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For many locally advanced tumors, the chemotherapy–radiotherapy (CT–RT) combination (“chemoradiation”) is currently the standard of care. Intratumoral (IT) CT-based chemoradiation has the potential to overcome the limitations of conventional systemic CT–RT (side effects). For maximizing the benefits of IT CT–RT, our laboratory has previously developed a radiation-controlled drug release formulation, in which anticancer drug paclitaxel (PTX) and radioluminescent CaWO4 (CWO) nanoparticles (NPs) are co-encapsulated with poly­(ethylene glycol)–poly­(lactic acid) (PEG-PLA) block copolymers (“PEG-PLA/CWO/PTX NPs”). These PEG-PLA/CWO/PTX NPs enable radiation-controlled release of PTX and are capable of producing sustained therapeutic effects lasting for at least one month following a single IT injection. The present article focuses on discussing our recent finding about the effect of the stereochemical structure of PTX on the efficacy of this PEG-PLA/CWO/PTX NP formulation. Stereochemical differences in two different PTX compounds (“PTX-S” from Samyang Biopharmaceuticals and “PTX-B” from Biotang) were characterized by 2D heteronuclear/homonuclear NMR, Raman spectroscopy, and circular dichroism measurements. The difference in PTX stereochemistry was found to significantly influence their water solubility (WS); PTX-S (WS ≈ 4.69 μg/mL) is about 19 times more water soluble than PTX-B (WS ≈ 0.25 μg/mL). The two PTX compounds showed similar cancer cell-killing performances in vitro when used as free drugs. However, the subtle stereochemical difference significantly influenced their X-ray-triggered release kinetics from the PEG-PLA/CWO/PTX NPs; the more water-soluble PTX-S was released faster than the less water-soluble PTX-B. This difference was manifested in the IT pharmacokinetics and eventually in the survival percentages of test animals (mice) treated with PEG-PLA/CWO/PTX NPs + X-rays in an in vivo human tumor xenograft study; at short times (<1 month), concurrent PEG-PLA/CWO/PTX-S NPs produced a greater tumor-suppression effect, whereas PEG-PLA/CWO/PTX-B NPs had a longer-lasting radio-sensitizing effect. This study demonstrates the importance of the stereochemistry of a drug in a therapy based on a controlled release formulation.

Previous studies have shown that calcium tungstate (CaWO 4 ) nanoparticles (NPs) can be used as a radiosensitizing/Xray contrast agent for cancer treatment. However, due to the propensity of calcium tungstate to agglomerate in physiological solutions, there is a need to encapsulate these NPs within poly(ethylene glycol)-poly(D,L-lactic acid) (PEG−PLA) polymeric micelles through a solvent exchange process. Several parameters including solvent type, polymer to NP ratio, mixing method, and lyophilization were studied to optimize the encapsulation and storage procedures for future scale-up. Herein, we report that the cosolvent that was previously used in this procedure (dimethylformamide) can be replaced with a less toxic cosolvent (acetone), the polymer to NP ratio can be reduced from 600:1 to 50:1 without increasing the particle size by 20%, and mixing methods that create a more uniform flow field produce a more homogenous and less polydisperse particle distribution. In addition, our results indicate that sucrose as a lyophilization excipient produces less agglomeration during freeze-drying compared to mannitol. The smaller molecular weight 2 kDa and 2 kDa ("2 k−2 k") PEG−PLA was less prone to agglomeration during freeze-drying compared to 5 k−5 k PEG−PLA.

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