Chemotherapy stays the first technique for medical most cancers remedy [1], [2]. Doxorubicin (DOX), a basic anthracycline chemotherapy drug, is extensively utilized within the therapy of varied malignant tumors, together with breast most cancers, ovarian most cancers, leukemia, and lung most cancers [3], [4]. DOX exerts its therapeutic results via intercalation into DNA and inhibition of topoisomerase II, leading to cell cycle arrest and tumor cell apoptosis [5], [6], [7]. However, its medical software is restricted by nonspecific distribution and extreme systemic toxicity, together with cardiotoxicity and myelosuppression[8], [9].
Nanodrug supply techniques (NDDS) have proven nice potential in prolonging circulation time and enhancing tumor accumulation [10], [11], [12]. As an example, Doxil, first long-circulating liposomal permitted by the U.S. Meals and Drug Administration (FDA), prolonged the circulation time of DOX and lowered cardiotoxicity [13], [14], [15]. Nevertheless, Doxil nonetheless faces unintended effects akin to hand-foot syndrome as a result of overlong circulation time, which severely restricts the dose elevation of Doxil and its antitumor efficacy [16], [17]. In addition to, the excessive immunogenicity and low biocompatibility of the nanocarrier supplies nonetheless pose potential security dangers [18], [19]. Human serum albumin (HSA) stands out as a perfect drug provider attributable to its non-immunogenicity, glorious biocompatibility and inherent tumor concentrating on potential [20], [21], [22]. Nevertheless, as a result of low affinity between DOX and HSA, conventional preparation know-how didn’t yield uniformly sized nanoparticles, leading to giant dimension (∼ 500 nm) and extensive dimension distribution (PDI > 0.6) [23], [24], [25].
Rational design of prodrug to reinforce the binding affinity of DOX with HSA maintain nice potential. The prodrug technique might enhance the undesirable traits of chemotherapeutic medicine via appropriate structural modifications [26], [27], [28]. Contemplating the traits of HSA as a pure fatty acid provider, the conjugation of drug molecules with fatty acid might enhance the affinity with HSA [29], [30]. Three components must be thought-about when designing the construction of prodrugs. Firstly, the chain size ought to influence the bonding affinity of prodrug to HSA. Secondly, the clever launch of the lively drug from the prodrug is important to realize the best therapeutic impact [31], [32]. The reduction-sensitive prodrug technique leverages the pronounced redox distinction between the tumor cells and regular cells, notably the elevated intracellular glutathione (GSH) concentrations in tumor cells [33]. Clever intracellular drug launch must be achieved by inserting disulfide bond as response modules into the prodrug construction, which has excessive responsivity with GSH [34], [35], [36]. Lastly, the linkage bond between the drug and the response modules additionally acts because the crucial barrier to drug launch, and its stability predominantly governs the drug launch charge [37].
On this research, 4 DOX-fatty alcohol prodrugs had been synthesized with completely different carbon chain lengths (C4, C8, C12, C20) to systematically consider the impact of chain size on the binding affinity between DOX and HSA. Disulfide bond was used as response module and conjugated with DOX via a steady carboxamide bond. Notably, when the carbon chain size reached eight, the DOX prodrug (DOX-CO-C8) exhibited considerably enhanced binding affinity to HSA, facilitating the formation of albumin-based nanoparticles (ANPs). Nevertheless, the cytotoxicity of all prodrugs was extraordinarily weak, suggesting the DOX couldn’t be launched on demand as a result of stability of carboxamide bond. Subsequently, we additional changed the steady carboxamide bond with relative lively carbamate bond (DOX-OCO-C8). In comparison with DOX-CO-C8, DOX-OCO-C8 exhibited stronger binding affinity to HSA, enabling the formation of extra steady ANPs, which considerably enhanced DOX circulation time and lowered its in vivo clearance charge. Furthermore, underneath the discount situations, DOX-OCO-C8 ANPs triggered efficient DOX launch, resulting in superior antitumor efficacy in comparison with DOX. Moreover, DOX-OCO-C8 ANPs considerably improved DOX security, with no important toxicity noticed in regular tissues, even at excessive doses (20 mg/kg equal to DOX). Subsequently, this albumin-based nano-system enhanced antitumor efficacy and successfully lowered systemic toxicity of DOX, demonstrating nice potential as a candidate for medical software (Fig. 1).