Enhancing the Effect of Cytotoxic and Targeted Therapies Through the Use of Multifunctional Nanoparticles

Traditional cancer chemotherapy has primarily been based on highly cytotoxic drugs that nonspecifically target any dividing cell, thereby inducing global systemic toxicity with only a modest improvement in patient survival.  There is clearly an urgent need for a new paradigm in the management of cancer since conventional cancer therapy is nonspecific, nonselective, and toxic.  Our goal is to engineer and test whether the next generation multifunctional nanoparticles (NPs), which deploy a combination of a signal transduction inhibitor, such as mTOR/PI3K, MAPK, receptor tyrosine kinase, VEGF, PARP inhibitors, specifically targeting cancer cells or cancer stem cells along with a cytotoxic chemotherapeutic agent (i.e., platinum, doxorubicin) exerts a superior antitumor outcome with reduced adverse effects in ovarian cancer.

In collaboration with bioengineers at BWH and MIT we have shown that both micellar and polymeric multifunctional NPs remain in circulation for prolonged periods of time and accumulate preferentially in tumors via an enhanced permeation and retention effect (EPR). Both forms of NPs are biocompatible and work through the same physiological mechanism.  The benefit of having multiple types of NPs is to fit the unique chemical structure and interactions between drugs.  Since, the chemistry of each compound differs this allows for optimizing the structure-activity between the NP and anti-tumor compound to create the most effective therapy possible.  In a recent study we were able to demonstrate that a polymeric-cisplatin NP significantly reduced primary ovarian tumors in animal models of disease as compared to an equal dosing concentration of “normal” cisplatin.  Equally as compelling was the reduced toxicity observed in mice treated with the cisplatin-NP conjugate.  In an assay that measures apoptosis it was clear that cisplatin distribution was concentrated in the tumor in mice treated with cisplatin-NPs.  Additionally, apoptosis was absent in organs normally affected by cisplatin therapy, suggesting that the cisplatin-NP was indeed preferentially “honing” into the tumor tissue via the EPR effect.  Similar results were seen in mice treated with a micellar-cisplatin conjugate NP where there was a four-fold increase in efficacy over traditional cisplatin. We also tested the effect of encapsulating a signal transduction MAPK inhibitor, in a polymeric NP, which also increased the anti-tumorigenic effect by 40% when compared to traditional PD98059 compound.