Researchers at the Center for Childhood Cancer Research (CCCR) led by Michael Chorny, PhD, are working on developing new therapeutic agents and nanoparticles with targeted delivery capabilities for more precise and effective cancer treatment.
Cancer chemotherapy relies on cytotoxic agents to kill tumor cells. However, the clinical utility of both established and experimental cytotoxic agents is often compromised by poor stability and a lack of solubility in conventional pharmaceutical vehicles used for drug administration.
In addition, a sizeable fraction of many anticancer drugs fails to reach the tumor and instead distributes to normal tissues and organs, greatly diminishing therapeutic effectiveness and causing serious adverse reactions.
These issues hampering the safe and effective use of these drugs in patients with neuroblastoma and other pediatric malignancies pose a formidable challenge addressed experimentally by a team of CCCR researchers. The researchers are carefully adjusting the chemical properties of drug molecules and then applying the reengineered therapeutic agents in combination with properly designed biodegradable nanocarriers.
Nanocarriers are flexible and efficient delivery systems that can protect drug molecules from inactivation and provide a means for administering both single agents and, when needed, their combinations at therapeutically effective doses. Nanocarriers can also dramatically improve the performance of chemotherapeutics by helping to guide and localize them to tumors and minimize the exposure of normal tissues.
For tumor-targeted delivery, drugs can be encapsulated within particles about 100 times smaller than a red blood cell, termed nanoparticles. Nanoparticles can be engineered from biodegradable components and constructed with the ability to stably bind to the elements of tumor tissue. Particles in this size range are small enough to not get stuck in capillaries, big enough to not pass through cell junctions of normal blood vessels, and the right size to get across through fenestrations characteristic of tumor vasculature, which makes possible confining drug delivery to the target.
Once the nanoparticle delivers its cargo to the tumor cells, it disintegrates and the breakdown products are fully eliminated from the body. Due to enhanced effectiveness of this targeted therapy, lower doses of anticancer drugs can be used, thus obviating or reducing untoward effects.
Nanoparticle-based delivery systems designed by researchers at the CCCR are tailored for different families of potent anticancer agents, including camptothecins, bioactive derivatives of staurosporine and podophyllotoxin, retinoids, taxanes, as well as new chemical entities, thus broadening the range of potential clinical applications. Improved stability, tumor-specific delivery and targeted pharmacological effects recently shown by the researchers in preclinical studies using a neuroblastoma model can provide the basis for new, safer and more effective, cancer treatments and strengthen the armamentarium of therapeutic strategies available to pediatric oncologists.