A Clinically-Achievable Injectable and Sprayable in Situ Lyotropic Liquid Crystalline Platform in Treating Hormone-Sensitive and Castration-Resistant Prostate Cancer

Abstract

When it comes to long-acting injections, lyotropic liquid crystals (LLCs) are considered as an effective and powerful drug delivery technology due to their low manufacturing and injection difficulty, consistent releasing behaviors with low burst, as well as broadly applicable drug loading capacity. However, monoolein and phytantriol, as two widely used LLC-forming materials, may give rise to tissue cytotoxicity and undesired immunological responses, which may hinder the wide application of this technology. In this study, we opted for two ingredients, phosphatidylcholine and α-tocopherol, as carriers on account of their nature-obtainable and biocompatible qualities. By changing the ratios between them, we conducted research on crystalline types, nanosized structures, viscoelastic differences, characteristics of releasing behaviors, and in vivo safety. To fully exploit this in situ LLC platform with both injectability and sprayability, we focused on the treatment of both hormone-sensitive (HSPC) and castration-resistant prostate cancer (CRPC). For HSPC, we found that spraying leuprolide and a cabazitaxel-loaded LLC platform on the tumor bed after resection greatly reduced tumor metastatic rate and prolonged the survival time. Besides, for CRPC, our results demonstrated that although leuprolide (a kind of drug for castration) alone could hardly limit the progression of CRPC with low MHC-I expression, its combination with cabazitaxel in our LLC platform achieved a significantly better tumor-inhibiting and anti-recurrent efficacy than single cabazitaxel-loaded LLC platform, owing to enhanced CD4 + T cell infiltration in tumors and immune-potentiating cytokines. In conclusion, our dual-functional and clinically achievable strategy might provide a treating solution toward both HSPC and CRPC.

A Long-Acting Lyotropic Liquid Crystalline Implant Promotes the Drainage of Macromolecules by Brain-Related Lymphatic System in Treating Aged Alzheimer’s Disease

“…Lyotropic liquid crystalline technology could accommodate drugs with different properties, and release incorporated drugs in a controlled and prolonged manner . To evaluate the releasing behaviors of donepezil hydrochloride and cilostazol-loaded LLC gel implants, both in vitro and in vivo releasing tests were performed (Figure A–D).…”

“…27,28 Besides, the situ-forming technology of LLC implants enables direct injection with low injecting difficulty, and avoids surgical embedding, which is different from traditional gel implants. 29,30 In this study, we incorporated donepezil hydrochloride and cilostazol into phosphatidylcholine and α-tocopherol-based lyotropic liquid crystalline implants, and found that when compared with daily oral delivery of donepezil hydrochloride +cilostazol solution (DCS) and subcutaneous delivery of donepezil hydrochloride+cilostazol-loaded LLC gel implant (DCG), administrating DCG near the dCLNs achieved the greatest drug concentrations in brains. Encouraged by this, we constructed old AD mice by injected Aβ 1−42 into bilateral hippocampus of the mice aged 20 months, and compared the therapeutic efficacy between different administration strategies on the elderly AD mice.…”

“…Lyotropic liquid crystalline technology could accommodate drugs with different properties, and release incorporated drugs in a controlled and prolonged manner. 29 To evaluate the releasing behaviors of donepezil hydrochloride and cilostazol-loaded LLC gel implants, both in vitro and in vivo releasing tests were performed (Figure 2A−D). Because donepezil hydrochloride and cilostazol have similar hydrophobic properties, in vitro releasing tests demonstrated that these two drugs were released in a comparable manner.…”

“…As a result, the manufacturing difficulty is low, which is conducive to mass production. By comparison, complicated and multiple fabrication process is required as for the manufacture of microspheres and multivesicular liposomes. , Besides, the situ -forming technology of LLC implants enables direct injection with low injecting difficulty, and avoids surgical embedding, which is different from traditional gel implants. , …”

Utilization of Lyotropic Liquid Crystalline Gels for Chronic Wound Management

“…The hydrophobic groups in the molecule are usually arranged side-by-side [ 61 ]. Due to its spontaneous phase transition characteristics, ordered lattice structure, excellent drug loading, good biosafety and biocompatibility [ 62 , 63 ], release profile and stabilization of various drugs [ 64 ], it is expected to act as a prospect candidate delivery system for chronic wound treatment. LLC not only has a healing effect on the wound, but also can be useful as a nano drug carrier in implants [ 65 , 66 ].…”