Targeted and nontargeted biopolymeric nanoparticles with identical hydrodynamic sizes and surface charges were quantitatively examined in terms of the pharmacokinetic and biodistribution differences in detail. In adding cancer cell targeting folate molecules to the surface of the heparin nanocarriers, the amount of drug delivered to the tumor is doubled, and tumor growth inhibition is significantly enhanced. The folate-targeted heparin particles offered similar therapeutic potentials compared to their synthetic long-circulating analogues, thus presenting a viable alternative for drug-delivery vehicle construction using biological polymers, which are easier for the body to eliminate.

The development of sophisticated nanoplatforms for in vivo targeted delivery of therapeutic agents to solid tumors has the potential for not only improving therapeutic efficacy but also minimizing systemic toxicity. However, the currently low delivery efficiency (about 1% of the injected dose) and the limited tumor penetration of nanoparticles remain two major challenges. Here we report a class of functionalized, long-circulating, and ultrasmall gold nanocarriers (5 nm gold core and 20 nm overall hydrodynamic diameter) for improved drug delivery and deep tumor penetration. By using doxorubicin as a model drug, our design also includes a pH-sensitive hydrazone linkage that is stable at neutral or slightly basic pH but is rapidly cleaved in the acidic tumor microenvironments and intracellular organelles. With a circulation halftime of 1.6 days, the small particle size is an important feature not only for efficient extravasation and accumulation via the enhanced permeability and retention (EPR) effect, but also for faster nanoparticle diffusion and improved tumor penetration. In xenograft animal models, the results demonstrate that up to 8% of the injected nanoparticles can be accumulated at the tumor sites, among the highest nanoparticle delivery efficiencies reported in the literature. Also, histopathological and direct visual examinations reveal dark-colored tumors with deep nanoparticle penetration and distribution throughout the tumor mass. In comparison with pure doxorubicin which is known to cause considerable heart, kidney, and lung toxicity, in vivo animal data indicate that this class of functionalized and ultrasmall gold nanoparticles indeed provides better therapeutic efficacies with no apparent toxicity in vital organs.

Diagnostics of Alzheimer’s disease (AD) commonly employ the use of fluorescent thioflavin derivatives having affinity for the amyloid-β (Aβ) proteins associated with AD progression. However, thioflavin probes have limitations in their diagnostic capabilities arising from a number of undesireable qualities, including poor photostability, weak emission intensity, and high emission overlap with the backgound tissue autofluorescence. To overcome such limitations, we have developed nanoformulated probes consisting of a red-emitting fluorescent quantum dot (QD) core encapsulated in a PEGylated shell with benzotriazole (BTA) targeting molecules on the surface (QD-PEG-BTA). The combination of strong red fluorescence, multivalent binding, and decreased backgound signal and nonspecific binding provided the ability of the QD-PEG-BTA probes to achieve detection sensitivites 4 orders of magnitude greater than those of conventional thioflavin derivatives. This study opens the door for the use of QDs in AD detection applications.

Tumor targeting agents including antibodies, peptides, and small molecules, are often used to improve the delivery efficiency of nanoparticles. Despite numerous studies investigating the abilities of targeting agents to increase the accumulation of nanosized therapeutics within diseased tissues, little attention has been focused on how these ligands can affect the self-assembly of the nanoparticle's modified polymer constituents upon chemical conjugation. Here we present an actively tumor targeted nanoparticle constructed via the self-assembly of a folate modified heparin. Folate conjugation unexpectedly allowed the self-assembly of heparin, where a majority of the folate molecules (>80%) resided inside the core of the nanoparticle. The folate–heparin nanoparticles could also physically encapsulate lipophilic fluorescent dyes, enabling the use of the constructs as activatable fluorescent probes for targeted in vivo tumor imaging.

We report the development and characterization of a multifunctional drug delivery system (Au–dox–PEG) for the treatment and SERS spectroscopic detection of tumors. Doxorubicin, a therapeutic agent and a SERS tag, was chemically conjugated to gold nanoparticles via a pH-sensitive hydrazone linker, and then PEG was added to develop Au–dox–PEG. The doxorubicin occupied a maximum of 20% of the total surface area of the gold nanoparticles which resulted in colloidal stability. SERS spectra were measured for non-aggregated Au–dox–PEG using near-infrared wavelength radiation, and the doxorubicin release was time and pH dependent. Consistency in the release profile and in vitro cell viability results supports the efficacy of the Au–dox–PEG system. Thus, the development of the Au–dox–PEG multifunctional system raises exciting opportunities for the simultaneous spectroscopic detection and therapy of tumors in the future.