Hypoxia Reversion by Low-Immunogenic Ultra-Acid-Sensitive Comicelles of Protein-Polymer Conjugates Sensitizes Tumors to Photodynamic Therapy.

Hypoxia is characteristic of the tumor microenvironment, which is correlated with resistance to photodynamic therapy (PDT), radiotherapy, chemotherapy, and immunotherapy. Catalase is potentially useful to catalyze the conversion of endogenous H2O2 to O2 for hypoxia reversion. However, the efficient delivery of catalase into the hypoxia regions of tumors is a huge challenge. Here, we report the self-assembly of ultra-acid-sensitive polymer conjugates of catalase and albumin into nanomicelles that are responsive to the acidic tumor microenvironment. The immunogenicity of catalase is mitigated by the presence of albumin, which reduces the cross-linking of catalase with B cell receptors, resulting in improved pharmacokinetics. The ultra acid sensitivity of the nanomicelles makes it possible to efficiently escape the lysosomal degradation after endocytosis and permeate into the interior of tumors to reverse hypoxia in vitro and in vivo. In mice bearing triple-negative breast cancer, the nanomicelles loaded with a photosensitizer effectively accumulate and penetrate into the whole tumors to generate a sufficient amount of O2 to reverse hypoxia, leading to enhanced efficacy of PDT without detectable side effects. These findings provide a general strategy of self-assembly to design low-immunogenic ultra-acid-sensitive comicelles of protein-polymer conjugates to reverse tumor hypoxia, which sensitizes tumors to PDT.

Spatiotemporally-Programmed Dual-Acid-Sensitive Nanoworms of Albumin-Poly(tertiary amine)-Doxorubicin Conjugates for Enhanced Cancer Chemotherapy.

Nanomedicines are potentially useful for targeted cancer chemotherapy; however, it is difficult to design nanomedicines with controllable structures and functions to overcome a series of biological and pathological barriers to efficiently kill cancer cells in vivo. Here, this work reports in situ growth of dual-acid-sensitive poly(tertiary amine)-doxorubicin conjugates from albumin to form dual-acid-sensitive albumin-poly(tertiary amine)-doxorubicin conjugates that self-assemble into nanospheres and nanoworms in a controlled manner. Both nanospheres and nanoworms rapidly dissociate into positively-charged unimers at pH < 6.9 and quickly releases the conjugated drug of doxorubicin at pH < 5.6, leading to enhanced penetration in tumor cell spheroids as well as improved uptake and cytotoxicity to tumor cells at pH < 6.9. Notably, nanoworms are less taken up by endothelial cells than nanospheres and doxorubicin, leading to improved pharmacokinetics. In a mouse model of triple negative breast cancer, nanoworms accumulate and penetrate into tumors more efficiently than nanospheres and doxorubicin, leading to enhanced tumor accumulation and penetration. As a result, nanoworms outperform nanospheres and doxorubicin in suppressing tumor growth and elongating the animal survival time, without observed side effects. These findings demonstrate that intelligent nanoworms with spatiotemporally programmed dual-acid-sensitive properties are promising as next-generation nanomedicines for targeted cancer chemotherapy.

Thermoresponsive Polypeptide Fused L-Asparaginase with Mitigated Immunogenicity and Enhanced Efficacy in Treating Hematologic Malignancies.

L-Asparaginase (ASP) is well-known for its excellent efficacy in treating hematological malignancies. Unfortunately, the intrinsic shortcomings of ASP, namely high immunogenicity, severe toxicity, short half-life, and poor stability, restrict its clinical usage. Poly(ethylene glycol) conjugation (PEGylation) of ASP is an effective strategy to address these issues, but it is not ideal in clinical applications due to complex chemical synthesis procedures, reduced ASP activity after conjugation, and pre-existing anti-PEG antibodies in humans. Herein, the authors genetically engineered an elastin-like polypeptide (ELP)-fused ASP (ASP-ELP), a core-shell structured tetramer predicted by AlphaFold2, to overcome the limitations of ASP and PEG-ASP. Notably, the unique thermosensitivity of ASP-ELP enables the in situ formation of a sustained-release depot post-injection with zero-order release kinetics over a long time. The in vitro and in vivo studies reveal that ASP-ELP possesses increased activity retention, improved stability, extended half-life, mitigated immunogenicity, reduced toxicity, and enhanced efficacy compared to ASP and PEG-ASP. Indeed, ASP-ELP treatment in leukemia or lymphoma mouse models of cell line-derived xenograft (CDX) shows potent anti-cancer effects with significantly prolonged survival. The findings also indicate that artificial intelligence (AI)-assisted genetic engineering is instructive in designing protein-polypeptide conjugates and may pave the way to develop next-generation biologics to enhance cancer treatment.

Active-targeting long-acting protein-glycopolymer conjugates for selective cancer therapy.

Non-fouling polymers are effective in improving the pharmacokinetics of therapeutic proteins, but short of biological functions for tumor targeting. In contrast, glycopolymers are biologically active, but usually have poor pharmacokinetics. To address this dilemma, herein we report in situ growth of glucose- and oligo(ethylene glycol)-containing copolymers at the C-terminal site of interferon alpha, an antitumor and antivirus biological drug, to generate C-terminal interferon alpha-glycopolymer conjugates with tunable glucose contents. The in vitro activity and in vivo circulatory half-life of these conjugates were found to decrease with the increase of glucose content, which can be ascribed to complement activation by the glycopolymers. Additionally, the cancer cell endocytosis of the conjugates was observed to maximize at a critical glucose content due to the tradeoff between complement activation and glucose transporter recognition by the glycopolymers. As a result, in mice bearing ovarian cancers with overexpressed glucose transporter 1, the conjugates with optimized glucose contents were identified to possess improved cancer-targeting ability, enhanced anticancer immunity and efficacy, and increased animal survival rate. These findings provided a promising strategy for screening protein-glycopolymer conjugates with optimized glucose contents for selective cancer therapy.

Hypoxia-Triggered Bioreduction of Poly(N-oxide)-Drug Conjugates Enhances Tumor Penetration and Antitumor Efficacy.

PEGylation prolongs the blood circulation time of drugs; however, it simultaneously reduces the tumor penetration of drugs due to the nonfouling function and bulky hydrodynamic volume of PEG, leading to unsatisfactory outcomes in the treatment of solid tumors. Herein, we report the in situ growth of a bioreducible polymer of poly(N-oxide) from an important protein drug of interferon alpha (IFN) to generate site-specific IFN-poly(N-oxide) conjugates with higher bioactivity than a clinically used PEGylated IFN of PEGASYS. An IFN-poly(N-oxide) conjugate is screened out to have a circulating half-life as long as 51 h, which is similar to that of PEGASYS but 96-fold greater than that of IFN. However, the conjugate greatly outperforms PEGASYS and IFN in tumor penetration and antitumor efficacy in mice bearing melanoma. This enhanced tumor penetration is ascribed to the adsorption-mediated transcytosis of the conjugate whose poly(N-oxide) is biologically reduced into poly(tertiary amine), under hypoxia, which can be further protonated in the acidic tumor microenvironment. These novel findings demonstrate that poly(N-oxide)s are not only long-circulating but also bioreducible under hypoxia and are of great promise as next-generation carriers to deliver drugs into the interior of solid tumors to enhance their antitumor efficacy.

Adsorption and photodegradation of reactive red 120 with nickel-iron-layered double hydroxide/biochar composites.

Layered double hydroxide (LDH) materials were widely applied for adsorption and photodegradation of pollutants for wastewater treatment. New efficient LDH materials with adsorption and photodegradation abilities will be promising candidates for pollutants removal. Hence, a series of NiFe-LDH/biochar (NiFe/BC) were fabricated by the coprecipitation method for synergistic adsorption and photodegradation anionic dyes of reactive red 120 (RR120). The removal experiment showed that the addition of an appropriate amount of biochar into NiFe-LDH enhanced the adsorption capacity and its photocatalytic ability. The optimized NiFe/BC2 composite can remove 88.5 % of RR120 under visible light by adsorption and photocatalysis, which was much better than NiFe-LDH (63.3 %) and biochar (2.6 %). The photodegradation kinetic constant of the NiFe/BC2 composite was 3.1 and 104.8 times that of NiFe-LDH and BC. In addition, active species capture experiments and electron spin resonance (ESR) tests revealed the removal mechanisms of NiFe/BC composites for RR120 removal. This work affords a feasible strategy for preparing LDH-based photocatalyst with excellent adsorption and photocatalytic performance for wastewater treatment.

Step scheme nickel-aluminium layered double hydroxides/biochar heterostructure photocatalyst for synergistic adsorption and photodegradation of tetracycline.

Improving the adsorption ability of layered double hydroxide (LDH) has been considered as a promising strategy to promote its photodegradation of aqueous pollutants. In this work, nickel-aluminium layered double hydroxides (NiAl-LDH)/biochar nanocomposites were prepared using a simple coprecipitation method, and then applied in synergistic adsorption-photodegradation of tetracycline (TC) in aqueous solutions. In addition, the governing TC removal mechanisms by the nanocomposites were revealed. All NiAl-LDH/BC samples showed strong adsorption and photodegradation of TC. The Langmuir maximum TC adsorption capacity of optimized NiAl-LDH/BC-0.5 reached 124.2 mg/g, which was much better than that of NiAl-LDH (56.1 mg/g) and biochar (11.1 mg/g). Besides, TC photodegradation rate constant of NiAl/BC-0.5 was 3.6 and 4.4 times of that of NiAl-LDH and BC, respectively. The NiAl/BC-0.5 exhibited the maximum TC adsorption-photodegradation efficiency 94.4% in 90 min compared to NiAl-LDH (73.7%) and BC (48.2%). The rate constant of modified Elovich kinetic model for synergistic adsorption and photodegradation on NiAl/BC-0.5 (9.477 min-1) was the highest among the composites. The NiAl-LDH/BC had significantly larger BET surface areas than NiAl-LDH and BC. The step scheme (S-scheme) heterostructures were constructed on the interface of BC and NiAl-LDH in nanocomposites, which facilitated the transfer of photo-induced charges. This work demonstrates that combination of NiAl-LDH and biochar can create synergy for TC adsorption-photodegradation, which is a promising and green strategy.