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Systemic drug delivery is the current clinically preferred route for cancer therapy. However, challenges associated with tumor localization and off-tumor toxic effects limit the clinical effectiveness of this route. Locoregional drug delivery is an emerging viable alternative to systemic therapies. With the improvement in real-time imaging technologies and tools for direct access to tumor lesions, the clinical applicability of locoregional drug delivery is becoming more prominent. Theoretically, locoregional treatments can bypass challenges faced by systemic drug delivery. Preclinically, locoregional delivery of drugs has demonstrated enhanced therapeutic efficacy with limited off-target effects while still yielding an abscopal effect. Clinically, an array of locoregional strategies is under investigation for the delivery of drugs ranging in target and size. Locoregional tumor treatment strategies can be classified into two main categories: 1) direct drug infusion via injection or implanted port and 2) extended drug elution via injected or implanted depot. The number of studies investigating locoregional drug delivery strategies for cancer treatment is rising exponentially, in both preclinical and clinical settings, with some approaches approved for clinical use. Here, we highlight key preclinical advances and the clinical relevance of such locoregional delivery strategies in the treatment of cancer. Furthermore, we critically analyze 949 clinical trials involving locoregional drug delivery and discuss emerging trends., Competing Interests: Declaration of competing interest SM is an inventor on patent applications related to the topics discussed in the review (owned and managed by Harvard University). SM is a board member and shareholder of Intumo Therapeutics., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Various anti-tumor nanomedicines have been developed based on the enhanced permeability and retention effect. However, the dense extracellular matrix (ECM) in tumors remains a major barrier for the delivery and accumulation of nanoparticles into tumors. While ECM-degrading enzymes, such as collagenase, hyaluronidase, and bromelain, have been used to facilitate the accumulation of nanoparticles, serious side effects arising from the current non-tumor-specific delivery methods limit their clinical applications. Here, we report targeted delivery of bromelain into tumor tissues through its covalent attachment to a hyaluronic acid (HA)-peptide conjugate with tumor ECM targeting ability. The ECM targeting peptide, collagen type IV-binding peptide (C4BP), was chosen from six candidate-peptides based on their ability to bind to frozen sections of triple-negative breast cancer, 4T1 tumor ex vivo. The HA- C4BP conjugate showed a significant increase in tumor accumulation in 4T1-bearing mice after intravenous administration compared to unmodified HA. We further demonstrated that the systemic administration of bromelain conjugated C4BP-HA (C4BP-HA-Bro) potentiates the anti-tumor efficacy of liposomal doxorubicin. C4BP-HA-Bro decreased the number and length of collagen fibers and improved the distribution of doxorubicin within the tumor. No infusion reaction was noted after delivery of C4BP-HA-Bro. C4BP-HA thus offers a potential for effective and safe delivery of bromelain for improved intratumoral delivery of therapeutics., (Copyright © 2022. Published by Elsevier B.V.)

Many efforts have been made to achieve targeted delivery of anticancer drugs to enhance their efficacy and to reduce their adverse effects. These efforts include the development of nanomedicines as they can selectively penetrate through tumor blood vessels through the enhanced permeability and retention (EPR) effect. The EPR effect was first proposed by Maeda and co-workers in 1986, and since then various types of nanoparticles have been developed to take advantage of the phenomenon with regards to drug delivery. However, the EPR effect has been found to be highly variable and thus unreliable due to the complex tumor microenvironment. Various physical and pharmacological strategies have been explored to overcome this challenge. Here, we review key advances and emerging concepts of such EPR-enhancing strategies. Furthermore, we analyze 723 clinical trials of nanoparticles with EPR enhancers and discuss their clinical translation., (Copyright © 2022 Elsevier B.V. All rights reserved.)