To address the need for localized
chemotherapy against unresectable
solid tumors, an injectable in situ depot-forming lipidic lyotropic
liquid crystal system (L3CS) is explored that can provide spatiotemporal
control over drug delivery. Although liquid crystals have been studied
extensively before but their application as an injectable intratumoral
depot system for locoregional chemotherapy has not been explored yet.
The developed L3CS in the present study is a low-viscosity injectable
fluid having a lamellar phase, which transforms into a hexagonal mesophase
depot system on subcutaneous or intratumoral injection. The transformed
depot system can be preprogrammed to provide tailored drug release
intratumorally, over a period of one week to one month. To establish
the efficacy of the developed L3CS, doxorubicin is used as a model
drug. The drug release mechanism is studied in detail both in vitro
and in vivo, and the efficacy of the developed system is investigated
in the murine 4T1 tumor model. The direct intratumoral injection of
the L3CS provided localized delivery of doxorubicin inside the tumor
and restricted its access within the tumor only for a sustained period
of time. This led to an over 10-fold reduction in tumor burden, reduced
cardiotoxicity, and a significant increase in the median survival
rate, compared to the control group. The developed L3CS thus provides
an efficient strategy for localized chemotherapy against unresectable
solid tumors with a great degree of spatial and temporal control over
drug delivery.
Though paclitaxel (PTX) and doxorubicin (DOX) are amongst the most widely used and investigated drug pair for combination chemotherapy but surprisingly, not a single validated HPLC-UV method is available to analyze PTX and DOX simultaneously. So, herein a HPLC-UV method is developed and validated for the same, filling an indispensable gap in the literature. As these two moieties have characteristically different polarities, resolving them under the common chromatographic conditions is a challenging task. Herein, the principle of ion pair chromatography is utilized to resolve these two moieties on a C18 column employing an isocratic mobile phase comprised of acetonitrile and octane sulfonic acid buffer (67 : 37) and detected simultaneously at 231 nm using a UV detector only. The retention time is 4.4 and 7.2 min for PTX and DOX, respectively, with a total analysis time of less than 10 minutes, suitable for the formulation development and research, while LOQ is less than 0.066 μg/ml for both the drugs, suitable for the therapeutic drug monitoring at preclinical and clinical research setup. To substantiate the applicability of the developed method, a nanoformulation coloaded with PTX and DOX was designed and analyzed using the developed protocol. The method is also applied successfully to study the plasma kinetic profile of both the moieties simultaneously in Balb/c mice. Further, the method is validated as per the ICH guidelines fulfilling the unmet need of a validated analytical tool to simultaneously estimate PTX and DOX. Moreover, the results suggest that the principal of common ion chromatography demonstrated here can also be applied further for the simultaneous chromatographic separation of other polar and nonpolar moieties too. Consequently, the reported method surely will advance the toolset required for the precision-based combination chemotherapy.
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