Polymer Nanoantidotes.

Intoxication is one of the most common causes of accidental death globally. Although some antidotes capable of neutralizing the toxicity of certain xenobiotics have become well established, the current reality is that clinicians primarily rely on nonspecific extracorporeal techniques to remove toxins. Nano-intervention strategies in which nanoantidotes neutralize toxicity in situ via physical interaction, chemical bonding, or biomimetic clearance have begun to show clinical potential. However, most nanoantidotes remain in the proof-of-concept stage, and the difficulty of constructing clinical relevance models and the unclear pharmacokinetics of nanoantidotes hinder their translation to clinic. This Concept reviews the detoxification mechanisms of polymer nanoantidotes and predicts the opportunities and challenges associated with their clinical application.

Ultrasound-Augmented Mitochondrial Calcium Ion Overload by Calcium Nanomodulator to Induce Immunogenic Cell Death.

Immunogenic cell death (ICD), a manner of tumor cell death that can trigger antitumor immune responses, has received extensive attention as a potential synergistic modality for cancer immunotherapy. Although many calcium ion (Ca2+) nanomodulators have been developed for cancer therapy through mitochondrial Ca2+ overload, their ICD-inducing properties have not been explored. Herein, an acid-sensitive PEG-decorated calcium carbonate (CaCO3) nanoparticle incorporating curcumin (CUR; a Ca2+ enhancer) (PEGCaCUR) was prepared using a simple one-pot strategy. PEGCaCUR served as not only a Ca2+ nanomodulator inducing efficient mitochondrial Ca2+ overload but also an ICD inducer during improved synergistic cancer therapy. Combination of PEGCaCUR with ultrasound (US), PEGCaCUR+US, led to an enhanced ICD effect attributable to the enhanced mitochondrial Ca2+ overload, along with subsequent upregulation of reactive oxygen species levels. PEGCaCUR also facilitates photoacoustic/fluorescence dual-mode imaging, as well as effectively suppressing tumor growth and metastasis, indicating promising theranostic properties.

Spatiotemporally Targeted Polypeptide Nanoantidotes Improve Chemotherapy Tolerance of Cisplatin.

The toxicity of drugs causes various adverse effects in patients. While antidotes that neutralize drug toxicity help reduce systemic damage during clinical therapy, these antidotes are generally accompanied by the loss of drug efficacy. Herein, the spatiotemporally targeted polycystine-based nanoantidotes were designed as a neutralizer of cisplatin (CDDP) to decrease its toxicity without affecting its anticancer efficacy. The nanoantidotes administered before CDDP selectively accumulated in the liver and kidney and then firmly bound to CDDP through the highly stable Pt-S bond during subsequent chemotherapy. This two-step administration strategy reduced the level of Pt in normal organs, shortened the half-life of CDDP in plasma, and increased the tolerance to CDDP. More importantly, the nanoantidotes maintained the anticancer efficacy of CDDP after reducing systemic toxicity, indicating its great potential in expanding the clinical application of CDDP.

Spatiotemporally Targeted Nanomedicine Overcomes Hypoxia-Induced Drug Resistance of Tumor Cells after Disrupting Neovasculature.

Vascular disrupting agents (VDAs) are emerging anticancer agents, which show rising demand for combination with cytostatic drugs (CSDs), owing to inadequate tumor inhibition when applied singly. Nevertheless, the combination remains a challenge due to the different working sites of VDAs and CSDs and hypoxia-induced drug resistance after disrupting neovasculature by VDAs. Herein, we developed a shell-stacked nanoparticle (SNP) for coencapsulation of a VDA combretastatin A-4 phosphate (CA4P) and a proteasome inhibitor bortezomib (BTZ). The SNP could spatiotemporally deliver CA4P to tumor neovasculature and BTZ to tumor cells mediated by the site-specific stimuli-activated drug release. Moreover, the SNP also reversed the drug resistance caused by the overexpressed ABCG2 under CA4P-induced hypoxic conditions. The spatiotemporally targeted combination therapy significantly inhibited the growth of both the human A549 pulmonary adenocarcinoma xenograft model and patient-derived xenograft (PDX) model of colon cancer in mice, providing a promising strategy for treating advanced cancers.

Dual Hypoxia-Targeting RNAi Nanomedicine for Precision Cancer Therapy.

As a hallmark of solid tumors, hypoxia promotes tumor growth, metastasis, and therapeutic resistance by regulating the expression of hypoxia-related genes. Hypoxia also represents a tumor-specific stimulus that has been exploited for the development of bioreductive prodrugs and advanced drug delivery systems. Cell division cycle 20 (CDC20) functions as an oncogene in tumorigenesis, and we demonstrated the significant upregulation of CDC20 mRNA in the tumor vs paratumor tissues of breast cancer patients and its positive correlation with tumor hypoxia. Herein, a hypoxia-responsive nanoparticle (HRNP) was developed by self-assembly of the 2-nitroimidazole-modified polypeptide and cationic lipid-like compound for delivery of siRNA to specifically target CDC20, a hypoxia-related protumorigenic gene, in breast cancer therapy. The delivery of siCDC20 by HRNPs sufficiently silenced the expression of CDC20 and exhibited potent antitumor efficacy. We expect that this strategy of targeting hypoxia-correlated protumorigenic genes by hypoxia-responsive RNAi nanoparticles may provide a promising approach in cancer therapy.

Reduction-responsive polypeptide nanomedicines significantly inhibit progression of orthotopic osteosarcoma.

Osteosarcoma (OS) is the most common malignant bone tumor with high metastasis and mortality. Neoadjuvant chemotherapy is an effective therapeutic regimen, but the clinical application is limited by the unsatisfactory efficacies and considerable side effects. In this study, the reduction-responsive polypeptide micelles based on methoxy poly(ethylene glycol)-block-poly(S-tert-butylmercapto-L-cysteine) copolymers (mPEG113-b-PBMLC4, P4M, and mPEG113-b-PBMLC9, P9M) were developed to control the delivery of doxorubicin (DOX) in OS therapy. Compared to free DOX, P4M/DOX and P9M/DOX exhibited 2.6 and 3.5 times increase in the area under the curve of pharmacokinetics, 1.6 and 2.0 times increase in tumor accumulation, and 1.6 and 1.7 times decrease of the distribution in the heart. Moreover, the selective accumulation of micelles, especially P9M/DOX, in tumors induced stronger antitumor effects on both primary and lung metastatic OSs with less systematic toxicity. These micelles with smart responsiveness to intracellular microenvironments are highly promising for the targeted delivery of clinical chemotherapeutic drugs in cancer therapy.

Thermosensitive Hydrogels as Scaffolds for Cartilage Tissue Engineering.

Articular cartilage defects, caused by trauma, osteoarthritis, or other diseases, always lead to severe joint pain and joint dysfunction. Without access to progenitor cells and the supply of blood and nutrients, the impaired articular cartilage would be short of the capability to self-repair. Although the present clinical treatments, including autogenous and allograft osteochondral transplantation, microfracture technique, and so forth, have shown some efficacies, their drawbacks, such as donor insufficiency and poor-integration with adjacent tissue, limit the satisfactory repair of articular cartilage defects and cause unsatisfied prognosis. Cartilage tissue engineering, involving the combination of progenitor cells with scaffolds, which serve as artificial extracellular matrices (ECMs), provides a promising strategy for cartilage regeneration. Recently, thermosensitive hydrogels have attracted much attention as scaffolds for cartilage tissue engineering owing to their unique physical properties analogous to the native ECM. In this review, we summarize the fabrication, characterization of newly reported thermosensitive hydrogels as cartilage tissue engineering scaffolds. The potential challenges and future perspectives are proposed.

Polymer-Mediated Penetration-Independent Cancer Therapy.

The development of polymer-based drug delivery systems provides efficient modalities for cancer therapy. Most of the polymer pharmaceuticals target cancer cells directly, but the insufficient penetration always results in unsatisfactory anticancer efficacy. To break the above bottleneck, strategies of penetration-independent cancer therapy have been developed as advanced treatments for various cancers in the past decade. In this Perspective, we discussed the pros and cons of polymer-mediated biological and physical penetration-independent approaches for cancer therapy and highlighted their further prospects from bench to bedsides.

Special Issue: "Smart and Functional Polymers".

Polymerization provides an efficient strategy for synthesizing macromolecules with versatile functionality [...].

PEGylated Polyurea Bearing Hindered Urea Bond for Drug Delivery.

In recent years, polyureas with dynamic hindered urea bonds (HUBs), a class of promising biomedical polymers, have attracted wide attention as a result of their controlled hydrolytic properties. The effect of the chemical structures on the properties of polyureas and their assemblies has rarely been reported. In this study, four kinds of polyureas with different chemical groups have been synthesized, and the polyureas from cyclohexyl diisocyanate and tert-butyl diamine showed the fastest hydrolytic rate. The amphiphilic polyurea composed of hydrophobic cyclohexyl-tert-butyl polyurea and hydrophilic poly(ethylene glycol) (PEG) was synthesized for the controlled delivery of the antitumor drug paclitaxel (PTX). The PTX-loaded PEGylated polyurea micelle more effectively entered into the murine breast cancer 4T1 cells and inhibited the corresponding tumor growth in vitro and in vivo. Therefore, the PEGylated polyurea with adjustable degradation might be a promising polymer matrix for drug delivery.