| Autor: |
Saklani R; Division of Pharmaceutics and Pharmacokinetics, CSIR-Central Drug Research Institute, Lucknow 226031, India.; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India., Yadav PK; Division of Pharmaceutics and Pharmacokinetics, CSIR-Central Drug Research Institute, Lucknow 226031, India.; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India., Tiwari AK; Division of Pharmaceutics and Pharmacokinetics, CSIR-Central Drug Research Institute, Lucknow 226031, India.; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India., Gawali SL; Nanotherapeutics and Biosensors Section, Chemistry Division, Bhabha Atomic Research Centre Trombay, Mumbai 400085, India., Hassan PA; Nanotherapeutics and Biosensors Section, Chemistry Division, Bhabha Atomic Research Centre Trombay, Mumbai 400085, India., Yadav K; Division of Toxicology, CSIR-Central Drug Research Institute, Lucknow, Uttar Pradesh 226031 India., Mugale MN; Division of Toxicology, CSIR-Central Drug Research Institute, Lucknow, Uttar Pradesh 226031 India., Kalleti N; Division of Toxicology, CSIR-Central Drug Research Institute, Lucknow, Uttar Pradesh 226031 India., Rath SK; Division of Toxicology, CSIR-Central Drug Research Institute, Lucknow, Uttar Pradesh 226031 India., Mishra DP; Division of Endocrinology, CSIR-Central Drug Research Institute, Lucknow 226031, India., Dierking I; Department of Physics and Astronomy, University of Manchester, Manchester M13 9PL, United Kingdom., Chourasia MK; Division of Pharmaceutics and Pharmacokinetics, CSIR-Central Drug Research Institute, Lucknow 226031, India.; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India. |
| Abstrakt: |
In this work, an injectable in situ depot-forming lipidic lyotropic liquid crystal (L3C) system is developed to codeliver a precisely synchronized combination of chemotherapeutics intratumorally. The developed L3C system is composed of amphiphilic lipids and surfactants, including monoolein, phosphatidylcholine, tocopherol acetate, and d-α-tocopherol polyethylene glycol 1000 succinate. Owing to its amphiphilic nature, the developed formulation can coaccommodate both hydrophobic and hydrophilic chemotherapeutic moieties simultaneously. The study presents a proof of concept by designing a combination chemotherapy regimen in vitro and demonstrating its in vivo translation using doxorubicin and paclitaxel as model hydrophilic and hydrophobic drug moieties, respectively. The synchronized combination of the two chemotherapeutics with maximum synergistic activity was identified, coloaded in the developed L3C system at predefined stoichiometric ratios, and evaluated for antitumor efficacy in the 4T1 breast tumor model in BALB/c mice. The drug-loaded L3C formulation is a low-viscosity injectable fluid with a lamellar phase that transforms into a hexagonal mesophase depot system upon intratumoral injection. The drug-loaded depot system locally provides sustained intratumoral delivery of the chemotherapeutics combination at their precisely synchronized ratio for over a period of one month. Results demonstrate that the exposure of the tumor to the precisely synchronized intratumoral chemotherapeutics combination via the developed L3C system resulted in significantly higher antitumor activity and reduced cardiotoxicity compared to the unsynchronized combination chemotherapy or the synchronized but uncoordinated drug delivery administered by a conventional intravenous route. These findings demonstrate the potential of the developed L3C system for achieving synchronized codelivery of the chemotherapeutics combination intratumorally and improving the efficacy of combination chemotherapy. |
