**7. Disease site targeting via covalent conjugation**

The delivery of drugs to sites of target, where the action of the drug is required, is challenging due to various physicochemical, biopharmaceutical, and pharmacokinetic barriers the drug may face [143]. In order to address these issues, new approaches such as drug covalently conjugated to nano/micro-delivery systems are being explored which alters the pharmacokinetic properties of the drug. This is achieved by using drug various carriers such as polymers [148, 149] liposomes [150], and dendrimers [151] that are capable of protecting the payload drug and delivering it to the disease site. The nano/micro-delivery systems help in accumulating the drug in the tumor site and prolong the circulation time [80]. This consequently leads to a successful drug target to the specific disease site. Drug conjugates have been widely utilized in the field of cancer therapy because they can passively target cancer disease sites by permeating and retain the drug via tumor's leaky vasculature [152]. Apart from the ability of the nano/micro-delivery system to protect the drug from degradative processes such as hydrolysis and metabolism before arriving at the target site, the drug is able to accumulate in the targeted site. This ability is a major advantage that drug conjugates proffers, which enhances their antitumor activity. Additionally, the ability of the drug conjugate to disassemble provides the opportunity to tune the drug release rate at the target site. More so, the tuning or decorating the surface of the nanostructure (drug conjugate) can lead to enhanced tumor targeting compared to drugs in their free form [143]. The enhanced drug efficacy reported in the studies discussed earlier is closely associated with the ability of the drug conjugate to target the specific disease site.

The advantages of covalently conjugating drugs to nano/micro-delivery systems to target disease sites or site of infections has shown effective by results obtained by various researchers who employed different therapeutic agents and nano/microdelivery systems in targeting specific disease sites as highlighted in **Table 3**. In all the reported study on drug targeting using drug conjugates, a superior targeting of drugs to disease site was displayed by the drug encapsulated to nano/micro-delivery systems via covalent conjugation compared to the free drug. Thus, it implies that covalently conjugated drug-nano/micro-delivery systems have the potential to specifically target disease site; hence, it can be used to treat and manage diseases that appear to be challenging to combat.
