The success rate of a drug heavily relies on the chosen mechanism of drug release, which should be suitable for its intended purpose. Controlled drug release is vital in clinical drug delivery systems, offering numerous advantages such as a consistent release rate in the body, lower peak plasma concentration, predictable onset of action, enhanced drug effectiveness, and reduced patient discomfort from repeated doses. Ultimately, this leads to improved patient outcomes and higher satisfactio [1]. Drug transfer through highly branched polymers and dendrimers can be achieved via two methods: physically loading the drug and chemically connecting the drug to the dendrimer. Dendrimer-drug conjugates have been shown to decrease drug side effects, improve efficacy and efficiency, and extend the drug's half-life. For example, binding methotrexate to a PAMAM dendrimer can extend its half-life from 24 minutes to 24 hours, enhancing drug effectiveness and reducing the need for frequent administration by altering the drug's half-life.
Conjugating the drug with the dendrimer can also impact the drug's solubility. The attachment of paclitaxel's mediator to the PAMAM dendrimer increases its solubility in water by up to 9000 times [2]. The separation of the drug from dendrimer-drug conjugates while preserving the drug's primary structure is a critical aspect when assessing drug release [3]. Therefore, when linking the drug to the dendrimer, it is done through a breakable or responsive link. Breakable bonds like disulfide and thioctal bonds, which can be cleaved by glutathione and reactive oxygen species (ROS), are commonly utilized in the design of dendrimer-drug conjugates [4–6].
pH-sensitive bonds, particularly acid-labile bonds (such as acetal bonds), are used in the creation of dendrimer-drug conjugates for cancer treatment [7]. These conjugates are engineered to target acidic tumor cells, enhancing drug delivery effectiveness. Dendrimers with a hydrophobic inner core are especially adept at encapsulating hydrophobic drugs [8]. By encapsulating the drug within the dendrimer, its water solubility is enhanced, resulting in improved efficacy [9].
Low-generation dendrimers have a limited capacity for drug loading due to their small internal space. When dendrimer molecules are aggregated with polyethylene glycol connections, the drug loading capacity increases [10]. PEGylated dendrimers can also enhance the permeation and retention effect (EPR) of encapsulated drugs [11]. By continuously releasing the drug at a controlled rate, they mimic the way hormones like insulin are utilized by the body. 5-Fluorouracil (5FU) is one of the most commonly used antimetabolite chemotherapy agents in recent decades[12]. Chemotherapy is a widely used treatment for many cancers, but it has limitations such as low bioavailability, short half-life, rapid metabolism, and the development of drug resistance. One commonly used drug in chemotherapy is 5FU, which is hydrophobic and frequently employed in the treatment of colon, breast, and pancreatic cancers. Various approaches have been developed to address the limitations of 5FU treatment, prevent side effects and drug resistance, and extend the drug's circulation time in the body [13]. One such method involves using poly(lactide-co-glycolide), which can accommodate up to 3.8% of 5FU[14]. To mitigate the toxic effects of 5FU, it is suggested to chemically bond it to sulfated polysaccharides, although its release characteristics may not be ideal for cancer treatment. The initial release occurs within the first 10 hours, with a subsequent increase in release observed. Cancerous tissues, being somewhat acidic, play a role in this process [15]. Chitosan has been utilized as a biomaterial for delivering 5FU drugs, while hydroxyapatite and chitosan have been employed as control agents for 5FU release with low loading [16, 17].
Recently, multi-walled carbon nanotubes have been utilized to deliver 5FU drugs, taking into account the effects of pH on drug loading and release, resulting in improved drug release conditions [18]. The latest research presents a novel and efficient method for developing smart polymeric nanocarriers capable of delivering 5FU drugs in a controlled manner. This approach holds significant therapeutic promise as it provides optimal conditions for drug loading. Furthermore, the incorporation of a temperature-sensitive monomer enables a programmed release mechanism that can address previous challenges in drug delivery.