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Anticancer nanomedicines have been proven effective in mitigating the side effects of chemotherapeutic drugs. However, challenges remain in augmenting their therapeutic efficacy. Nanomedicines responsive to the pathological abnormalities in the tumor microenvironment (TME) are expected to overcome the biological limitations of conventional nanomedicines, enhance the therapeutic efficacies, and further reduce the side effects. This Review aims to quantitate the various pathological abnormalities in the TME, which may serve as unique endogenous stimuli for the design of stimuli-responsive nanomedicines, and to provide a broad and objective perspective on the current understanding of stimuli-responsive nanomedicines for cancer treatment. We dissect the typical transport process and barriers of cancer drug delivery, highlight the key design principles of stimuli-responsive nanomedicines designed to tackle the series of barriers in the typical drug delivery process, and discuss the "all-into-one" and "one-for-all" strategies for integrating the needed properties for nanomedicines. Ultimately, we provide insight into the challenges and future perspectives toward the clinical translation of stimuli-responsive nanomedicines.

Tumor enzyme-responsive charge-reversal carriers can induce efficient transcytosis and lead to efficient tumor infiltration and potent anticancer efficacy. However, the correlations of molecular structure with charge-reversal property, tumor penetration, and drug delivery efficiency are unknown. Herein, aminopeptidase N (APN)-responsive conjugates were synthesized to investigate these correlations. We found that the monomeric unit structure and the polymer chain structure determined the enzymatic hydrolysis and charge-reversal rates, and accordingly, the transcytosis and tumor accumulation and penetration of the APN-responsive conjugates. The conjugate with moderate APN responsiveness balanced the in vitro transcytosis and in vivo overall drug delivery process and achieved the best tumor delivery efficiency, giving potent antitumor efficacy. This work provides new insight into the design of tumor enzyme-responsive charge-reversal nanomedicines for efficient cancer drug delivery., (© 2023 Wiley-VCH GmbH.)

Over the past three decades, the enhanced permeability and retention (EPR) effect has been considered the basis of tumor-targeted drug delivery. Various cancer nanomedicines, including macromolecular drugs, have been designed to utilize this mechanism for preferential extravasation and accumulation in solid tumors. However, such nanomedicines have not yet achieved convincing therapeutic benefits in clinics. Increasing evidence suggests that the EPR effect is over-represented in human tumors, especially in metastatic tumors. This review covers the evolution of the concept, the heterogeneity and limitation of the EPR effect in clinical realities, and prospects for alternative strategies independent of the EPR effect., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Extravasation is the first step for nanomedicines in circulation to reach targeted solid tumors. Traditional nanomedicines have been designed to extravasate into tumor interstitium through the interendothelial gaps previously assumed rich in tumor blood vessels, i.e., the enhanced permeability and retention (EPR) effect. While the EPR effect has been validated in animal xenograft tumor models, accumulating evidence implies that the EPR effect is very limited and highly heterogeneous in human tumors, leading to highly unpredictable and inefficient extravasation and thus limited therapeutic efficacy of nanomedicines, including those approved in clinics. Enabling EPR-independent extravasation is the key to develop new generation of nanomedicine with enhanced efficacy. Transcytosis of tumor endothelial cells can confer nanomedicines to actively extravasate into solid tumors without relying on the EPR effect. Here, we review and prospectthe development of transcytosis-inducing nanomedicines, in hope of providing instructive insights for design of nanomedicines that can undergo selective transcellular transport across tumor endothelial cells, and thus inspiring the development of next-generation nanomedicines for clinical translation., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Orally administrable anticancer nanomedicines are highly desirable due to their easy and repeatable administration, but are not yet feasible because the current nanomedicine cannot simultaneously overcome the strong mucus and villi barriers and thus have very low bioavailability (BA). Herein, this work presents the first polymeric micelle capable of fast mucus permeation and villi absorption and delivering paclitaxel (PTX) efficiently to tumors with therapeutic efficacy even better than intravenously administered polyethylene glycol based counterpart or free PTX. Poly[2-(N-oxide-N,N-diethylamino)ethyl methacrylate] (OPDEA), a water-soluble polyzwitterion, is highly nonfouling to proteins and other biomacromolecules such as mucin but can weakly bind to phospholipids. Therefore, the micelle of its block copolymer with poly(ε-caprolactone) (OPDEA-PCL) can efficiently permeate through the viscous mucus and bind to villi, which triggers transcytosis-mediated transepithelial transport into blood circulation for tumor accumulation. The orally administered micelles deliver PTX to tumors, efficiently inhibiting the growth of HepG2 and patient-derived hepatocellular carcinoma xenografts and triple-negative breast tumors. These results demonstrate that OPDEA-based micelles may serve as an efficient oral nanomedicine for delivering other small molecules or even large molecules., (© 2022 Wiley-VCH GmbH.)

The cancer drug delivery process involves a series of biological barriers, which require the nanomedicine to exhibit different, even opposite properties for high therapeutic efficacy. The prevailing design philosophy, i.e., integrating these properties within one nanomedicine via on-demand property transitions such as PEGylation/dePEGylation, complicates nanomedicines' composition and thus impedes clinical translation. Here, polyzwitterionic micelles of poly(tertiary amine-oxide)-block-poly(ε-caprolactone) (PTAO-PCL) amphiphiles that enable all the required functions are presented. The zwitterionic nature and unique cell membrane affinity confer the PTAO micelles long blood circulation, efficient tumor accumulation and penetration, and fast cellular internalization. The mitochondrial targeting capability allows drug delivery into the mitochondria to induce mitochondrial dysfunction and overcome tumor multidrug resistance. As a result, the PTAO/drug micelles exhibit potent anticancer efficacy. This simple yet multipotent carrier system holds great promise as a generic platform for potential clinical translation., (© 2022 The Authors. Advanced Science published by Wiley-VCH GmbH.)

Polymeric nanocapsules hold considerable applications in cancer drug delivery, but the synthesis of well-defined nanocapsules with a tunable drug release property remains a significant challenge in fabrication. Herein, we demonstrate a supramolecular complexation strategy to assemble small molecular platinum (Pt) compounds into well-defined nanocapsules with high drug loading, acidity-sensitivity, and tunable Pt releasing profile. The design utilizes poly(ethylene glycol)-dendritic polylysine-G4/amides to complex with Pt compounds, forming stable nanocapsules with diameters approximately ∼20 nm and membrane thickness around several nanometers. The stability, drug content, and release profiles are tunable by tailoring the dendritic structure. The designated polymer-Pt nanocapsules, PEG-G4/MSA-Pt, showed sustained blood retention, preferential tumor accumulation, enhanced cellular uptake, lysosomal drug release, and nuclear delivery capability. PEG-G4/MSA-Pt showed enhanced antitumor efficacy compared to free cisplatin and other nanocapsules, which stopped the progression of both A549 cell xenografts and patient-derived xenografts (PDXs) of hepatocellular carcinoma on a mice tumor model. Thus, we believe this strategy is promising for developing Pt-based nanomedicine for cancer drug delivery.

Cisplatin (CDDP) is a potent first-line antitumor drug but suffers severe side effects and poor pharmacokinetics. Its complexation with polycarboxylic acids, such as polyglutamic acids, is generally used to fabricate nanoformulations for CDDP delivery; however, the multiple strong complexations makes intracellular drug release slow. Herein, we report a novel polyphenol-metal coordination method to fabricate CDDP-incorporated core-shell nanoparticles, which are stable in blood circulation but dissociate in the tumor. Methoxyl-PEG terminated with one or two gallic acids (PEG-GA or PEG-GA2) complexed CDDP and produced well-defined nanoparticles (PEG-GAx/Pt) with CDDP loading contents as high as 17.7% to 29.8%. The PEG-GAx/Pt nanoparticles were very stable in the physiological conditions and had slow blood clearance and efficient tumor accumulation, but dissociated quickly and released CDDP in response to the tumor acidity or elevated levels of reactive oxygen species (ROS). PEG-GAx/Pt nanoparticles exhibited improved antitumor efficiency against 4 T1 breast cancer and A549 lung carcinoma with much-reduced toxicity compared to free CDDP. The work demonstrates a new strategy of cisplatin-polyphenol coordination for developing platinum drugs' nanomedicines., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Nanotechnology-based drug delivery platforms have been explored for cancer treatments and resulted in several nanomedicines in clinical uses and many in clinical trials. However, current nanomedicines have not met the expected clinical therapeutic efficacy. Thus, improving therapeutic efficacy is the foremost pressing task of nanomedicine research. An effective nanomedicine must overcome biological barriers to go through at least five steps to deliver an effective drug into the cytosol of all the cancer cells in a tumor. Of these barriers, nanomedicine extravasation into and infiltration throughout the tumor are the two main unsolved blockages. Up to now, almost all the nanomedicines are designed to rely on the high permeability of tumor blood vessels to extravasate into tumor interstitium, i.e., the enhanced permeability and retention (EPR) effect or so-called "passive tumor accumulation"; however, the EPR features are not so characteristic in human tumors as in the animal tumor models. Following extravasation, the large size nanomedicines are almost motionless in the densely packed tumor microenvironment, making them restricted in the periphery of tumor blood vessels rather than infiltrating in the tumors and thus inaccessible to the distal but highly malignant cells. Recently, we demonstrated using nanocarriers to induce transcytosis of endothelial and cancer cells to enable nanomedicines to actively extravasate into and infiltrate in solid tumors, which led to radically increased anticancer activity. In this perspective, we make a brief discussion about how active transcytosis can be employed to overcome the difficulties, as mentioned above, and solve the inherent extravasation and infiltration dilemmas of nanomedicines., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Tumor enzyme‐responsive charge‐reversal carriers can induce efficient transcytosis and lead to efficient tumor infiltration and potent anticancer efficacy. However, the correlations of molecular structure with charge‐reversal property, tumor penetration, and drug delivery efficiency are unknown. Herein, aminopeptidase N (APN)‐responsive conjugates were synthesized to investigate these correlations. We found that the monomeric unit structure and the polymer chain structure determined the enzymatic hydrolysis and charge‐reversal rates, and accordingly, the transcytosis and tumor accumulation and penetration of the APN‐responsive conjugates. The conjugate with moderate APN responsiveness balanced the in vitro transcytosis and in vivo overall drug delivery process and achieved the best tumor delivery efficiency, giving potent antitumor efficacy. This work provides new insight into the design of tumor enzyme‐responsive charge‐reversal nanomedicines for efficient cancer drug delivery. [ABSTRACT FROM AUTHOR]

Cancer drug delivery systems often suffer from premature drug leakage during transportation and/or inefficient drug release within cancer cells. We present here a polymeric prodrug nanoassembly that addresses these problems simultaneously. This nanoassembly comprises a polymeric prodrug with novel trivalent phenylboronate moieties for drug conjugation via ether linkages, as well as β -lapachone (Lapa). While the ether linkage enables nearly no drug release under physiological conditions, the Lapa molecules can induce the reactive oxygen species (ROS) burst specifically in cancer cells via NAD(P)H: quinone oxidoreductase-1 catalysis, which triggers the cleavage of the ether bonds and thus cascade amplification drug release in cancer cells. As a result, the nanoassemblies exhibit much higher cytotoxicity against cancer cells than normal cells, and also increased therapeutic efficacy and reduced side effects compared to the clinically used irinotecan. We anticipate that this strategy can be applied to other drug delivery platforms to enable more precise drug release. A novel polyprodrug of 7-ethyl-10-hydroxycamptothecin, bearing an ether-bridged trivalent phenylboronate moiety, co-assemble with β-lapachone to form stable micelles, achieving cancer cell-specific NQO1-triggered cascade amplification drug release. [Display omitted] [ABSTRACT FROM AUTHOR]

Celastrol, a natural triterpene extracted from traditional Chinese medicine, shows anticancer effects on various cancer cells. However, its poor water-solubility, short plasma half-life, and high systemic toxicity impede its applications in vivo , necessitating a stable drug delivery system to overcome these critical drawbacks. We present here a block copolymer, poly(2-(N -oxide- N , N -dimethylamino)ethyl methacrylate)- block -poly(2-hydroxyethyl methacrylate) (OPDMA-HEMA), as the carrier for celastrol delivery. The amphiphilic polymer-celastrol conjugate can self-assemble into nanoparticles in aqueous solutions. The OPDMA outer shell confers the nanoparticles with improved pharmacokinetics and efficient mitochondria targeting capacity, and profoundly potentiates celastrol's induction of immunogenic cell death, which collectively contribute to the enhanced therapeutic effects of celastrol in vivo. This mitochondria-targeted polymer-celastrol conjugate may promise the applications of celastrol in cancer treatment. [Display omitted] • A polyzwitterionic-celastrol conjugate was synthesized to enable the mitochondrial-targeted delivery of celastrol. • This conjugate could disrupt mitochondrial functions and induce potent immunogenic cell death. • This conjugate exhibited high anticancer efficacy and low systemic toxicity. [ABSTRACT FROM AUTHOR]