Covalent modification of therapeutic compounds is a clinically proven strategy to devise prodrugs with enhanced treatment efficacies. This prodrug strategy relies on modified drugs that possess advantageous pharmacokinetic properties and administration routes over their parent drug. Self-assembling prodrugs represent an emerging class of therapeutic agents capable of spontaneously associating into well-defined supramolecular nanostructures in aqueous solutions. The self-assembly of prodrugs expands the functional space of conventional prodrug design, providing a possible pathway to more effective therapies as the assembled nanostructure possesses distinct physicochemical properties that can be tailored to specific administration routes and disease treatment. In this review, we will discuss the various types of self-assembling prodrugs in development, providing an overview of the methods used to control their structure and function and, ultimately, our perspective on their current and future potential.

Immune checkpoint blockers (ICBs) have shown great promise at harnessing immune system to combat cancer. However, only a fraction of patients can directly benefit from the anti–programmed cell death protein 1 (aPD1) therapy, and the treatment often leads to immune-related adverse effects. In this context, we developed a prodrug hydrogelator for local delivery of ICBs to boost the host’s immune system against tumor. We found that this carrier-free therapeutic system can serve as a reservoir for extended tumoral release of camptothecin and aPD1 antibody, resulting in an immune-stimulating tumor microenvironment for boosted PD-1 blockade immune response. Our in vivo results revealed that this combination chemoimmunotherapy elicits robust and durable systemic anticancer immunity, inducing tumor regression and inhibiting tumor recurrence and metastasis. This work sheds important light into the use of small-molecule prodrugs as both chemotherapeutic and carrier to awaken and enhance antitumor immune system for improved ICBs therapy.

One key design feature in the development of any local drug delivery system is the controlled release of therapeutic agents over a certain period of time. In this context, we report the characteristic feature of a supramolecular filament hydrogel system that enables a linear and sustainable drug release over the period of several months. Through covalent linkage with a short peptide sequence, we are able to convert an anticancer drug, paclitaxel (PTX), to a class of prodrug hydrogelators with varying critical gelation concentrations. These self-assembling PTX prodrugs associate into filamentous nanostructures in aqueous conditions and consequently percolate into a supramolecular filament network in the presence of appropriate counterions. The intriguing linear drug release profile is rooted in the supramolecular nature of the self-assembling filaments which maintain a constant monomer concentration at the gelation conditions. We found that molecular engineering of the prodrug design, such as varying the number of oppositely charged amino acids or through the incorporation of hydrophobic segments, allows for the fine-tuning of the PTX linear release rate. In cell studies, these PTX prodrugs can exert effective cytotoxicity against glioblastoma cell lines and also primary brain cancer cells derived from patients and show enhanced tumor penetration in a cancer spheroid model. We believe this drugbearing hydrogel platform offers an exciting opportunity for the local treatment of human diseases.

Malignant brain tumor, including the most common type glioblastoma, are histologically heterogeneous and invasive tumors known as the most devastating neoplasms with high morbidity and mortality. Despite multimodal treatment including surgery, radiotherapy, chemotherapy, and immunotherapy, the disease inevitably recurs and is fatal. This lack of curative options has motivated researchers to explore new treatment strategies and to develop new drug delivery systems (DDSs); however, the unique anatomical, physiological, and pathological features of brain tumors greatly limit the effectiveness of conventional chemotherapy. In this context, we review the recent progress in the development of nanoparticle-based DDSs aiming to address the key challenges in transporting sufficient amount of therapeutic agents into the brain tumor areas while minimizing the potential side effects. We first provide an overview of the standard treatments currently used in the clinic for the management of brain cancers, discussing the effectiveness and limitations of each therapy. We then provide an indepth review of nanotherapeutic systems that are intended to bypass the bloodbrain barrier, overcome multidrug resistance, infiltrate larger tumorous tissue areas, and/or release therapeutic agents in a controlled manner. © 2017 Wiley Periodicals, Inc. How to cite this article:WIREs Nanomed Nanobiotechnol 2018, 10:e1479. doi: 10.1002/wnan.1479 INTRODUCTIONC ancer originating in the brain and other parts of the central nervous system (CNS) is a devastating disease with extremely low survival rates, with 23,770 new cases and 16,050 deaths estimated in 2016. 1 Other than primary brain tumors, brain metastasis of other types of cancers during their later stages occurs in around 15% of all cancer patients. 2 In particular cases such as lung adenocarcinoma, 54% of patients will develop brain metastases that are refractory to the systemic treatments for lung cancer. 3,4 Thus, the treatment of brain tumors has become a significant challenge in cancer therapy and management.The presence of the blood-brain barrier (BBB), the blood-tumor barrier (BTB), and the invasiveness of brain tumors are the leading causes responsible for the low 5-year survival rate (35% 1 ) of brain tumor patients (Figure 1). The BBB is a physiological barrier composed of tightly bounded cerebral capillary endothelium, pericytes, astrocytes, and basal membranes, with scarce endocytosis and transcytosis but active efflux due to the highly expressed P-glycoproteins on cerebral endothelial cells. 5 The BBB prevents the penetration of almost all macromolecules and >95% of small molecules (including anticancer drugs) into the brain, 5 and is thus, to a large extent, responsible for the failure of most chemotherapies. Recent studies have shown some evidence that BBB breakdown can occur to some extent as a result of glioma-induced remodeling, or can be induced by some secreted chemicals that could potentially degrade tight junctions and disrupt the BBB. [6][7][8][9] However, these disrup...

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