Nanotheranostics is one of the biggest scientific breakthroughs in nanomedicine. Most of the currently available diagnosis and therapies are invasive, time-consuming, and associated with severe toxic side effects. Nanotheranostics, on the other hand, has the potential to bridge this gap by harnessing the capabilities of nanotechnology and nanomaterials for combined therapeutics and diagnostics with markedly enhanced efficacy. However, nanomaterial applications in nanotheranostics are still in its infancy. This is due to the fact that each disease has a particular microenvironment with well-defined characteristics, which promotes deeper selection criteria of nanomaterials to meet the disease needs. In this review, we have outlined how nanomaterials are designed and tailored for nanotheranostics of cancer and other diseases such as neurodegenerative, autoimmune (particularly on rheumatoid arthritis), and cardiovascular diseases. The penetrability and retention of a nanomaterial in the biological system, the therapeutic strategy used, and the imaging mode selected are some of the aspects discussed for each disease. The specific properties of the nanomaterials in terms of feasibility, physicochemical challenges, progress in clinical trials, its toxicity, and their future application on translational medicine are addressed. Our review meticulously and critically examines the applications of nanotheranostics with various nanomaterials, including graphene, across several diseases, offering a broader perspective of this emerging field.

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Nanomaterials for Nanotheranostics: Tuning Their Properties According to Disease Needs.

Although notable progress has been made on novel cancer treatments, the overall survival rate and therapeutic effects are still unsatisfactory for cancer patients. Chemoimmunotherapy, combining chemotherapeutics and immunotherapeutic drugs, has emerged as a promising approach for cancer treatment, with the advantages of cooperating two kinds of treatment mechanism, reducing the dosage of the drug and enhancing therapeutic effect. Moreover, nano-based drug delivery system (NDDS) was applied to encapsulate chemotherapeutic agents and exhibited outstanding properties such as targeted delivery, tumor microenvironment response and site-specific release. Several nanocarriers have been approved in clinical cancer chemotherapy and showed significant improvement in therapeutic efficiency compared with traditional formulations, such as liposomes (Doxil®, Lipusu®), nanoparticles (Abraxane®) and micelles (Genexol-PM®). The applications of NDDS to chemoimmunotherapy would be a powerful strategy for future cancer treatment, which could greatly enhance the therapeutic efficacy, reduce the side effects and optimize the clinical outcomes of cancer patients. Herein, the current approaches of cancer immunotherapy and chemoimmunotherapy were discussed, and recent advances of NDDS applied for chemoimmunotherapy were further reviewed.
Highlights:
1 The current approaches of cancer immunotherapy were summarized.2 The prospects in combination of chemotherapy and immunotherapy were discussed.3 The recent progress of nano-based drug delivery systems applied for cancer chemoimmunotherapy was further categorized and reviewed.

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A Review on Nano-Based Drug Delivery System for Cancer Chemoimmunotherapy.

Conventional chemotherapy for cancer treatment is usually compromised by shortcomings such as insufficient therapeutic outcome and undesired side effects. The past decade has witnessed the rapid development of combination therapy by integrating chemotherapy with hyperthermia for enhanced therapeutic efficacy. Near-infrared (NIR) light-mediated photothermal therapy, which has advantages such as great capacity of heat ablation and minimally invasive manner, has emerged as a powerful approach for cancer treatment. A variety of nanomaterials absorbing NIR light to generate heat have been developed to simultaneously act as carriers for chemotherapeutic drugs, contributing as heat trigger for drug release and/or inducing hyperthermia for synergistic effects. This review aims to summarize the recent development of advanced nanomaterials in chemo-photothermal combination therapy, including metal-, carbon-based nanomaterials and particularly organic nanomaterials. The potential challenges and perspectives for the future development of nanomaterials-based chemo-photothermal therapy were also discussed.

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Recent Advances in Nanomaterials-Based Chemo-Photothermal Combination Therapy for Improving Cancer Treatment.

Platinum-based drugs cisplatin, carboplatin, and oxaliplatin are widely used for chemotherapeutic eradication of cancer. However, the side effects of platinum drugs, such as lack of selectivity, high systemic toxicity, and drug resistance, seriously limit their clinical application. With advancements in nanotechnology and chemical synthesis, Pt-based anti-cancer drugs have made great progress in cancer therapy in recent years. Many strategies relied on the anti-cancer mechanism similar to cisplatin and achieved some success by modifying existing platinum drugs. Pt-based nanodrugs, such as platinum nanoclusters, have novel anti-cancer mechanisms and great potential in tumor-targeted therapy and have shown promising results in clinical application. In this review, we systematically explored the development of first-line platinum chemotherapy drugs in the clinic and their anti-cancer mechanisms. We also summarize the progress of Pt-based anti-cancer drug application in cancer therapy, emphasizing their modification to enhance the anti-tumor effect. Finally, we address challenges faced by platinum chemotherapy drugs, especially Pt nanocluster-based nanodrugs, in cancer treatment. The new platinum drugs and their targeted modifications undoubtedly provide a promising prospect for improving the current anti-cancer treatments.

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Platinum-based drugs for cancer therapy and anti-tumor strategies

Chalcones (1,3-diaryl-2-propen-1-ones) are precursors for flavonoids and isoflavonoids, which are common simple chemical scaffolds found in many naturally occurring compounds. Many chalcone derivatives were also prepared due to their convenient synthesis. Chalcones as weandhetic analogues have attracted much interest due to their broad biological activities with clinical potentials against various diseases, particularly for antitumor activity. The chalcone family has demonstrated potential in vitro and in vivo activity against cancers via multiple mechanisms, including cell cycle disruption, autophagy regulation, apoptosis induction, and immunomodulatory and inflammatory mediators. It represents a promising strategy to develop chalcones as novel anticancer agents. In addition, the combination of chalcones and other therapies is expected to be an effective way to improve anticancer therapeutic efficacy. However, despite the encouraging results for their response to cancers observed in clinical studies, a full description of toxicity is required for their clinical use as safe drugs for the treatment of cancer. In this review, we will summarize the recent advances of the chalcone family as potential anticancer agents and the mechanisms of action. Besides, future applications and scope of the chalcone family toward the treatment and prevention of cancer are brought out.

https://www.mdpi.com/2218-273X/11/6/894/pdf

Chalcone Derivatives: Role in Anticancer Therapy

The specific-targeting approach could promote the specificity of diagnosis and the accuracy of cancer treatment. The choice of a specific-targeting receptor is the key step in this approach. Glypican-3 (GPC3) is an oncofetal proteoglycan anchored on the cell membrane. It is overexpressed even in the early stage of hepatocellular carcinoma (HCC), whereas it shows almost no expression in the healthy adult liver. Therefore, GPC3 may be applied as a specific-targeting receptor for HCC theranostics. In this study, a GPC3 specific-targeting theranostics nanodevice, GPC3 targeting peptide (named G12)-modified liposomes co-loaded with sorafenib (SF) and IR780 iodide (IR780), was developed (GSI-Lip), which aims to realize early diagnosis and precise chemo-photothermal therapy of HCC. SF was the first-line chemotherapy drug for the treatment of HCC. IR780 was used for photothermal therapy and near-infrared fluorescence imaging. The evaluation of early diagnosis verified that early-stage tumors (3.45 ± 0.98 mm3, 2 days after 5 × 105 H22 cells' inoculation in mice) could be clearly detected using GSI-Lip, which was significantly more sensitive than folic acid-modified liposomes ( p < 0.01, 32.90 ± 10.01 mm3, 4 days after 1 × 106 H22 cells' inoculation in mice). The study of the endocytic pathway indicated that specific G12/GPC3 recognition may induce caveolae-mediated endocytosis of GSI-Lip. Notably, the accumulation of GSI-Lip in tumors was significantly increased compared with that observed with folic acid-modified liposomes ( p < 0.01). Specific-targeting endowed the precise antitumor effect of GSI-Lip. GSI-Lip showed a higher antitumor efficacy in comparison with folic acid-modified liposomes (inhibition rate: 90.52% vs 84.22%, respectively; p < 0.01). During a period of 21 days, the synergistic chemo-photothermal therapy (GSI-Lip + laser) exhibited a better antitumor effect versus GSI-Lip without laser (inhibition rate: 94.93% vs 90.52%, respectively; p < 0.01). Overall, GPC3-targeted GSI-Lip promoted the sensitivity and specificity of HCC early diagnosis and achieved synergistic efficacy of chemo-photothermal theranostics, which has potential clinical applications. Furthermore, the present study revealed that a more specific-targeting ligand could further improve the efficacy of theranostics against HCC.

Promoting Early Diagnosis and Precise Therapy of Hepatocellular Carcinoma by Glypican-3-Targeted Synergistic Chemo-Photothermal Theranostics.

Cell therapy is a promising strategy for cancer therapy. However, its therapeutic efficiency remains limited due to the complex and immunosuppressive nature of tumor microenvironments. In this study, the “cell-chemotherapy” strategy was presented to enhance antitumor efficacy. M1-type macrophages, which are therapeutic immune cells with both of immunotherapeutic ability and targeting ability, carried sorafenib (SF)-loaded lipid nanoparticles (M1/SLNPs) were developed. M1-type macrophages were used both as therapeutic tool to provide immunotherapy and as delivery vessel to target deliver SF to tumor tissues for chemotherapy simultaneously. M1-type macrophages were obtained by polarizing macrophages using lipopolysaccharide, and M1/SLNPs were obtained by incubating M1-type macrophages with SLNP. Tumor accumulation of M1/SLNP was increased compared with SLNP (p < 0.01), which proved M1/SLNP could enhance tumor targeting of SF. An increased ratio of M1-type macrophages to M2-type macrophages, and the CD3+CD4+ T cells and CD3+CD8+ T cell quantities in tumor tissues after treatment with M1/SLNP indicated M1/SLNP could relieve the immunosuppressive tumor microenvironments. The tumor volumes in the M1/SLNP group were significantly smaller than those in the SLNP group (p < 0.01), indicating M1/SLNP exhibited enhanced antitumor efficacy. Consequently, M1/SLNP showed great potential as a novel cell-chemotherapeutic strategy combining both cell therapy and targeting chemotherapy.
Highlights:
1 A polarized-macrophages-based drug delivery system (M1/SLNP) was presented for the cell-chemotherapy of cancer.2 Polarized-macrophages were used both as therapeutic tool to provide immunotherapy and as delivery vessel to target deliver chemotherapeutic drugs to tumor tissues for chemotherapy simultaneously.3 M1/SLNP was a multifunctional delivery system with simple structure, excellent safety, and without complex synthesis process.

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Nanoparticle-Loaded Polarized-Macrophages for Enhanced Tumor Targeting and Cell-Chemotherapy

Reshaping Antitumor Immunity with Chemo-Photothermal Integrated Nanoplatform to Augment Checkpoint Blockade-Based Cancer Therapy

Combination therapy is a current hot topic in cancer treatment. Multiple synergistic effects elicited by combined drugs are essential in improving antitumor activity. Herein, a pH-triggered charge and size dual switchable nanocage co-loaded with abemaciclib and IMD-0354 (PA/PI-ND) is reported, exhibiting a novel triple-interlocked combination of chemotherapy, immunotherapy, and chemoimmunotherapy. The charge reversal polymer NGR-poly(ethylene glycol)-poly(l-lysine)-dimethylmaleic anhydride (NGR-PEG-PLL-DMA, ND) in PA/PI-ND promotes the pH-triggered charge reversal from negative to positive and size reduction from about 180 to 10 nm in an acidic tumor microenvironment, which greatly enhances cellular uptake and tumor tissue deep penetration. With the PA/PI-ND triple-interlocked combination therapy, the chemotherapeutic effect is enhanced by the action of abemaciclib to induce cell cycle arrest in the G1 phase, together with the reduction in cyclin D levels caused by IMD-0354. The dual anti-tumor promoting immunotherapy is achieved by abemaciclib selectively inhibiting the proliferation of regulatory T cells (Tregs) and by IMD-0354 promoting tumor-associated macrophage (TAM) repolarization from an M2 to M1 phenotype. Furthermore, PA/PI-ND has improved anti-tumor efficiency resulting from the third synergistic effect provided by chemoimmunotherapy. Taken together, PA/PI-ND is a promising strategy to guide the design of future drug delivery carriers and cancer combination therapy.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/advs.202000906

Charge and Size Dual Switchable Nanocage for Novel Triple-Interlocked Combination Therapy Pattern

The tumor penetration of nanomedicines constitutes a great challenge in the treatment of solid tumors, leading to the highly compromised therapeutic efficacy of nanomedicines. Here, we developed small morph nanoparticles (PDMA) by modifying polyamidoamine (PAMAM) dendrimers with dimethylmaleic anhydride (DMA). PDMA achieved deep tumor penetration via an active, energy-dependent, caveolae-mediated transcytosis, which circumvented the obstacles in the process of deep penetration. PDMA remained negatively charged under normal physiological conditions and underwent rapid charge reversal from negative to positive under acidic conditions in the tumor microenvironment (pH < 6.5), which enhanced their uptake by tumor cells and their deep penetration into tumor tissues in vitro and in vivo. The deep tumor penetration of PDMA was achieved mainly by caveolae-mediated transcytosis, which could be attributed to the small sizes (5-10 nm) and positive charge of the morphed PDMA. In vivo studies demonstrated that PDMA exhibited increased tumor accumulation and doxorubicin-loaded PDMA (PDMA/DOX) showed better antitumor efficacy. Overall, the small morph PDMA for enhanced deep tumor penetration via caveolae-mediated transcytosis could provide new inspiration for the design of anticancer drug delivery systems.

Shuang Liang

Papers

Promoting Early Diagnosis and Precise Therapy of Hepatocellular Carcinoma by Glypican-3-Targeted Synergistic Chemo-Photothermal Theranostics.

Nanoparticle-Loaded Polarized-Macrophages for Enhanced Tumor Targeting and Cell-Chemotherapy

Reshaping Antitumor Immunity with Chemo-Photothermal Integrated Nanoplatform to Augment Checkpoint Blockade-Based Cancer Therapy

Charge and Size Dual Switchable Nanocage for Novel Triple-Interlocked Combination Therapy Pattern

Small Morph Nanoparticles for Deep Tumor Penetration via Caveolae-Mediated Transcytosis.