pH/H2 O2 Cascade-Responsive Nanoparticles of Lipid-Like Prodrugs through Dynamic-Covalent and Coordination Interactions for Chemotherapy.

Traditional lipid nanoparticles (LNPs) suffer from low drug loading capacity (DLC), weak stability, and lack of responsiveness. Conventional approaches to address these issues involve the synthesis of lipid-prodrug by incorporating responsive covalent linkers. However, such approaches often result in suboptimal sensitivity for drug release and undermine therapeutic effectiveness. Herein, the study reports a fundamentally different concept for designing lipid-like prodrugs through boron-nitrogen (B-N) coordination and dynamic covalent interaction. The 5-fluorouracil-based lipid-like prodrugs, featuring a borate ester consisting of a glycerophosphoryl choline head and a boronic acid-modified 5Fu/dodecanamine complex tail, are used to prepare pH/H2 O2 cascade-responsive LNPs (5Fu-LNPs). The 5Fu-LNPs exhibit enhanced DLC and stability in a neutral physiological environment due to the B-N coordination and enhanced hydrophobicity. In tumors, acidic pH triggers the dissociation of B-N coordination to release prodrugs, which further responds to low H2 O2 concentrations to release drugs, showcasing a potent pH/H2 O2 -cascade-responsive property. Importantly, 5Fu-LNPs demonstrate greater antitumor efficiency and lower toxicity compared to the commercial 5Fu. These results highlight 5Fu-LNPs as a safer and more effective alternative to chemotherapy. This work presents a unique LNP fabrication strategy that can overcome the limitations of conventional LNPs and broaden the range of intelligent nanomaterial preparation techniques.

Deliver on a Promise: Hydrogen-Bonded Polymer Nanomedicine with a Precise Ratio of Chemodrug and Photosensitizer for Intelligent Cancer Therapy.

The outcomes of combined cancer therapy are largely related to loading content and contribution of each therapeutic agent; however, fine-tuning the ratio of two coloaded components toward precise cancer therapy is a great challenge and still remains in its infancy. We herein develop a supramolecular polymer scaffold to optimize the coloading ratio of chemotherapeutic agent and photosensitizer through hydrogen-bonding (H-bonding) interaction, for maximizing the efficacy of intelligent cancer chemo/photodynamic therapies (CT/PDT). To do so, we first synthesize a thymine (THY)-functionalized tetraphenylporphyrin photosensitizer (i.e., TTPP), featuring the same molecular configuration of H-bonding array with chemotherapeutic carmofur (e.g., 1-hexylcarbamoyl-5-fluorouracil, HCFU). Meanwhile, a six-arm star-shaped amphiphilic polymer vehicle P(DAPA-co-DPMA-co-OEGMA)6 (poly(diaminopyridine acrylamide-co-2-(diisopropylamino)ethyl methacrylate-co-oligo(ethylene glycol) monomethyl ether methacrylate)6) is prepared, bearing hydrophilic and biocompatible POEGMA segment, along with hydrophobic PDAPA and PDPMA segments, characterizing the randomly dispersed dual functionalities, i.e., heterocomplementary H-bonding DAP motifs and pH-responsive protonation DPMA content. Thanks to the identical DAP/HCFU and DAP/TTPP H-bonding association capability, the incorporation of both HCFU and TTPP to six-arm star-shaped P(DAPA-co-DPMA-co-OEGMA)6 vehicle, with an optimized coloading ratio, can be straightforwardly realized by adjusting the feeding concentrations, thus yielding the hydrogen-bonded supramolecular nanoparticles (i.e., HCFU-TTPP-SPNs), demonstrating the codelivery of two components with the promise to optimize the combined CT/PDT efficacy.

Polyphenol-sodium alginate supramolecular injectable hydrogel with antibacterial and anti-inflammatory capabilities for infected wound healing.

Injectable hydrogel has attracted appealing attention for skin wound treatment. Although multifunctional injectable hydrogels can be prepared by introducing bioactive ingredients with antibacterial and anti-inflammatory capabilities, their preparation remains complicated. Herein, a polyphenol-based supramolecular injectable hydrogel (PBSIH) based on polyphenol gallic acid and biological macromolecule sodium alginate is developed as a wound dressing to accelerate wound healing. We show that such PBSIH can be rapidly formed within 15 s by mixing the sodium alginate and gallic acid solutions based on the hydrogen bonding and hydrophobic interactions. The PBSIH shows excellent cytocompatibility, antibacterial, and antioxidant properties, which enhance infected wound healing by inhibiting bacterial infection and alleviating inflammation after treatment of 11 days. Moreover, we show that the preparative strategies of injectable supramolecular hydrogels can be extended to other polyphenols, including protocatechuic and tannic acids. This study provides a facile yet highly effective method to design injectable polyphenol- sodium alginate hydrogel for wound dressing based on naturally bioactive ingredients.

Involvement of RFC3 in tamoxifen resistance in ER-positive breast cancer through the cell cycle.

Since the establishment of the molecular subtyping system, ER positive breast cancer was considered to be the most prevalent type of breast cancer, and endocrine therapy was a very important solution. However, numerous studies have shown that the cell cycle plays a key role in the progression and metastasis of breast cancer. The present study showed that RFC3 was involved in the cell cycle through DNA replication. Furthermore, RFC3 expression was significantly higher in breast cancer-resistant cells than in parental cells, which correlated with the cell cycle. We confirmed these results by established drug-resistant cell lines for breast cancer, raw letter analysis and immunohistochemical analysis of primary and recurrent tissues from three ER+ breast cancers. In addition, analysis of the results through an online database revealed that RFC3 expression was significantly associated with poor prognosis in ER+ breast cancer. We also demonstrated that in ER positive breast cancer-resistant cells, knockdown of RFC3 blocked the S-phase of cells and significantly attenuated cell proliferation, migration and invasion. Furthermore, RFC3 overexpression in ER positive breast cancer cells enhanced cell proliferation, migration and invasion. Taking all these findings into account, we could conclude that RFC3 was involved in endocrine resistance in breast cancer through the cell cycle. Thus, RFC3 may be a target to address endocrine therapy resistance in ER positive breast cancer and may be an independent prognostic factor in ER positive breast cancer.

Tamoxifen induces ferroptosis in MCF-7 organoid.

BACKGROUND: Breast cancer is the most common female malignant tumor type globally. The occurrence and development of breast cancer involve ferroptosis, which is closely related to its treatment. The development of breast cancer organoids facilitates the analysis of breast cancer molecular background and tumor biological behavior, including clinical pathological characteristics, drug response, or drug resistance relationship, and promotes the advancement of precision treatment for breast cancer. The three-dimensional (3D) cell culture of breast cancer MCF-7 organoid is more similar to the in vivo environment and thus obtains more realistic results than 2D cell culture. Our study examined the new mechanism of tamoxifen in treating breast cancer through breast cancer MCF-7 organoids. METHODS: We used 3D cells to culture breast cancer MCF-7 organoid, as well as tamoxifen-treated MCF-7 and tamoxifen-resistant MCF-7 (MCF-7 TAMR) cells. We used transcriptome sequencing. We detected GPX4 and SLC7A11 protein levels using Western blotting and the content of ATP, glutathione, and ferrous ions using the Cell Counting Lite 3D Kit. We assessed cell viability using the Cell Counting Kit-8 (CCK-8) assay. RESULTS: Tamoxifen significantly inhibited the growth of MCF-7 organoids and significantly induced ferroptosis in MCF-7 organoids. The ferroptosis inhibitor reversed the significant tamoxifen-induced MCF-7 organoid inhibition activity. Moreover, the ferroptosis activator enhanced the tamoxifen-induced MCF-7 TAMR cell activity inhibition. CONCLUSION: Our study revealed that ferroptosis plays an important role in tamoxifen-induced MCF-7 organoid cell death and provides a new research idea for precise treatment of breast cancer through an organoid model.

Hydrogen-Bonded Polymer Nanomedicine with AIE Characteristic for Intelligent Cancer Therapy.

One of the major goals of biomedical science is to pioneer advanced strategies toward precise and smart medicine. Hydrogen-bonding (H-bonding) assembly incorporated with an aggregation-induced emission (AIE) capability can serve as a powerful tool for developing supramolecular nanomedicine with clear tumor imaging and smart therapeutic performance. We here report a H-bonded polymeric nanoformulation with an AIE characteristic toward smart antitumor therapy. To do so, we first design a structurally novel tetraphenylethylene (TPE)-based H-bonding theranostic prodrug, TPE-(FUA)4, characterized by four chemotherapeutic fluorouracil-1-acetic acid (FUA) moieties arched to the TPE core. A six-arm star-shaped amphiphilic polymer vehicle, P(DAP-co-OEGEA)6, is prepared, bearing hydrophilic and biocompatible POEGEA (poly(oligo (ethylene glycol) ethyl acrylate) segments, along with a hydrophobic and H-bonding PDAP (poly(diaminopyridine acrylamide)) segment. Thanks to the establishment of the DAP/FUA H-bonding association, incorporating the TPE-(FUA)4 prodrug to the P(DAP-co-OEGEA)6 vehicle can yield H-bond cross-linked nanoparticles with interpenetrating networks. For the first time, AIE luminogens are interwoven into a six-arm star-shaped polymer via an intrinsic H-bonding array of the chemotherapeutic agent FUA, thus imposing an effective restriction of TPE molecular rotations. Concomitantly, encapsulated photothermal agent (IR780) via a hydrophobic interaction facilitates the formation of nanoassemblies, TPE-(FUA)4/IR780@P(DAP-co-OEGEA)6, featuring synergistic cancer chemo/photothermal therapy (CT/PTT). Our study can contribute a practical solution to fulfill biomedical requirements with a conductive advance in precision nanomedicine.

Mitochondria-Targeting Upconversion Nanoparticles@MOF for Multiple-Enhanced Photodynamic Therapy in Hypoxic Tumor.

The effect of photodynamic therapy (PDT) is severely limited by tumor hypoxia and the short half-life of reactive oxygen species (ROS). Herein, we constructed a near-infrared (NIR) light-regulated PDT nanoplatform (TPP-UCNPs@MOF-Pt) consisting of an upconversion nanoparticle (UCNP) core and porphyrin-based metal-organic framework (MOF) shell with platinum nanoparticles (PtNPs) and a mitochondria-targeting triphenylphosphine (TPP) group on the surface. TPP-UCNPs@MOF-Pt could effectively relieve the tumor hypoxia by converting intracellular H2O2 to oxygen (O2) and elevated the ROS level to enhance PDT efficacy under NIR light irradiation. In addition, the mitochondria-targeting TPP-UCNPs@MOF-Pt was localized on the mitochondria, leading to severe depolarization of the mitochondrial membrane and activation of the apoptotic pathway, further amplifying the therapeutic efficacy. In vitro and in vivo experiments demonstrated that the greatly enhanced photodynamic therapeutic efficacy of TPP-UCNPs@MOF-Pt was achieved by combining relief of tumor hypoxia with mitochondrial targeting and NIR activation. This study provides a promising strategy for construction of an MOF-based multifunctional nanoplatform to address the current limitations of PDT treatment for hypoxic tumors.

Development and validation of a prognostic model for HER2-low breast cancer to evaluate neoadjuvant therapy.

Background: Human epidermal growth factor receptor 2 (HER2) low breast cancer (BC) accounts for 30-51% of all BCs. How to precisely assess the response to neoadjuvant therapy in this heterogenous tumor is currently unanswered. With the advance in multi-omics, refining the molecular subtyping other than the current hormone receptor (HR)-based subtyping to guide the neoadjuvant therapy for HER2-low BC is potentially feasible. Methods: The messenger RNA (mRNA), clinical, and pathological data of all HER2-low BC patients (n=368) from the Neoadjuvant I-SPY2 Trial, were retrieved. Ninety-eight patients achieved pathological complete response (pCR) were randomly divided into the training and validation sets with 8:2 ratio. The non-pCR cases were corporated into the above datasets with 1:1 ratio. The rest non-pCR cases were served as the test set. Random forest (RF), support vector machine (SVM), and fully connected neural network (FCNN) were applied to establish a 1-dimensional (1D) model based on mRNA data. The method with best prediction value among the 3 models was selected for further modeling when combining pathological features. A new classification of deep learning (CDn) was proposed based on a multi-omics model. After identifying pCR-related features by the integral gradient and unsupervised hierarchical clustering method, the responses to neoadjuvant therapy associated with these features across different subgroups were analyzed. Results: Compared with the RF and SVM models, the FCNN model achieved the best performance [area under the curve (AUC): 0.89] based on the mRNA feature. By combining mRNA and pathological features, the FCNN model proposed 2 new subtypes including CD1 and CD0 for HER2-low BC. CD1 increased the sensitivity to predict pCR by 23.5% [to 87.8%; 95% confidence interval (CI): 78% to 94%] and improved the specificity to pCR by 12.2% (to 77.4%; 95% CI: 69% to 87%) when comparing with the current HR classification for HER2-low BC. Conclusions: The new typing method (CD1 and CD0) proposed in this study achieved excellent performance for predicting the pCR to neoadjuvant therapy in HER2-low BC. The patients who were not sensitive to neoadjuvant therapy according to multi-omics models might receive surgical treatment directly.

Monolayer LDH Nanosheets with Ultrahigh ICG Loading for Phototherapy and Ca2+-Induced Mitochondrial Membrane Potential Damage to Co-Enhance Cancer Immunotherapy.

Tumor recurrence and metastasis are the main causes of cancer mortality; traditional chemotherapeutic drugs have severe toxicity and side effects in cancer treatment. To overcome these issues, here, we present a pH-responsive, self-destructive intelligent nanoplatform for magnetic resonance/fluorescence dual-mode image-guided mitochondrial membrane potential damage (MMPD)/photodynamic (PDT)/photothermal (PTT)/immunotherapy for breast cancer treatment with external near infrared (NIR) light irradiation. To do so, we construct multifunctional monolayer-layered double hydroxide (LDH) nanosheets (MICaP), co-loading indocyanine green (ICG) with ultrahigh loading content realized via electrostatic interactions, and calcium phosphate (Ca3(PO4)2) coating via biomineralization. Such a combined therapy design is featured by the outstanding biocompatibility and provokes immunogenic cell death (ICD) of tumors toward cancer immunotherapy. The active transport of excess Ca2+ released from pH-sensitive Ca3(PO4)2 can induce MMPD of tumor cells to minimize oxygen consumption in the tumor microenvironment (TME). The presence of ICG not only generates singlet oxygen (1O2) to induce apoptosis by photodynamic therapy (PDT) but also initiates tumor cell necrosis by photothermal therapy (PTT) under near-infrared (NIR) light radiation. Eventually, the immune response generated by MMPD/PDT/PTT greatly promotes a cytotoxic T lymphocyte (CTL) response that can limit tumor growth and metastasis. Both in vitro and in vivo studies indeed illustrate outstanding antitumor efficiency and outcomes. We anticipate that such precisely designed nanoformulations can contribute in a useful and advantageous way that is conducive to explore novel nanomedicines with notable values in antitumor therapy.

Starvation-assisted and photothermal-thriving combined chemo/chemodynamic cancer therapy with PT/MR bimodal imaging.

Chemodynamic therapy (CDT) reflects a novel reactive oxygen species (ROS)-related cancer therapeutic approach. However, CDT monotherapy is often limited by weak efficacy and insufficient endogenous H2O2. Herein, a multifunctional combined bioreactor (MnFe-LDH/MTX@GOx@Ta, MMGT) relying on MnFe-layered double hydroxide (MnFe-LDH) loaded with methotrexate (MTX) and coated with glucose oxidase (GOx)/tannin acid (Ta) is established for applications in H2O2 self-supply and photothermal enhanced chemo/chemodynamic combined therapy along with photothermal (PT) /magnetic resonance (MR) dual-modality imaging ability for cancer treatment. Once internalized into tumor cells, MMGT achieves starvation therapy by catalyzing the oxidation of glucose with GOx, accompanied by the regeneration of H2O2, enabling a Fenton-like reaction to accomplish GOx catalytic amplified CDT. Moreover, MMGT manifests significant tumor-killing ability through improved CDT performance with outstanding photothermal conversion efficiency (η = 52.2%) under 808 nm laser irradiation. In addition, the release of Mn2+ from MnFe-LDH in a solid tumor can significantly enhance T1-contrast MR imaging signals. Combined with MnFe-LDH-induced PT imaging under 808 nm laser irradiation, a dual-modality imaging directed theranostic nanoplatform has been developed. The present study provides a new strategy to design H2O2 self-supply and ROS evolving NIR light-absorption theranostic nanoagent for highly efficient and combined chemo/chemodynamic cancer treatment.

Assembled Morphology of Copper-Thiourea Coordination-Mediated Metallo-Supramolecular Polymers.

Metallo-supramolecular polymers represent a powerful platform to construct self-assembled morphologies. Copper-thiourea (Cu-TU) coordination interactions, though have been extensively studied in small molecular system, the role of TU motifs in synthetic polymers using metal-ligand coordination to afford supramolecular aggregation and their morphology are often overlooked. Herein, an amphiphilic random copolymer, poly(oligo(ethylene glycol) ethyl acrylate-r-acylthiourea) (P(OEGEA-r-ATU)), bearing pendant TU motifs behaving as the ligand to coordinate Cu, a design characterized by core-coordinated metallo-supramolecular polymer is rationally synthesized. Indeed, rod-like nano-objects are successfully generated via the self-assembly and coordination interaction between P(OEGEA-r-ATU) and Cu. The spatial distribution of TU moieties in polymer chain, along with their Cu chelating capability, featuring the interchain coordination interaction, is tightly related to metallo-supramolecular polymer organization. The specific Cu-TU coordination interactions enable the prompted robustness and stability of soft P(OEGEA-r-ATU), induce the polymer chain configuration, which eventually furnish efficient fabrication of rod-like nano-objects via straightforward nanoprecipitation procedure. These structural motifs of copper-coordinated, rod-like nano-objects from such metallo-supramolecular polymers endow the potential therapeutic properties, such as anti-inflammatory and antitumor effects.

Core-Coordinated Elliptic Polymer Nanoparticles Loading Copper(II) and Chlorambucil for Cooperative Chemodynamic/Chemotherapy.

Chemodynamic therapy (CDT) reflects an innovative cancer treatment modality; however, to enhance its relatively low therapeutic efficiency, rational combination with extra therapeutic modes is highly appreciated. Here, core-coordinated amphiphilic, elliptic polymer nanoparticles (Cu/CBL-POEGEA NPs) are constructed via the self-assembly of a glutathione (GSH)-responsive polymer-drug conjugate, bearing side-chain acylthiourea (ATU) motifs which behave as ligands capable of coordinating Cu(II), such a design is featured by combined chemo (CT)/CDT with dual GSH depletion collectively triggered by the Cu(II) reduction reaction and disulfide bond breakage. To do so, an amphiphilic random copolymer poly[oligo(ethylene glycol)ethyl acrylate-co-thiourea] [P(OEGEA-co-ATU)] is synthesized, followed by conjugation of chlorambucil (CBL) to ATU motifs linked via a disulfide bond, thus yielding the targeted P[OEGEA-co-(ATU-g-CBL)]. In such a system, hydrophilic POEGEA serves as the biocompatible section and ATU motifs coordinate Cu(II), resulting in core-coordinated elliptic Cu/CBL-POEGEA NPs. Benefitting from the GSH-induced reduction reaction, Cu(II) is converted into Cu(I) and subsequently react with endogenous H2O2 to create •OH, realizing GSH-depletion-promoted CDT. Additionally, the disulfide bond endows GSH-responsive CBL release and provokes further GSH decline, finally realizing combined CDT/CT toward enhancing antitumor outcomes, and in vitro as well as in vivo studies indeed reveal remarkable efficacy. Such a system can provide valuable advantages to create novel nanomedicines toward cascade antitumor therapy.

Modified hollow mesoporous silica nanoparticles as immune adjuvant-nanocarriers for photodynamically enhanced cancer immunotherapy.

Nanomedicine has demonstrated great potential in enhancing cancer immunotherapy. However, nanoparticle (NP)-based immunotherapy still has limitations in inducing effective antitumor responses and inhibiting tumor metastasis. Herein, polyethylenimine (PEI) hybrid thin shell hollow mesoporous silica NPs (THMSNs) were applied as adjuvant-nanocarriers and encapsulated with very small dose of photosensitizer chlorine e6 (Ce6) to realize the synergy of photodynamic therapy (PDT)/immunotherapy. Through PEI etching, the obtained Ce6@THMSNs exhibited enhanced cellular internalization and endosome/lysosome escape, which further improved the PDT efficacy of Ce6@THMSNs in destroying tumor cells. After PDT treatment, the released tumor-associated antigens with the help of THMSNs as adjuvants promoted dendritic cells maturation, which further boosted CD8+ cytotoxic T lymphocytes activation and triggered antitumor immune responses. The in vivo experiments demonstrated the significant potency of Ce6@THMSNs-based PDT in obliterating primary tumors and inducing persistent tumor-specific immune responses, thus preventing distant metastasis. Therefore, we offer a THMSNs-mediated and PDT-triggered nanotherapeutic system with immunogenic property, which can elicit robust antitumor immunity and is promising for future clinical development of immunotherapy.

Morphological Transformation and In Situ Polymerization of Caspase-3 Responsive Diacetylene-Containing Lipidated Peptide Amphiphile for Self-Amplified Cooperative Antitumor Therapy.

In order to artificially regulate cell behaviors, intracellular polymerization as an emerging chemical technique has attracted much attention. Yet, it is still a challenge to achieve effective intracellular polymerization to conquer tumors in the complex cellular environment. Herein, this work develops a tumor-targeting and caspase-3 responsive nanoparticle composed of a diacetylene-containing lipidated peptide amphiphile and mitochondria-targeting photosensitizer (C3), which undergoes nanoparticle-to-nanofiber transformation and efficient in situ polymerization triggered by photodynamic treatment and activation of caspase-3. The locational nanofibers on the mitochondria membranes lead to mitochondrial reactive oxygen species (mtROS) burst and self-amplified circulation, offering persistent high oxidative stress to induce cell apoptosis. This study provides a strategy for greatly enhanced antitumor therapeutic efficacy through mtROS burst and self-amplified circulation induced by intracellular transformation and in situ polymerization.

Hydrogen Bond-Mediated Supramolecular Polymeric Nanomedicine with pH/Light-Responsive Methotrexate Release and Synergistic Chemo-/Photothermal Therapy.

Complete cancer cure and healing are still difficult, owing to its complexity and heterogeneity. Integration of supramolecular forces, for example, hydrogen bonds (H-bonds), to anti-cancer nanomedicine affords new scaffolds for biomedical material decoration, featuring the advantages of dynamic property and easier processability. Here, we target the construction of H-bond-mediated supramolecular polymer micelles, loaded with a chemotherapeutic drug along with a photothermal agent for synergistic chemo-/photothermal therapies (CT/PTT). To do so, we design and synthesize an amphiphilic ABA-type triblock copolymer, bearing H-bonding moiety (barbiturate, Ba) within the middle hydrophobic B block. The presence of pendant Ba moieties within the hydrophobic core promotes the loading capability of methotrexate (MTX) and transportation stability, benefitting from the formation of specific Ba/MTX H-bonding interactions. IR780, a photothermal agent, concomitantly encapsulated via hydrophobic interactions, facilitates the development of a synergistic CT/PTT modalities, where MTX can be released on demand owing to the dissociation of Ba/MTX H-bonding interactions induced by elevated temperature. Such H-bonding nanomedicine possesses enhanced drug loading capacity and transport performance and can also trigger stimuli-responsive drug release in the tumor zone. We believe that H-bonded nanomedicines provide a fine toolbox that is conducive to attaining biomedical requirements with remarkable values in theranostics that are highly promising in clinical applications.

Skin optical clearing enabled by dissolving hyaluronic acid microneedle patches.

Optical imaging and phototherapy are of great significance in the detection, diagnosis, and therapy of diseases. Depth of light in the skin tissues in optical imaging and phototherapy can be significantly improved with the assistance of optical clearing technology by weakening the scattering from the refractive indexes inhomogeneity among skin constituents. However, the barrier of the stratum corneum restricts the penetration of optical clearing agents into deep tissues and limits the optical clearing effects. Herein, we develop an optical clearing strategy by using dissolving microneedle (MN) patches made of hyaluronic acid (HA), which can effortlessly and painlessly penetrate the stratum corneum to reach the epidermis and dermis. By using the HA MN patches, the transmittance of skin tissues is improved by about 12.13 %. We show that the HA MN patches enhance the clarity of blood vessels to realize naked-eyes observation. Moreover, a simulated subcutaneous tumor cells experiment also verifies that the optical clearing effects of the HA MN patch efficiently boost the efficiency of the photodynamic killing of tumor cells by 26.8 %. As a courageous attempt, this study provides a promising avenue to improve the optical clearing effects for further clinical application of optical imaging and phototherapy.

Microneedle Patches with O2 Propellant for Deeply and Fast Delivering Photosensitizers: Towards Improved Photodynamic Therapy.

Photodynamic therapy (PDT) is an emerging technique for treating tumors. Especially, topical administration of photosensitizers (PSs) is more favorable for superficial tumor treatments with low systematic phototoxicity. Yet, ineffective migration of PSs to targeted tumor tissues and rapid consumption of O2 during PDT greatly limit their effects. Herein, PS-loaded microneedle (MN) patches with O2 propellant for a deeper and faster transdermal delivery of PS and improved PDT by embedding sodium percarbonate (SPC) into dissolving poly(vinyl pyrrolidone) MNs are presented. It is shown that SPC in the MNs can react with surrounding fluid to generate gaseous oxygen bubbles, forming vigorous fluid flows and thus greatly enhancing PS of chlorin e6 (Ce6) penetration in both hydrogel models and skin tissues. Reactive oxygen species (ROS) in hypoxic breast cancer cells (4T1 cells) are greatly increased by rapid penetration of PS and relief of hypoxia in vitro, and Ce6-loaded SPC MNs show an excellent cell-killing effect. Moreover, lower tumor growth rate and tumor mass after a 20-d treatment in tumor-bearing mice model verify the improved PDT in gaseous oxygen-droved delivery of PS. This study demonstrates a facile yet effective route of MN delivery of PSs for improved PDT in hypoxic tumor treatment.

Electrostatically Controlled ex Situ and in Situ Polymerization of Diacetylene-Containing Peptide Amphiphiles in Living Cells.

Precise control of diacetylene-containing peptide amphiphile (DPA) based supramolecular architectures is important for their in cellulo polymerization behaviors and biomedical applications. Herein, we reported two DPAs (cationic PA-NH2 and zwitterionic PA-OH) with a similar molecular structure, which exhibited completely opposite polymerization behaviors in aqueous solution and living cells. Specifically, PA-NH2 was unpolymerizable in aqueous solution but underwent in cellulo polymerization to respond to the intracellular microenvironment. On the contrary, zwitterionic PA-OH was polymerized in solution, rather than inside living cells. Based on the results of cell viability and total internal reflection fluorescent microscopy measurement, PA-OH exhibited higher affinity with cell membranes and lower cytotoxicity than those of PA-NH2. Therefore, it is suggested that the in cellulo polymerization of PA-NH2 should be responsive for greater cytotoxicity, rather than the membrane affinity. This study provides an in-depth understanding of the role of charge properties in the polymerization behavior of DPAs and seeks their potential biomedical applications.

Advanced nanocarrier- and microneedle-based transdermal drug delivery strategies for skin diseases treatment.

Skin diseases are the fourth leading cause of nonfatal and chronic skin diseases, acting as a global burden and affecting the world economy. Skin diseases severely impact the patients' quality of life and have influenced their physical and mental state. Treatment of these skin disorders with conventional methods shows a lack of therapeutic efficacy, long treatment duration, recurrence of the condition, and systemic side effects due to improper drug delivery. However, these pitfalls can be overcome with the applications of advanced nanocarrier- and microneedle (MN)-based transdermal drug delivery strategies that provide efficient site-specific drug delivery at the target site. These advanced transdermal drug delivery strategies can be more effective than other drug administration routes by avoiding first-pass metabolism, enhancing the drug concentration in local skin lesions, and reducing systemic toxicity. Compared with traditional transdermal delivery methods, nanocarrier- or MN-based drug delivery systems are painless, noninvasive, or minimum-invasive and require no expensive equipment. More importantly, they can introduce more advanced functions, including increased skin penetration efficiency, controlled drug release rates, enhanced targeting abilities, and theranostic functions. Here, the emergence of versatile advanced transdermal drug delivery systems for the transdermal delivery of various drugs is reviewed, focusing on the design principles, advantages, and considerations of nanocarrier- and MN-based transdermal drug delivery strategies and their applications in treating diverse skin diseases, including psoriasis, dermatitis, melanoma, and other skin diseases. Moreover, the prospects and challenges of advanced transdermal delivery strategies for treating dermatological disorders are summarized.

Hydrogen-Bonds-Mediated Nanomedicine: Design, Synthesis, and Applications.

Among the various challenges in medicine, diagnosis, complete cure, and healing of cancers remain difficult given the heterogeneity and complexity of such a disease. Differing from conventional platforms with often unsatisfactory theranostic capabilities, the contribution of supramolecular interactions, such as hydrogen-bonds (H-bonds), to cancer nanotheranostics opens new perspectives for the design of biomedical materials, exhibiting remarkable properties and easier processability. Thanks to their dynamic characteristics, a feature generally observed for noncovalent interactions, H-bonding (macro)molecules can be used as supramolecular motifs for yielding drug- and diagnostic carriers that possess attractive features, arising from the combination of assembled nanoplatforms and the responsiveness of H-bonds. Thus, H-bonded nanomedicine provides a rich toolbox that is useful to fulfill biomedical needs with unique advantages in early-stage diagnosis and therapy, demonstrating the promising potential in clinical translations and applications. Here the design and synthetic routes toward H-bonded nanomedicines, focus on the growing understanding of the structure-function relationship for efficient cancer treatment are summarized. A guidance for designing new H-bonded intelligent theranostic agents is proposed, to inspire more successful explorations of cancer nanotheranostics and finally to promote potential clinical translations.