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.
Head and neck squamous cell carcinoma (HNSCC) is the 8th most common cancer in the United States predominantly affecting people over 65 years of age with an increasing rate of incidence across the world. Current therapies for HNSCC include surgical resection, chemotherapy (CT), and radiotherapy (RT). For locally advanced/unresectable HNSCC, the CT-RT combination (“chemoradiation”) has been shown to be more effective than CT or RT alone, and is currently the standard of care. Intratumoral (IT) chemotherapy-based chemoradiation has the potential to overcome the limitations of conventional systemic CT-RT that severely affects a patient’s quality of life. For realization of maximum benefits from IT CT-RT, our team has developed a radiation-controlled drug release nanoparticle formulation (paclitaxel (PTX) and CaWO4 nanoparticles (CWO NPs) co-encapsulated within a capsule formed by poly(ethylene glycol)-poly (lactic acid) (PEG-PLA), named “PEG-PLA/CWO/PTX NPs”). This unique formulation releases PTX only when it is exposed to X-ray irradiation. We have previously reported that IT-administered PEG-PLA/CWO/PTX NPs stay within the tumor for at least a month, producing significant therapeutic effects in terms of tumor suppression and survival in mouse models of HNSCC. This work demonstrates the effect of PTX stereochemistry on radiation-controlled release of the drug from a nano polymer matrix system (PEG-PLA/CWO/PTX NPs). The stereoisomertic characteristics of PTX products from two different manufacturers (“PTX-S”, and “PTX-B”) were analyzed by Raman spectroscopy, circular dichroism and 2D HMQC/NOESY NMR measurements. In their unencapsulated (free) state, PTX-S and PTX-B were comparable in their ability to kill cancer cells in vitro. However, they were found to be significantly different in water solubility; PTX-S (water solubility ≈ 4.69 μg/mL) is about 19 times more water soluble than PTX-B (water solubility ≈ 0.25 μg/mL). This difference in water solubility was found to cause a large difference in X-ray-triggered release kinetics of the PTX loaded within the PEG-PLA/CWO/PTX NPs in both in vitro and in vivo environments; PTX-S is released from PEG-PLA/CWO NPs significantly faster upon X-ray irradiation than PTX-B. This difference in release kinetics produced an interesting difference in their time-dependent therapeutic effects; at short times (< 1 month), concurrent PEG-PLA/CWO/PTX-S NPs produced a greater tumor suppression effect; on the other hand, PEG-PLA/CWO/PTX-B NPs had a longer lasting radio-sensitizing effect. In summary, the stereoisomers of PTX exhibit significantly different PK characteristics when used with controlled release carriers, even though they are pharmacologically indistinguishable in their unformulated form.
Citation Format: Kaustabh Sarkar, Sandra Torresgrossa-Allen, Mark P. Langer, Gregory Durm, Sanjeev Narayanan, Bennett D. Elzey, You-Yeon Won. Effect of paclitaxel stereochemistry on x-ray-triggered release of paclitaxel from CaWO4/paclitaxel-coloaded PEG-PLA nanoparticles [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 304.
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