Intracellular Antitumor Drug Delivery Research Articles

Phosphatidylcholine-Engineered Exosomes for Enhanced Tumor Cell Uptake and Intracellular Antitumor Drug Delivery.

Exosomes derived from non-tumor cells hold great potential as drug delivery vehicles because of their good biosafety and natural transference of bioactive cargo between cells. However, compared to tumor-derived exosomes, efficient delivery is limited by their weak interactions with tumor cells. It is essential to engineer exosomes that improve tumor cellular internalization efficiency. A simple and effective strategy to enhance tumor cell uptake by engineering the exosome membrane lipids can be established by drawing on the role of lipids in tumor exosomes interacting with tumor cells. Amphiphilic phosphatidylcholine (PC) molecules are inserted into the membrane lipid layer of reticulocyte-derived exosomes (Exos) by simple incubation to construct PC-engineered exosomes (PC-Exos). It is demonstrated that PC-Exos showed significantly enhanced tumor cell internalization and uptake rate compared to native Exos, up to a twofold increase. After therapeutic agent loading, PC-Exos remarkably promotes intracellular drug or RNA accumulation in cancer cells, thus showing enhanced in vitro anti-tumor activity. This work demonstrates the crucial role of engineering exosomal lipids in modulating cancer cellular uptake, which may shed light on the design of high-efficiency exosome-based drug delivery carriers.

Reduction-Responsive Polypeptide Micelles for Intracellular Delivery of Antineoplastic Agent.

Reduction-responsive methoxy poly(ethylene glycol)-block-poly(S-tert-butylmercapto-L-cysteine) copolymers (i.e., mPEG113-b-PBMLC4 and mPEG113-b-PBMLC9) were facilely synthesized through primary amino-initiated ring-opening polymerization (ROP) of disulfide-containing N-carboxyanhydride monomer. The reduction-responsive block copolymers were then investigated for intracellular delivery of antitumor drug after forming smart micelles in vitro and in vivo. The micelles were denoted as P4M and P9M, respectively. Doxorubicin (DOX) was selected as a model chemotherapeutic agent, which was loaded into micelles via hydrophobic interaction. The drug loading efficiency (DLE) were detected to be 55.4 and 61.7 wt % for P4M and P9M, respectively. The loaded micelles, referred as P4M/DOX and P9M/DOX, exhibited spherical morphologies with hydrodynamic radii of 92.3 ± 2.3 and 80.2 ± 2.8 nm, respectively. Compared to P4M/DOX, P9M/DOX with a smaller size exhibited upregulated cell endocytosis and higher cytotoxicity to human breast cancer MCF-7 cells. Furthermore, the loading micelles, especially P9M/DOX, demonstrated improved antitumor efficacy toward an MCF-7 breast tumor-bearing BALB/c nude mouse model compared with free doxorubicin hydrochloride (DOX·HCl). This was also confirmed by the histopathological and immunohistochemical results. The above results demonstrated that the facially prepared smart polypeptide micelles exhibited a potent prospect in intracellular drug delivery in vitro and in vivo.

Facile preparation of bioreducible polymeric nanocarrier for the reduction-triggered intracellular delivery of anti-tumor drug

Facile preparation of bioreducible polymeric nanocarrier for the reduction-triggered intracellular delivery of anti-tumor drug

Intracellularly Swollen Polypeptide Nanogel Assists Hepatoma Chemotherapy.

Nowadays, chemotherapy is one of the principal modes of treatment for tumor patients. However, the traditional formulations of small molecule drugs show short circulation time, low tumor selectivity, and high toxicity to normal tissues. To address these problems, a facilely prepared, and pH and reduction dual-responsive polypeptide nanogel was prepared for selectively intracellular delivery of chemotherapy drug. As a model drug, doxorubicin (DOX) was loaded into the nanogel through a sequential dispersion and dialysis technique, resulting in a high drug loading efficiency (DLE) of 96.7 wt.%. The loading nanogel, defined as NG/DOX, exhibited a uniform spherical morphology with a mean hydrodynamic radius of 58.8 nm, pH and reduction dual-triggered DOX release, efficient cell uptake, and cell proliferation inhibition in vitro. Moreover, NG/DOX exhibited improved antitumor efficacy toward H22 hepatoma-bearing BALB/c mouse model compared with free DOX·HCl. Histopathological and immunohistochemical analyses were implemented to further confirm the tumor suppression activity of NG/DOX. Furthermore, the variations of body weight, histopathological morphology, bone marrow cell micronucleus rate, and white blood cell count verified that NG/DOX showed excellent safety in vivo. With these excellent properties in vitro and in vivo, the pH and reduction dual-responsive polypeptide nanogel exhibits great potential for on-demand intracellular delivery of antitumor drug, and holds good prospect for future clinical application.

Reduction-responsive polypeptide nanogel delivers antitumor drug for improved efficacy and safety

Chemotherapy plays an irreplaceable role in the treatment of various malignant tumors today. The traditional drug formulations lack of selectivity, cause serious damage to normal tissues, and can’t achieve a desired therapeutic efficacy. For this situation, a facilely prepared reduction-responsive polypeptide nanogel was employed for targeting intracellular delivery of antitumor drug in this study. Doxorubicin (DOX) as a model drug was loaded into nanogel through a sequential dispersion and dialysis approach with a drug loading efficiency (DLE) of 56.8wt.%. The loading nanogel, i.e., NG/DOX, exhibited a medium hydrodynamic radius of 56.1±3.5nm, glutathione-accelerated DOX release, and efficient cellular uptake and proliferation inhibition. Moreover, NG/DOX exhibited upregulated intratumoral accumulation and improved antitumor efficacy toward HepG2 hepatoma-xenografted BALB/c nude mouse model compared with free drug. The enhanced tumor suppression of NG/DOX was further confirmed by the histopathological and immunohistochemical analyses. Furthermore, the excellent in vivo security of NG/DOX was systematically demonstrated by the variation detection of body weight, histopathological assay, levels of bone marrow cell micronucleus rate (BMMR) and white blood cells (WBCs), and detection of clinical parameters in corresponding organs and serum. With controllable large-scale preparation and fascinating properties in vitro and in vivo, the reduction-responsive polypeptide nanogel is revealed to exhibit great potential for on-demand intracellular delivery of antitumor drugs, and shows a good prospect for clinical chemotherapy. Statement of SignificanceThe traditional drug formulations lack of selectivity, cause serious damage to normal tissues, and can’t achieve a desired therapeutic effect. For this situation, a facilely prepared reduction-responsive polypeptide nanogel is employed for targeting intracellular delivery of antitumor drug in this study. The laden nanogel keeps structural integrity and less drug release in the circulatory system after intravenous injection, releases the payload triggered by the intracellular high concentration of GSH, and exhibits the excellent tumor inhibition and security in vivo. Furthermore, the other hydrophobic antitumor drugs can also be on-demand delivered by the smart nanogel. All of the above advantages confirm the bright prospect of reduction-responsive nanogel on the road of malignancy chemotherapy.

Plasmonic Nanobubbles Rapidly Detect and Destroy Drug-Resistant Tumors

The resistance of residual cancer cells after oncological resection to adjuvant chemoradiotherapies results in both high recurrence rates and high non-specific tissue toxicity, thus preventing the successful treatment of such cancers as head and neck squamous cell carcinoma (HNSCC). The patients' survival rate and quality of life therefore depend upon the efficacy, selectivity and low non-specific toxicity of the adjuvant treatment. We report a novel, theranostic in vivo technology that unites both the acoustic diagnostics and guided intracellular delivery of anti-tumor drug (liposome-encapsulated doxorubicin, Doxil) in one rapid process, namely a pulsed laser-activated plasmonic nanobubble (PNB). HNSCC-bearing mice were treated with gold nanoparticle conjugates, Doxil, and single near-infrared laser pulses of low energy. Tumor-specific clusters of gold nanoparticles (solid gold spheres) converted the optical pulses into localized PNBs. The acoustic signals of the PNB detected the tumor with high specificity and sensitivity. The mechanical impact of the PNB, co-localized with Doxil liposomes, selectively ejected the drug into the cytoplasm of cancer cells. Cancer cell-specific generation of PNBs and their intracellular co-localization with Doxil improved the in vivo therapeutic efficacy from 5-7% for administration of only Doxil or PNBs alone to 90% thus demonstrating the synergistic therapeutic effect of the PNB-based intracellular drug release. This mechanism also reduced the non-specific toxicity of Doxil below a detectable level and the treatment time to less than one minute. Thus PNBs combine highly sensitive diagnosis, overcome drug resistance and minimize non-specific toxicity in a single rapid theranostic procedure for intra-operative treatment.