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Among other nanoparticle systems, gold nanoparticles have been explored as radiosensitizers. While most of the research in this area has focused on either gold nanoparticles with diameters of less than 2 nm or particles with micrometer dimensions, it has been shown that nanoparticles 50 nm in diameter have the highest cellular uptake. We present the results of in vitro studies that focus on the radiosensitization properties of nanoparticles in the size range from 14-74 nm. Radiosensitization was dependent on the number of gold nanoparticles internalized within the cells. Gold nanoparticles 50-nm in diameter showed the highest radiosensitization enhancement factor (REF) (1.43 at 220 kVp) compared to gold nanoparticles of 14 and 74 nm (1.20 and 1.26, respectively). Using 50-nm gold nanoparticles, the REF for lower- (105 kVp) and higher- (6 MVp) energy photons was 1.66 and 1.17, respectively. DNA double-strand breaks were quantified using radiation-induced foci of gamma-H2AX and 53BP1, and a modest increase in the number of foci per nucleus was observed in irradiated cell populations with internalized gold nanoparticles. The outcome of this research will enable the optimization of gold nanoparticle-based sensitizers for use in therapy.

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The current study describes the impact of particle size and/or molecular targeting (epidermal growth factor, EGF) on the in vivo transport of block copolymer micelles (BCMs) in athymic mice bearing human breast cancer xenografts that express differential levels of EGF receptors (EGFR). BCMs with diameters of 25 nm (BCM-25) and 60 nm (BCM-60) were labeled with indium-111 ((111)In) or a fluorescent probe to provide a quantitative and qualitative means of evaluating their whole body, intratumoral, and subcellular distributions. BCM-25 was found to clear rapidly from the plasma compared to BCM-60, leading to an almost 2-fold decrease in their total tumor accumulation. However, the tumoral clearance of BCM-25 was delayed through EGF functionalization, enabling the targeted BCM-25 (T-BCM-25) to achieve a comparable level of total tumor deposition as the nontargeted BCM-60 (NT-BCM-60). Confocal fluorescence microscopy combined with MATLAB analyses revealed that NT-BCM-25 diffuses further away from the blood vessels (D(mean) = 42 +/- 9 microm) following extravasation, compared to NT-BCM-60 which mainly remains in the perivascular regions (D(mean) = 23 +/- 4 microm). The introduction of molecular targeting imposes the "binding site barrier" effect, which retards the tumor penetration of T-BCM-25 (D(mean) = 29 +/- 7 microm, p < 0.05). The intrinsic nuclear translocation property of EGF/EGFR leads to a significant increase in the nuclear uptake of T-BCM-25 in vitro and in vivo via active transport. Overall, these results highlight the need to consider multiple design parameters in the development of nanosystems for delivery of anticancer agents.

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Micelles formed from polycaprolactone-b-poly(ethylene oxide) (PCL-b-PEO) diblock copolymers were investigated as a novel drug delivery system. The affinity of the micelles for hydrophobic solubilizates was assayed by determining the partition coefficient for the lipophilic compound, pyrene, between the micelles and water; the partition coefficient was found to be on the order of 10(2). The Trypan blue and Alamar blue survival assays were used to assess the in vitro biocompatibility of the micelles with PC 12 cells, MCF-7 breast cancer cells, and primary cultures of human microglia, astrocytes, and cortical neurons. The micelles were then studied as a delivery vehicle for the neurotrophic agents FK506 and L-685,818 in PC 12 cell cultures. In both cases, the micelle-incorporated drugs, in the presence of nerve growth factor (5 ng/mL), were able to promote the degree of differentiation of the PC 12 rat pheochromocytoma cells.

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