Co‐Delivery of Precisely Prescribed Multi‐Prodrug Combination by an Engineered Nanocarrier enables Efficient Individualized Cancer Chemotherapy

Abstract

Meanwhile, the occurrence of undesirable side effects, low bioavailability, and emergence of drug resistance are also depleting the existing drug library. Considering the slow pace of new drug development, combination of two or more currently available drugs with non-overlapping systemic toxicities and different therapeutic mechanisms, [6] for example, the FOLFIRINOX regimen in advanced pancreatic cancer therapy, [7] which consists of 5-fluorouracil, leucovorin, irinotecan, and oxaliplatin, is recognized as the cornerstone of cancer therapy. The ideal combination therapy should be individualized, which means that the class and dosage of drug combinations should be customized for patients, [8] making the ratiometric delivery of multiple drugs a new trend. [9] However, distinct pharmacokinetics and biodistribution of different drugs make it impossible to control the optimal dosages and deliver a predefined drug ratio at the target tissue using the current combination regimens in clinical practice, which involves administration of free drug mixture and offers little flexibility for treatment optimization. [10] In contrast to the administration of free drug mixture, nanocarrier-based combination therapy has many advantages, [11] for example, co-encapsulation of both soluble and poorly soluble drugs, co-delivery of small molecular drugs and macro molecular agents, [12] drug protection, cellular uptake of nanoparticles (NPs) via endocytosis, and passive tumor accumulation. [13] Compared to co-administration of NPs, co-delivery of multiple drugs using a single NP is preferred due to its ability to achieve synergistic therapeutic effect and reduce drug resistance, [10a,14] and unify the pharmacokinetics and biodistribution of different drug molecules, leading to dosage optimization in vivo. The concurrent delivery of multiple free drugs for combination chemotherapy using a single vehicle, such as liposomes, polymeric NPs, and other nanocarriers, has made tremendous progress. Several strategies have been employed to co-encapsulate multiple drugs into a single nanocarrier, including physical loading, surface conjugation, and covalent linkage, prior to NP synthesis. [15] A very recent macrocyclic-amphiphile-based NP platform has shown attractive benefits of ratiometric deliveryThe limited anticancer drug library and the frequent occurrence of drug resistance have driven monotherapy-based cancer therapy into a difficult situation. Considering the formidable process of new drug discovery, combination therapy using currently available drugs is a potential alternative. Nevertheless, the barrier between in vitro combination screening and precise in vivo delivery remains insurmountable in the current free-drug-or nanoparticle (NP)-based combination therapy, which substantially hinders the application of combination therapy. Herein, a novel, precise drug delivery strategy to realize efficient and individualized combination therapy is proposed. Nanomedicine (NM) is engineered using a microfluidics-based mixer by combining ration...

Recent Advances in Chitosan and its Derivatives in Cancer Treatment

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Assessing the Potential of New Lignin-Based pH-Responsive Nanoparticles as Drug Carriers for Cancer Treatment

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