Stimuli-responsive Lipid-drug Conjugates for Cancer Therapy:Mechanisms, Linker Chemistry, and Tumour MicroenvironmentInteractions

Lipid Drug Conjugates (LDCs) are the conjugates of drug molecules in which covalently bound lipids are attached, enhancing lipophilicity and altering other pharmaceutical properties. Overall, conjugates show improved oral bioavailability, targeted delivery to the lymphatic system and tumours, and reduced toxicity. The coupling of drugs with lipids can be performed using a variety of techniques and chemical linkers, which are considered crucial for optimal drug delivery and good therapeutic outcomes. The choice of linker and conjugation strategy affects the delivery of the drug from the LDC, thereby influencing the formulation's performance and safety. Such traditional lipid-based drug formulations face challenges, including poor blood circulation, inadequate tumor targeting, and potential toxicities arising from the release of drugs during anticancer therapy from systemic circulation. However, recent advances in bioconjugation strategies have improved the physicochemical properties, pharmacokinetics, and antitumor activity of LDCs. Such improvements have been reported mainly in preclinical models, where LDCs generally exhibit reduced toxicity and enhanced therapeutic efficacy compared to conventional lipid formulations. An exciting new approach is the use of stimuli-responsive linkers in LDCs, which release the drug in response to specific triggers in the tumor microenvironment. These systems have the advantage of releasing a sustained amount of drug at the tumor site while minimizing systemic exposure. Moreover, the amphiphilic nature of most lipid-drug conjugates facilitates the self-assembly of nanoparticles for targeted drug delivery. This review focuses on various stimuli-responsive chemical bonds in lipids, conjugation strategies, and delivery forms used in LDCs, and highlights the prospects they offer for improving cancer treatments.