Drug delivery is the administration of a pharmaceutical compound that achieves a therapeutic effect in humans and animals. Drug delivery methods include the preferred non-invasive oral (through the mouth), topical (skin), transmucosal (nasal, sublingual, vaginal, ocular, and rectal) and inhalation routes. Some medications in the form of peptide and/or protein, antibody, vaccine, and gene based drugs may not be delivered using these routes because of possible susceptibility to enzymatic degradation or these cannot be efficiently absorbed into the systemic circulation because of molecular size and charge issues to be effective therapeutically. Thus, many of these types of drugs have to be delivered by injection.
The latest efforts in the area of drug delivery include the development of targeted drug delivery methods. In targeted drug delivery, the drug is only active in the target area of the body (i.e. in the liver or tumor tissue) and is designed for sustained release in which the drug is released over a period of time in a controlled manner from the formulation. Existing types of sustained release formulations include the use of drug loaded biodegradable microspheres, liposomes, and drug polymer conjugates.
One of the major challenges in cancer treatment is the inability to deliver sufficient amounts of therapeutic agents into the tumor cells to maximize the therapeutic effect and minimize the side effects on normal tissues. Recent advances in nanotechnology have shown the feasibility of using nanocrystals for targeted drug delivery and simultaneous tumor imaging. With unique pharmacokinetics, nanocrystals with sizes between 10 and 100 nm have a prolonged circulation time compared with other small molecules because they are too large to be excreted by the kidneys in a short time but are small enough to avoid uptake by the reticuloendothelial system within the liver or spleen. Additionally, it has been shown that tumor vasculatures are not well developed and are usually leaky, which allows nanoparticles with sizes smaller than 100 nm to pass through the endothelial cell layer and enter into the tumor mass. Delivery of therapeutic agents using nanocrystals offers a chance to improve the water solubility and bioavailability of hydrophobic drugs. Because of their large surface area and diverse surface chemistry, one of the advantages of nanocrystals over other systems is that they can potentially combine the delivery of several functionalities and applications simultaneously to a tumor mass. Furthermore, targeting ligands that bind to cellular receptors that are highly expressed in tumor cells can be conjugated to the nanocrystals surface to facilitate selective and efficient delivery of drugs into the tumor cells. This could potentially overcome drug resistance due to excretion of the drug out of tumor cells by multi-drug resistant mechanisms.
Recently, Ocean NanoTech has developed a new drug carrier that can deliver the relative hydrophobic drug to the target site in cooperation with its collaborators. This drug loading mechanism is accomplished with a unique polymer surface coating of Ocean NanoTech’s biocompatible nanocrystals. In this coating process, the hydrocarbon chains of amphiphilic polymer interdigitize into the hydrophobic layer of the nanocrystals surface through hydrophobic interaction that orients the carboxylic acid groups on the surface making the nanocrystals hydrophilic, bio-reactive, and stable against harsh conditions during bioconjugation. The hydrophobic drug can be loaded into the hydrophobic layer between the polymer and inorganic core of the nanocrystals. The drug can be released through pH and/or temperature changes.
In our studies, we used a recombinant protein containing the first 135 amino acids of the amino-terminal fragment (ATF) of urokinase plasminogen activator (uPA) to target to urokinase plasminogen receptor (uPAR). Using a model drug, doxorubicin (Dox) which is one of the most commonly used chemotherapeutic drugs for the treatment of breast cancer, we have demonstrated that this hydrophobic drug can be efficiently encapsulated into iron oxide nanocrystals. These Dox-loaded nanocrystals have a compact size and are stable at pH 7.4. The encapsulated Dox can be released from the nanocrystals at pH 4.0 to 5.0 within 2 hrs. In comparison with the effect of equivalent dosage of the free drug or non-targeted iron oxide-Dox nanocrystals, uPAR-targeted iron oxide-Dox nanocrystals deliver higher levels of Dox into breast cancer cells and produce a stronger inhibitory effect on the growth of tumor cells. More importantly, Dox-loaded iron oxide nanocrystals retain their magnetic signal strength after being internalized into the tumor cells and generate significant susceptibility effect resulting in strong T2 contrast in the cells. The studies indicate that the drug loaded nanocrystals show potential in effective targeted therapeutic delivery as well as imaging probes for monitoring the therapeutic response using non-invasive tumor imaging. The details about this in vitro study can be found in our recent publication in J. Med. Nanotech. Ocean NanoTech and its collaborator is actively working on in vivo drug delivery.