Advances in Natural Polymer-Based Transdermal Drug Delivery Systems for Tumor Therapy

As an alternative to traditional oral and intravenous injections with limited efficacy, transdermal drug delivery (TDD) has shown great promise in tumor treatment. Over the past decade, natural polymers have been designed into various nanocarriers due to their excellent biocompatibility, biodegradability, and easy availability, providing more options for TDD. In addition, surface functionalization modification of the rich functional groups of natural polymers, which in turn are developed into targeted and stimulus-responsive functional materials, allows precise delivery of drugs to tumor sites and release of drugs in response to specific stimuli. It not only improves the treatment efficiency of tumor but also reduces the toxic and side effects to normal tissues. Therefore, the development of natural polymer-based TDD (NPTDD) systems has great potential in tumor therapy. In this review, the mechanism of NPTDD systems such as penetration enhancers, nanoparticles, microneedles, hydrogels and nanofibers prepared from hyaluronic acid, chitosan, sodium alginate, cellulose, heparin and protein, and their applications in tumor therapy are overviewed. This review also outlines the future prospects and current challenges of NPTDD systems for local treatment tumors.     

Stimulus-Responsive Drug Delivery Nanoplatforms for Osteoarthritis Therapy

Osteoarthritis (OA) is one of the most prevalent age-related degenerative diseases. With an increasingly aging global population, greater numbers of OA patients are providing clear economic and societal burdens. Surgical and pharmacological treatments are the most common and conventional therapeutic strategies for OA, but often fall considerably short of desired or optimal outcomes. With the development of stimulus-responsive nanoplatforms has come the potential for improved therapeutic strategies for OA. Enhanced control, longer retention time, higher loading rates, and increased sensitivity are among the potential benefits. This review summarizes the advanced application of stimulus-responsive drug delivery nanoplatforms for OA, categorized by either those that depend on endogenous stimulus (reactive oxygen species, pH, enzyme, and temperature), or those that depend on exogenous stimulus (near-infrared ray, ultrasound, magnetic fields). The opportunities, restrictions, and limitations related to these various drug delivery systems, or their combinations, are discussed in areas such as multi-functionality, image guidance, and multi-stimulus response. The remaining constraints and potential solutions that are represented by the clinical application of stimulus-responsive drug delivery nanoplatforms are finally summarized.     

Tubulin-Based Nanotubes as Delivery Platform for Microtubule-Targeting Agents

Tubulin-based nanotubes (TNTs) to deliver microtubule-targeting agents (MTAs) for clinical oncology are reported. Three MTAs, docetaxel (DTX), laulimalide (LMD), and monomethyl auristatin E (MMAE), which attach to different binding sites in a tubulin, are loaded onto TNTs and cause structural changes in them, including shape anisotropy and tubulin layering. This drug-driven carrier transformation leads to changes in the drug-loading efficiency and stability characteristics of the carrier. TNTs coloaded with DTX and LMD efficiently deliver dual drug cargoes to cellular tubulins by the endolysosomal pathway, and results in synergistic anticancer and antiangiogenic action of the drugs in vitro. In in vivo tests, TNTs loaded with a microtubule-destabilizing agent MMAE suppress the growth of tumors with much higher efficacy than free MMAE did. This work suggests a new concept of using a drug's target protein as a carrier. The findings demonstrate that the TNTs developed here can be used universally as a delivery platform for many MTAs.     

Nanodiamond‐Based Theranostic Platform for Drug Delivery and Bioimaging

Nanodiamonds (NDs) are promising candidates for biomedical application due to their excellent biocompatibility and innate physicochemical properties. In this Concept article, nanodiamond‐based theranostic platforms, which combine both drug delivery features and bioimaging functions, are discussed. The latest developments of therapeutic strategies are introduced and future perspectives for theranostic NDs are addressed.     

Theranostic GO‐Based Nanohybrid for Tumor Induced Imaging and Potential Combinational Tumor Therapy

Graphene oxide (GO)‐based theranostic nanohybrid is designed for tumor induced imaging and potential combinational tumor therapy. The anti‐tumor drug, Doxorubicin (DOX) is chemically conjugated to the poly(ethylenimine)‐co‐poly(ethylene glycol) (PEI‐PEG) grafted GO via a MMP2‐cleavable PLGLAG peptide linkage. The therapeutic efficacy of DOX is chemically locked and its intrinsic fluorescence is quenched by GO under normal physiological condition. Once stimulated by the MMP2 enzyme over‐expressed in tumor tissues, the resulting peptide cleavage permits the unloading of DOX for tumor therapy and concurrent fluorescence recovery of DOX for in situ tumor cell imaging. Attractively, this PEI‐bearing nanohybrid can mediate efficient DNA transfection and shows great potential for combinational drug/gene therapy. This tumor induced imaging and potential combinational therapy will open a window for tumor treatment by offering a unique theranostic approach through merging the diagnostic capability and pathology‐responsive therapeutic function.     

Oral Delivery of Biologics for Precision Medicine

The emerging field of precision medicine is rapidly growing, fostered by the advances in genome mapping and molecular diagnosis. In general, the translation of these advances into precision treatments relies on the use of biological macromolecules, whose structure offers a high specificity and potency. Unfortunately, due to their complex structure and limited ability to overcome biological barriers, these macromolecules need to be administered via injection. The scientific community has devoted significant effort to making the oral administration of macromolecules plausible thanks to the implementation of drug delivery technologies. Here, an overview of the current situation and future prospects in the field of oral delivery of biologics is provided. Technologies in clinical trials, as well as recent and disruptive delivery systems proposed in the literature for local and systemic delivery of biologics including peptides, antibodies, and nucleic acids, are described. Strategies for the specific targeting of gastrointestinal regions—stomach, small bowel, and colon—cell populations, and internalization pathways, are analyzed. Finally, challenges associated with the clinical translation, future prospects, and identified opportunities for advancement in this field are also discussed.     

Rekindling RNAi Therapy: Materials Design Requirements for In Vivo siRNA Delivery

With the recent FDA approval of the first siRNA‐derived therapeutic, RNA interference (RNAi)‐mediated gene therapy is undergoing a transition from research to the clinical space. The primary obstacle to realization of RNAi therapy has been the delivery of oligonucleotide payloads. Therefore, the main aims is to identify and describe key design features needed for nanoscale vehicles to achieve effective delivery of siRNA‐mediated gene silencing agents in vivo. The problem is broken into three elements: 1) protection of siRNA from degradation and clearance; 2) selective homing to target cell types; and 3) cytoplasmic release of the siRNA payload by escaping or bypassing endocytic uptake. The in vitro and in vivo gene silencing efficiency values that have been reported in publications over the past decade are quantitatively summarized by material type (lipid, polymer, metal, mesoporous silica, and porous silicon), and the overall trends in research publication and in clinical translation are discussed to reflect on the direction of the RNAi therapeutics field.     

Theranostic Upconversion Nanobeacons for Tumor mRNA Ratiometric Fluorescence Detection and Imaging‐Monitored Drug Delivery

Remote optical detection and imaging of specific tumor‐related biomarkers and simultaneous activation of therapy according to the expression level of the biomarkers in tumor site with theranostic probes should be an effective modality for treatment of cancers. Herein, an upconversion nanobeacon (UCNPs‐MB/Dox) is proposed as a new theranostic nanoprobe to ratiometrically detect and visualize the thymidine kinase 1 (TK1) mRNA that can simultaneously trigger the Dox release to activate the chemotherapy accordingly. UCNPs‐MB/Dox is constructed with the conjugation of a TK1 mRNA‐specific molecular beacon (MB) bearing a quencher (BHQ‐1) and an alkene handle modified upconversion nanoparticle (UCNP) through click reaction and subsequently loading with a chemotherapy drug (Dox). With this nanobeacon, quantitative ratiometric upconversion detection of the target with high sensitivity and selectivity as well as the target triggered Dox release in vitro is demonstrated. The sensitive and selective ratiometric detection and imaging of TK1 mRNA under the irradiation of near infrared light (980 nm) and the mRNA‐dependent release of Dox for chemotherapy in the tumor MCF‐7 cells and A549 cells are also shown. This work provides a smart and robust platform for gene‐related tumor theranostics.     

Magnetoresponsive Virus‐Mimetic Nanocapsules with Dual Heat‐Triggered Sequential‐Infected Multiple Drug‐Delivery Approach for Combinatorial Tumor Therapy

Stimuli‐responsive drug‐delivery systems constitute an appealing approach to direct and restrict drug release spatiotemporally at the specific site of interest. However, it is difficult for most systems to affect every cancer cell in a tumor tissue due to the presence of the natural tumor barrier, leading to potential tumor recurrence. Here, core–shell magnetoresponsive virus‐mimetic nanocapsules (VNs), which can infect cancer cells sequentially and double as a magnetothermal agent fabricated through anchoring iron oxide nanoparticles in a single‐component protein (lactoferrin) shell, are reported. With large payload of hydrophilic/hydrophobic anticancer cargos, doxorubicin and palictaxel, VNs can simultaneously give a rapid drug release and intense heat while applying an external high‐frequency magnetic field (HFMF). Furthermore, after being liberated from dead cells by HFMF manipulation, the constructive VNs can sequentially infect neighboring cancer cells and deliver sufficient therapeutic agents to next targeted sites. With high efficiency for sequential cell infections, VNs have successfully eliminated subcutaneous tumor after a combinatorial treatment. These results demonstrate that the VNs could be used for locally targeted, on‐demand, magnetoresponsive chemotherapy/hyperthermia, combined with repeated cell infections for tumor therapy and other therapeutic applications.     

A Highly Translatable Dual-arm Local Delivery Strategy To Achieve Widespread Therapeutic Coverage in Healthy and Tumor-bearing Brain Tissues

Drug delivery nanoparticles (NPs) based entirely on materials generally recognized as safe that provide widespread parenchymal distribution following intracranial administration via convection-enhanced delivery (CED) are introduced. Poly(lactic-co-glycolic acid) (PLGA) NPs are coated with various poloxamers, including F68, F98, or F127, via physical adsorption to render particle surfaces non-adhesive, thereby resisting interactions with brain extracellular matrix. F127-coated PLGA (F127/PLGA) NPs provide markedly greater distribution in healthy rat brains compared to uncoated NPs and widespread coverage in orthotopically-established brain tumors. Distribution analysis of variously-sized F127/PLGA NPs determines the average rat brain tissue porosity to be between 135 and 170 nm while revealing unprecedented brain coverage of larger F127/PLGA NPs with an aid of hydraulic pressure provided by CED. Importantly, F127/PLGA NPs can be lyophilized for long-term storage without compromising their ability to penetrate the brain tissue. Further, 65- and 200-nm F127/PLGA NPs lyophilized-reconstituted and administered in a moderately hyperosmolar infusate solution show further enhance particle dissemination in the brain via osmotically-driven enlargement of the brain tissue porosity. Combination of F127/PLGA NPs and osmotic tissue modulation provides a means with a clear regulatory path to maximize the brain distribution of large NPs that enable greater drug loading and prolong drug release.     

光热/pH响应B-CuS-DOX纳米药物用于化疗-光热协同治疗肿瘤

基于纳米材料的化疗-光热协同治疗是一种高效的肿瘤治疗方式, 但如何构建具有高载药量与良好光热转换性能的纳米药物依然面临挑战。本研究通过超声剥离法制备二维硼(boron, B)纳米片, 进一步在其表面原位负载超小粒径硫化铜(CuS)纳米颗粒和化疗药阿霉素(DOX), 形成B-CuS-DOX纳米药物。B-CuS具有高的DOX药物装载能力(864 mg/g)和优异的光热转化性能(在808 nm处的光热转换效率为55.8%), 同时可实现pH及近红外激光双重刺激响应而释放药物。细胞实验表明在808 nm近红外光的照射下, B-CuS-DOX展示了良好的化疗-光热协同治疗效果。本研究构建的纳米药物有望为体内肿瘤治疗提供一种有效的化疗-光热协同治疗策略。     

Intermittent Fasting Primes the Tumor Microenvironment and Improves Nanomedicine Delivery in Hepatocellular Carcinoma

Fasting has many health benefits, including reduced chemotherapy toxicity and improved efficacy. It is unclear how fasting affects the tumor microenvironment (TME) and tumor-targeted drug delivery. Here the effects of intermittent (IF) and short-term (STF) fasting are investigated on tumor growth, TME composition, and liposome delivery in allogeneic hepatocellular carcinoma (HCC) mouse models. To this end, mice are inoculated either subcutaneously or intrahepatically with Hep-55.1C cells and subjected to IF for 24 d or to STF for 1 d. IF but not STF significantly slows down tumor growth. IF increases tumor vascularization and decreases collagen density, resulting in improved liposome delivery. In vitro, fasting furthermore promotes the tumor cell uptake of liposomes. These results demonstrate that IF shapes the TME in HCC towards enhanced drug delivery. Finally, when combining IF with liposomal doxorubicin treatment, the antitumor efficacy of nanochemotherapy is found to be increased, while systemic side effects are reduced. Altogether, these findings exemplify that the beneficial effects of fasting on anticancer therapy outcomes go beyond modulating metabolism at the molecular level.     

Surface Modifications for Improved Delivery and Function of Therapeutic Bacteria

Live therapeutic bacteria (LTBs) hold promise to treat microbiome‐related diseases. However, few approaches to improve the colonization of LTBs in the gastrointestinal tract exist, despite colonization being a prerequisite for efficacy of many LTBs. Here, a modular platform to rapidly modify the surface of LTBs to enable receptor‐specific interactions with target surfaces is reported. Inspired by bacterial adhesins that facilitate colonization, synthetic adhesins (SAs) are developed for LTBs in the form of antibodies conjugated to their surface. The SA platform is nontoxic, does not alter LTB growth kinetics, and can be used with any antibody or bacterial strain combination. By improving adhesion, SA‐modified bacteria demonstrate enhanced in vitro pathogen exclusion from cell monolayers. In vivo kinetics of SA‐modified LTBs is tracked in the feces and intestines of treated mice, demonstrating that SA‐modified bacteria alter short‐term intestinal transit and improve LTB colonization and pharmacokinetics. This platform enables rapid formation of an intestinal niche, leading to an increased maximum concentration and a 20% improvement in total LTB exposure. This work is the first application of traditional pharmacokinetic analysis to design and evaluate LTB drug delivery systems and provides a platform toward controlling adhesion, colonization, and efficacy of LTBs.     

In Situ Tumor Vaccine for Lymph Nodes Delivery and Cancer Therapy Based on Small Size Nanoadjuvant

Tumor vaccine is a promising cancer treatment modality, however, the convenient antigens loading in vivo and efficient delivery of vaccines to lymph nodes (LNs) still remain a formidable challenge. Herein, an in situ nanovaccine strategy targeting LNs to induce powerful antitumor immune responses by converting the primary tumor into whole-cell antigens and then delivering these antigens and nanoadjuvants simultaneously to LNs is proposed. The in situ nanovaccine is based on a hydrogel system, which loaded with doxorubicin (DOX) and nanoadjuvant CpG-P-ss-M. The gel system exhibits ROS-responsive release of DOX and CpG-P-ss-M, generating abundant in situ storage of whole-cell tumor antigens. CpG-P-ss-M adsorbs tumor antigens through the positive surface charge and achieves charge reversal, forming small-sized and negatively charged tumor vaccines in situ, which are then primed to LNs. Eventually, the tumor vaccine promotes antigens uptake by dendritic cells (DCs), maturation of DCs, and proliferation of T cells. Moreover, the vaccine combined with anti-CTLA4 antibody and losartan inhibits tumor growth by 50%, significantly increasing the percentage of splenic cytotoxic T cells (CTLs), and generating tumor-specific immune responses. Overall, the treatment effectively inhibits primary tumor growth and induces tumor-specific immune response. This study provides a scalable strategy for in situ tumor vaccination.     

Photosensitization Priming of Tumor Microenvironments Improves Delivery of Nanotherapeutics via Neutrophil Infiltration

Remodeling of tumor microenvironments enables enhanced delivery of nanoparticles (NPs). This study shows that direct priming of a tumor tissue using photosensitization rapidly activates neutrophil infiltration that mediates delivery of nanotherapeutics into the tumor. A drug delivery platform is comprised of NPs coated with anti‐CD11b antibodies (Abs) that target activated neutrophils. Intravital microscopy demonstrates that the movement of anti‐CD11b Abs‐decorated NPs (NPs‐CD11b) into the tumor is mediated by neutrophil infiltration induced by photosensitization (PS) because the systemic depletion of neutrophils completely abolishes the nanoparticle tumor deposition. The neutrophil uptake of NPs does not alter neutrophil activation and transmigration. For cancer therapy in mice, tumor PS and photothermal therapy of anti‐CD11b Abs‐linked gold nanorods (GNRs‐CD11b) are combined to treat the carcinoma tumor. The result indicates that neutrophil tumor infiltration enhances nanoparticle cancer therapy. The findings reveal that promoting tumor infiltration of neutrophils by manipulating tumor microenvironments could be a novel strategy to actively deliver nanotherapeutics in cancer therapies.     

Recovery of Drug Delivery Nanoparticles from Human Plasma Using an Electrokinetic Platform Technology

The effect of complex biological fluids on the surface and structure of nanoparticles is a rapidly expanding field of study. One of the challenges holding back this research is the difficulty of recovering therapeutic nanoparticles from biological samples due to their small size, low density, and stealth surface coatings. Here, the first demonstration of the recovery and analysis of drug delivery nanoparticles from undiluted human plasma samples through the use of a new electrokinetic platform technology is presented. The particles are recovered from plasma through a dielectrophoresis separation force that is created by innate differences in the dielectric properties between the unaltered nanoparticles and the surrounding plasma. It is shown that this can be applied to a wide range of drug delivery nanoparticles of different morphologies and materials, including low‐density nanoliposomes. These recovered particles can then be analyzed using different methods including scanning electron microscopy to monitor surface and structural changes that result from plasma exposure. This new recovery technique can be broadly applied to the recovery of nanoparticles from high conductance fluids in a wide range of applications.