. The approaches have generally been classifiable into two categories--those for diagnosis and those for therapy. The targets for diagnostic probes and therapy are often the same, however, and separate approaches to develop diagnostic and therapeutic agents can miss opportunities to improve the efficiency and effectiveness of both. A close and continuous linkage between therapy and diagnosis is also important, because a patient’s diagnosis/prognosis will evolve during treatment. The unique physical properties of nanomaterials enable them to serve as 1) bases for superior imaging probes to locate and report cancerous lesions, and 2) vehicles to deliver therapeutics preferentially to those lesions. These technologies for probes and vehicles have converged in the current efforts to develop nano-theranostics—that is, nanoplatforms with both imaging and therapeutic functionalities. These latest multimodal platforms are highly versatile and valuable components of the emerging beneficial trend toward personalized medicine, which emphasizes tailoring practices to individual needs so as to optimize outcomes. Unlike conventional methods, imaging and therapeutic functions are seamlessly unified in nano-theranostics, thereby permitting updates to diagnosis/prognosis along with treatment, and enabling opportunities to switch to alternative, possibly more suitable, regimens. Magnetic nanoparticles, especially superparamagnetic iron oxide nanoparticles (hereafter referred to as IONPs), have long been studied as contrast agents for magnetic resonance imaging (MRI). Owing to recent progress in synthesis and surface modification, many new avenues have opened, though, for this class of biomaterials. The idea is to conceptualize the nanoparticles not as merely tiny magnetic crystals, but rather as platforms with large surface-to-volume ratios. By taking advantage of the well developed surface chemistry of these materials, one can load a wide range of functionalities, such as targeting, imaging and therapeutic features, onto their surfaces. This makes magnetic nanoparticles excellent scaffolds to construct theranostic agents and has attracted many efforts toward this goal. In this account we will summarize the progress made in our recent studies. We will introduce the surface engineering techniques that we and others have developed, with an emphasis on how the techniques affect the role of nanoparticles as imaging or therapeutic agents.