Emerging non-antibody‒drug conjugates (non-ADCs) therapeutics of toxins for cancer treatment.

The non-selective cytotoxicity of toxins limits the clinical relevance of the toxins. In recent years, toxins have been widely used as warheads for antibody‒drug conjugates (ADCs) due to their efficient killing activity against various cancer cells. Although ADCs confer certain targeting properties to the toxins, low drug loading capacity, possible immunogenicity, and other drawbacks also limit the potential application of ADCs. Recently, non-ADC delivery strategies for toxins have been extensively investigated. To further understand the application of toxins in anti-tumor, this paper provided an overview of prodrugs, nanodrug delivery systems, and biomimetic drug delivery systems. In addition, toxins and their combination strategies with other therapies were discussed. Finally, the prospect and challenge of toxins in cancer treatment were also summarized.

Natural Amino Acid-Bearing Carbamate Prodrugs of Daidzein Increase Water Solubility and Improve Phase II Metabolic Stability for Enhanced Oral Bioavailability.

Daidzein (DAN) is an isoflavone, and it is often found in its natural form in soybean and food supplements. DAN has poor bioavailability owing to its extremely low water solubility and first-pass metabolism. Herein, we hypothesized that a bioactivatable natural amino acid-bearing carbamate prodrug strategy could increase the water solubility and metabolic stability of DAN. To test our hypothesis, nine amino acid prodrugs of DAN were designed and synthesized. Compared with DAN, the optimal prodrug (daidzein-4'-O-CO-N-isoleucine, D-4'-I) demonstrated enhanced water solubility and improved phase II metabolic stability and activation to DAN in plasma. In addition, unlike the passive transport of DAN, D-4'-I maintained high permeability via organic anion-transporting polypeptide 2B1 (OATP2B1)-mediated transport. Importantly, D-4'-I increased the oral bioavailability by 15.5-fold, reduced the gender difference, and extended the linear absorption capacity in the pharmacokinetics of DAN in rats. Furthermore, D-4'-I exhibited dose-dependent protection against liver injury. Thus, the natural amino acid-bearing carbamate prodrug strategy shows potential in increasing water solubility and improving phase II metabolic stability to enhance the oral bioavailability of DAN.

Inhibition of alanine-serine-cysteine transporter 2-mediated auto-enhanced photodynamic cancer therapy of co-nanoassembly between V-9302 and photosensitizer.

The efficiency of reactive oxygen species (ROS)-based photodynamic therapy (PDT) is far from satisfactory, because cancer cells can adapt to PDT by upregulating glutathione (GSH) levels. The GSH levels in tumor cells are determined based on glutamine availability via alanine-serine-cysteine transporter 2 (ASCT2)-mediated entry into cells. Herein, we develop co-assembled nanoparticles (PPa/V-9302 NPs) of the photosensitizer pyropheophorbide a (PPa) and V-9302 (a known inhibitor of ASCT2) in a 1:1 M ratio using a one-step precipitation method to auto-enhance photodynamic therapy. The computational simulations revealed that PPa and V-9302 could self-assemble through different driving forces, such as π-π stacking, hydrophobic interactions, and ionic bonds. Such PPa/V-9302 NPs could disrupt the intracellular redox homeostasis due to enhanced ROS production via PPa-induced PDT and reduced GSH synthesis via inhibition of the ASCT2-mediated glutamine flux by V-9302. The in vivo assays reveal that PPa/V-9302 NPs could increase the drug accumulation in tumor sites and suppress tumor growth in BALB/c mice bearing mouse breast carcinoma (4 T1) tumor. Our findings provide a new paradigm for the rational design of the PDT-based combinational cancer therapy.

Lymph node-targeting nanovaccines for cancer immunotherapy.

Cancer immunotherapies such as tumor vaccines, chimeric antigen receptor T cells and immune checkpoint blockades, have attracted tremendous attention. Among them, tumor vaccines prime immune response by delivering antigens and adjuvants to the antigen presenting cells (APCs), thus enhancing antitumor immunotherapy. Despite tumor vaccines have made considerable achievements in tumor immunotherapy, it remains challenging to efficiently deliver tumor vaccines to activate the dendritic cells (DCs) in lymph nodes (LNs). Rational design of nanovaccines on the basis of biomedical nanotechnology has emerged as one of the most promising strategies for boosting the outcomes of cancer immunotherapy. In recent years, great efforts have been made in exploiting various nanocarrier-based LNs-targeting tumor nanovaccines. In view of the rapid advances in this field, we here aim to summarize the latest progression in LNs-targeting nanovaccines for cancer immunotherapy, with special attention to various nano-vehicles developed for LNs-targeting delivery of tumor vaccines, including lipid-based nanoparticles, polymeric nanocarriers, inorganic nanocarriers and biomimetic nanosystems. Moreover, the recent trends in nanovaccines-based combination cancer immunotherapy are provided. Finally, the rationality, advantages and challenges of LNs-targeting nanovaccines for clinical translation and application are spotlighted.

Structurally defined tandem-responsive nanoassemblies composed of dipeptide-based photosensitive derivatives and hypoxia-activated camptothecin prodrugs against primary and metastatic breast tumors.

Substantial progress in the use of chemo-photodynamic nano-drug delivery systems (nano-DDS) for the treatment of the malignant breast cancer has been achieved. The inability to customize precise nanostructures, however, has limited the therapeutic efficacy of the prepared nano-DDS to date. Here, we report a structurally defined tandem-responsive chemo-photosensitive co-nanoassembly to eliminate primary breast tumor and prevent lung metastasis. This both-in-one co-nanoassembly is prepared by assembling a biocompatible photosensitive derivative (pheophorbide-diphenylalanine peptide, PPA-DA) with a hypoxia-activated camptothecin (CPT) prodrug [(4-nitrophenyl) formate camptothecin, N-CPT]. According to computational simulations, the co-assembly nanostructure is not the classical core-shell type, but consists of many small microphase regions. Upon exposure to a 660 nm laser, PPA-DA induce high levels of ROS production to effectively achieve the apoptosis of normoxic cancer cells. Subsequently, the hypoxia-activated N-CPT and CPT spatially penetrate deep into the hypoxic region of the tumor and suppress hypoxia-induced tumor metastasis. Benefiting from the rational design of the chemo-photodynamic both-in-one nano-DDS, these nanomedicines exhibit a promising potential in the inhibition of difficult-to-treat breast tumor metastasis in patients with breast cancer.

Paclitaxel derivative-based liposomal nanoplatform for potentiated chemo-immunotherapy.

The combination of chemotherapy with the immune checkpoint blockade (ICB) therapy is bringing a tremendous hope in the treatment of malignant tumors. However, the treatment efficacy of the existing chemo-immunotherapy is not satisfactory due to the high cost and immunogenicity of ICB antibodies, low response rate to ICB, off-target toxicity of therapeutic agents, and low drug co-delivery efficacy. Therefore, a high-efficient nanosystem combining the delivery of chemotherapeutics with small molecule ICB inhibitors may be promising for an efficient cancer therapy. Herein, a novel reactive oxygen species (ROS)-activated liposome nanoplatform was constructed by the loading of a ROS-sensitive paclitaxel derivative (PSN) into liposomes to overcome the difficulties on delivering paclitaxel mostly represented by premature drug release and a low amount accumulated into the tumor. The innovative liposomal nanosystem was rationally designed by a remote loading of BMS-202 (a small molecule PD-1/PD-L1 inhibitor) and PSN into the liposomes for a ROS-sensitive paclitaxel release and sustained BMS-202 release. The co-loaded liposomes resulted in a high co-loading ability and improved pharmacokinetic properties. An orthotopic 4 T1 breast cancer model was used to evaluate the efficiency of our nanoplatform in vivo, resulting in a superior antitumor activity. The antitumor immunity was activated by paclitaxel-mediated immunogenic cell death, while BMS-202 continuously blocked PD-L1 which could be up-regulated by paclitaxel in tumors to increase the response to ICB and further recover the host immune surveillance. These results revealed that this dual-delivery liposome might provide a promising strategy for a high-efficient chemo-immunotherapy, exhibiting a great potential for clinical translation.

A computer-aided chem-photodynamic drugs self-delivery system for synergistically enhanced cancer therapy.

The therapeutic strategy that gives consideration to the combination of photodynamic therapy and chemotherapy, has emerged as a potential development of effective anti-cancer medicine. Nevertheless, co-delivery of photosensitizers (PSs) and chemotherapeutic drugs in traditional carriers still remains great limitations due to low drug loadings and poor biocompatibility. Herein, we have utilized a computer-aided strategy to achieve a desired carrier-free self-delivery of pyropheophorbide a (PPa, a common PS) and podophyllotoxin (PPT, a classical chemotherapeutic drug) for synergistic cancer therapy. First, the computational simulation method identified the similar molecular sizes and rigid molecular structures between two drugs molecules. Based on the molecular docking, the intermolecular interactions were found to include π-π stackings, hydrophobic interactions and hydrogen bonds. Next, both drugs could co-assemble into nanoparticles (NPs) via one-step nanoprecipitation method. The various spectral experiments (UV, IR and FL) were conducted to evaluate the formation mechanism of spherical NPs. Moreover, in vitro and in vivo experiments systematically demonstrated that PPT/PPa NPs not only showed better cellular uptake efficiency, stronger cytotoxicity and higher accumulation in tumor sites, but also exhibited synergistic antitumor effect in female BALB/C bearing-4T1 tumor mice. Such a computer-aided design strategy of chem-photodynamic drugs self-delivery systems pave the way for efficient synergistic cancer therapy.

Recent progress of hypoxia-modulated multifunctional nanomedicines to enhance photodynamic therapy: opportunities, challenges, and future development.

Hypoxia, a salient feature of most solid tumors, confers invasiveness and resistance to the tumor cells. Oxygen-consumption photodynamic therapy (PDT) suffers from the undesirable impediment of local hypoxia in tumors. Moreover, PDT could further worsen hypoxia. Therefore, developing effective strategies for manipulating hypoxia and improving the effectiveness of PDT has been a focus on antitumor treatment. In this review, the mechanism and relationship of tumor hypoxia and PDT are discussed. Moreover, we highlight recent trends in the field of nanomedicines to modulate hypoxia for enhancing PDT, such as oxygen supply systems, down-regulation of oxygen consumption and hypoxia utilization. Finally, the opportunities and challenges are put forward to facilitate the development and clinical transformation of PDT.

Intestinal OCTN2- and MCT1-targeted drug delivery to improve oral bioavailability.

Various drug transporters are widely expressed throughout the intestine and play important roles in absorbing nutrients and drugs, thus providing high quality targets for the design of prodrugs or nanoparticles to facilitate oral drug delivery. In particular, intestinal carnitine/organic cation transporter 2 (OCTN2) and mono-carboxylate transporter protein 1 (MCT1) possess high transport capacities and complementary distributions. Therefore, we outline recent developments in transporter-targeted oral drug delivery with regard to the OCTN2 and MCT1 proteins in this review. First, basic information of the two transporters is reviewed, including their topological structures, characteristics and functions, expression and key features of their substrates. Furthermore, progress in transporter-targeting prodrugs and nanoparticles to increase oral drug delivery is discussed, including improvements in the oral absorption of anti-inflammatory drugs, antiepileptic drugs and anticancer drugs. Finally, the potential of a dual transporter-targeting strategy is discussed.

Monocarboxylate Transporter 1 in Brain Diseases and Cancers.

BACKGROUND: Monocarboxylate Transporter 1 (MCT1), an important membrane transport protein, mediates the translocation of monocarboxylates together with protons across biological membranes. Due to its pathological significance, MCT1 plays an important role in the progression of some diseases, such as brain diseases and cancers. METHODS: We summarize the general description of MCT1 and provide a comprehensive understanding of the role of MCT1 in brain diseases and cancers. Furthermore, this review discusses the opportunities and challenges of MCT1- targeting drug-delivery systems in the treatment of brain diseases and cancers. RESULTS: In the brain, loss of MCT1 function is associated with pathologies of degeneration and injury of the nervous system. In tumors, MCT1 regulates the activity of signaling pathways and controls the exchange of monocarboxylates in aerobic glycolysis to affect tumor metabolism, proliferation and invasion. Meanwhile, MCT1 also acts as a good biomarker for the prediction and diagnosis of cancer progressions. CONCLUSION: MCT1 is an attractive transporter in brain diseases and cancers. Moreover, the development of MCT1- based small molecule drugs and MCT1 inhibitors in the clinic is promising. This review systematically summarizes the basic characteristics of MCT1 and its role in brain diseases and cancers, laying the foundation for further research on MCT1.

Justification of Biowaiver and Dissolution Rate Specifications for Piroxicam Immediate Release Products Based on Physiologically Based Pharmacokinetic Modeling: An In-Depth Analysis.

A quantitative prediction of human pharmacokinetic (PK) profiles has become an increasing demand for the reduction of the clinical failure of drug formulations. The existing in vitro and in vivo correlation (IVIVC) methodology could achieve this goal, but the development of IVIVC for immediate release (IR) products is challenging. Herein, we report that for certain weakly acidic biopharmaceutical classification system (BCS) class II molecules (piroxicam, PIRO), physiologically based PK (PBPK) modeling could be used as a tool to quantitatively predict PK in beagle dogs and to conduct an interspecies extrapolation to humans. First, robust PBPK models were constructed in beagle dogs under both fasted and fed states. Then, a Z-factor model was integrated to assess the effect of in vitro dissolution rates on the in vivo PK performance, and the results illustrated that PIRO IR products had a much wider dissolution space than was anticipated by bioequivalence. In addition, the parameter sensitivity analysis (PSA) assay showed that good oral absorption was achieved only when the particle size was below 150 µm. Finally, the combined PBPK models were extrapolated to humans to specify a quality control strategy; this extrapolation constituted an extension of a biowaiver for PIRO IR formulations. The results showed that the developed method can be utilized to quantitatively predict human PK, which would be meaningful for future scale-up or postapproval changes.

High Co-loading Capacity and Stimuli-Responsive Release Based on Cascade Reaction of Self-Destructive Polymer for Improved Chemo-Photodynamic Therapy.

Photodynamic therapy (PDT) shows a promising synergy with chemotherapy in the therapeutic outcome of malignant cancers. The minimal invasiveness and nonsystemic toxicity are appealing advantages of PDT, but combination with chemotherapy brings in the nonselective toxicity. We designed a polymeric nanoparticle system that contains both a chemotherapeutic agent and a photosensitizer to seek improvement for chemo-photodynamic therapy. First, to address the challenge of efficient co-delivery, polymer-conjugated doxorubicin (PEG-PBC-TKDOX) was synthesized to load photosensitizer chlorin e6 (Ce6). Ce6 is retained with DOX by a π-π stacking interaction, with high loading (41.9 wt %) and the optimal nanoparticle size (50 nm). Second, light given in PDT treatment not only excites Ce6 to produce cytotoxic reactive oxygen species (ROS) but also spatiotemporally activates a cascade reaction to release the loaded drugs. Finally, we report a self-destructive polymeric carrier (PEG-PBC-TKDOX) that depolymerizes its backbone to facilitate drug release upon ROS stimulus. This is achieved by grafting the ROS-sensitive pendant thioketal to aliphatic polycarbonate. When DOX is covalently modified to this polymer via thioketal, target specificity is controlled by light, and off-target delivery toxicity is mostly avoided. An oral squamous cell carcinoma that is clinically relevant to PDT was used as the cancer model. We put forward a polymeric system with improved efficiency for chemo-photodynamic therapy and reduced off-target toxicity.

Detection of related substances in polyene phosphatidyl choline extracted from soybean and in its commercial capsule by comprehensive supercritical fluid chromatography with mass spectrometry compared with HPLC with evaporative light scattering detection.

Supercritical fluid chromatography with tandem mass spectrometry was used to comprehensively profile polyene phosphatidyl choline (PPC) extracted from soybean. We achieved an efficient chromatographic analysis using a BEH-2EP column (3 × 100 mm(2) , 1.7 µm) with a mobile phase consisting of CO2 and a cosolvent in gradient combination at a flow rate of 1.0 mL/min. The cosolvent consisted of methanol, acetonitrile, and water (containing 10 mM ammonium acetate and 0.2% formic acid). The total single-run time was 7 min. We used this method to accurately detect ten different phospholipids (PLs) during extraction. The limits of quantification for phosphatidyl choline, lyso-phosphatidylcholine (LPC), phosphatidic acid (PA), sphingomyelin, phosphatidyl glycerol, phosphatidyl inositol (PI), cholesterol, cardiolipin, phosphatidyl serine, and phosphatidyl ethanolamine (PE) were 20.6, 19.52, 1.21, 2.38, 0.50, 2.28, 54.3, 0.60, 0.65, and 4.85 ng/mL, respectively. However, adopting the high-performance liquid chromatography with evaporative light scattering detection method issued by the China Food and Drug Administration, only PA, LPC, PE, PI, and PPC could be analyzed accurately, and the limits of quantification were 33.89, 60.5, 30.3, 10.9, and 61.79 µg/mL, respectively. The total single-run time was at the least 20 min. Consequently, the supercritical fluid chromatography with tandem mass spectrometry method was more suitable for the analysis of related PLs.