In recent years, chemotherapy considered one of the most used therapeutic approaches in cancer treatment owing to its non-invasive or minimally-invasive nature [1,2]. However, the direct administration of traditional chemotherapeutic drugs suffers from a lack of selectivity for target tissues, unfavorable pharmacokinetics, and poor biodistribution which reduce their utilization [3]. To tackle these problems, in recent years, researchers have made many efforts to develop new systems like hydrogels, micelles, dendrimers, and hyperbranched polymers for anticancer drug delivery [[4], [5], [6], [7], [8]]. In the meantime, nanotechnology has some unique advantages for the development of novel drug delivery systems [9,10]. Metal-organic frameworks (MOFs) are nanoporous materials formed by metal or metal cluster nodes that are linked together in an ordered structure via the multitopic organic ligands. Moreover, it should be noted that owing to their special structure and properties these materials have been evaluated for use in several other areas like fuel purification, water treatment, etc. [[11], [12], [13], [14]]. Tailorable structures, excellent biocompatibility, large surface areas, manageable chemical composition, ease of functionalization, and higher porosities are some advantages of MOFs [[15], [16], [17], [18]]. Therefore, by virtue of these unique features, MOFs have drawn huge research attention in bio-related applications such as drug delivery [19,20]. So, for the first time then 2006, Férey et al. proposed that MOFs have drug delivery capability, because of their special drug loading capacities and controlled release. This research team built up two different MOFs based on Cr metal [21]. Additionally, a survey of the literature shows that MOFs render several advantages over existing drug delivery systems, which are frequently purely inorganic or organic. So, the former are less biocompatible and can offer higher drug loadings but their low degradation rate can result in accumulation in the human body, while the latter present lower drug payloads although are more biocompatible [[22], [23], [24]]. Up to now, several MOFs like MOF-5, UiO-66, MIL-100, MIL-101, and zeolitic imidazolate frameworks (ZIFs) have been explored as drug carriers [[25], [26], [27]]. In particular zirconium based MOFs with post-synthetic modification possibility, high thermal and chemical stabilities toward hydrolysis, and low toxicity are some of the most appropriate for biological applications [15,28,29]. Considering these, in the following research, the zirconium-based MOF having free carboxylic acid functional group was selected for evaluation as a drug carrier [30]. It is noted that the modification of MOFs with secondary molecules can improve their features and make a new structure with high applicability. Dendrimers are regularly three-dimensional branched polymers with a special configuration involving many branches [[31], [32], [33]]. These macromolecules have a large number of end functional groups and therefore can be used for MOFs modifications [[34], [35], [36], [37]]. Citric acid (CA) is a sustainable, natural, and low-cost material which received extensive research interest in functional materials like dendrimer synthesis [38,39]. Furthermore, the biocompatibility and targeted drug delivery of each newly synthesized system can be improved by its conjugation with various targeted molecules like hyaluronic acid (HA) [40,41]. HA is a hydrophilic non-sulfated anionic glycosaminoglycan composed of β-D-glucuronic acid and N-acetyl-β-D-glucosamine segments. The carboxyl, hydroxyl, and acetamido functional groups on HA can be used for its chemical modification [42,43]. Biocompatibility, targeted delivery to overexpressed receptors in cancer cells such as CD44 receptors, and biodegradability are some other promising physiochemical and biological properties of HA [44,45]. In connection with targeted drug delivery, HA-modified systems displayed an enhanced cancer cell-killing effect in the CD44+ cell lines. Up to now, various anticancer drugs have been used for cancer treatment. DNR is an anthracycline antitumor drug which extensively administered for the treatment of some cancers [46]. This chemotherapy drug has significant cytotoxic and antimitotic activity as it is able to form a complex with deoxyribonucleic acid (DNA) by intercalation blocking any transcription or replication process [47].

Taking the aforesaid discussion into account and considering the main aim of the present work in the design and fabrication of a new MOF based controlled drug delivery system, in the present report, for the first time the pre-synthesized UiO-66-COOH was functionalized with HA after CAD growth on it. DNR was selected as a model drug for evaluation of the UiO-66-COOH-CAD-HA capability as an anticancer drug carrier. Otherwise, the main attention of the current work was on synthesizing hybrid material as a new carrier and investigating its drug delivery aspect. Although there are some studies on the potential of the modified MOFs as drug delivery agents and the literature on functionalized MOFs is growing fast, there is no report on DNR delivery by UiO-66-COOH-CAD-HA. Therefore, we have hypothesized that this for the first time prepared combined system from easily available precursors with acceptable drug loading potential, stimuli-responsive drug release properties, biodegradable nature, biocompatibility, and colloidal stability advantages can provide acceptable novelty for controlled anticancer drug delivery.