To efficiently manage localized cancer, drug concentrations should consistently remain within the therapeutic window (TW) to minimize toxicity while maintaining therapeutic activity. Although drug levels often fluctuate far outside the TW, in vivo drug release-monitoring can provide accurate information to guide drug dosing. However, current release-monitoring strategies remain inadequate, for example due to intrinsic/background signal convolution and/or penetration depth limitations. Additionally, monitoring drug release alone is often insufficient because local drug concentrations cannot be modified once administered in vivo. Herein, we overcome these challenges by combining innovative remote-controlled drug release with magnetic particle imaging (MPI) to maintain intratumoral drug concentrations within the TW simply by turning ON/OFF the near-infrared (NIR) laser.

We designed an optically-responsive superparamagnetic iron oxide@poly(lactide-co-glycolide acid) core−shell nanocomposite loaded with chemotherapy (doxorubicin). If drug concentrations are too low (based on assessment using MPI), nanocomposite degradation can be accelerated optically via NIR light on-demand (e.g., controlled drug release acceleration to ~46% of loaded drug within 5 mins). NIR-driven doxorubicin release and MPI signal increase are linearly correlated (R²=0.99) in vitro, enabling drug release monitoring in murine breast cancer models by applying MPI+NIR, resulting in precise, whole-body image-based quantification of drug release (Fig a). Interestingly, the prepared nanocomposites are stable for weeks at the pH of neutral extracellular environments and blood.

Employing NIR-triggered drug release from nanocomposites, it showed that the intratumoral doxorubicin concentration after 1 min NIR is well below the minimum effective drug dose (MED) and intratumoral doxorubicin concentration after 5 mins NIR is near, but still sub-MED. In order to ensure intratumoral drug concentrations within the TW, we boosted the intratumoral doxorubicin concentration above MED by increasing the NIR time to 7 mins. By monitoring drug release to precisely accelerate concentrations into the TW, our platform inhibits DOX-sensitive 4T1 tumor growth and prolongs time to tumor recurrence (75 days post-injection). In the case of DOX-resistant BT549 tumors, our platform eliminates cancer after the 4^th dose, with no tumor recurrence for >10 months.

Doxorubicin is well-known to cause cardiotoxicity and hepato-renal toxicities. We defined intratumoral IC50s as the MED, and maximum tolerated drug dose (MTD) was defined as the dose at which ‘unacceptable’ side effects occur. These effects are drug-dependent, and in this case, such doxorubicin-related effects are defined to include ≥15% body weight decrease, significant cardiovacuolation, or significant change in one or more sensitive indicators of cardio/hepatotoxicity (LDH, ALT, and cTnl). Unlike the control groups such as doxorubicin alone, our nanoplatform did not significantly decrease mouse body weight, did not increase the expression of cardiotoxicity- (LDH, cTnl) and hepatotoxicity-related biomarkers (ALT) (Fig b-e), did not decrease spleen size, did not significantly shrink the size of white pulps and the number of red pulps, and did not produce significant cardiovacuolation histologically. Collectively, these data reveal our nanoplatform strategy not only maintained drug concentrations within the TW by simply turning ON/OFF the NIR laser, significantly improving anti-cancer therapeutic efficacy, but also minimized side effects.

Our nanoplatform has potential for clinical translation given that all the materials comprising nanoparticles have been used in humans and MPI is in the process of being translated clinically, particularly in view of the increased efficacy and decreased side effects we observed. NIR laser treatments are already clinically approved by regulatory agencies including the FDA and European Medicines Agency (EMEA). Thus, our NIR laser (808 nm, 1W/cm²) based nanoplatform is expected to show good biosafety translationally. In summary, our drug release monitoring nanoplatform has the potential to maintain drug concentrations in the TW, thereby improving patient response and reaction to chemotherapy in the precision medicine paradigm.

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