Compound Capecitabine Colon-Targeted Microparticle Prepared by Coaxial Electrospray for Treatment of Colon Tumors.

To improve the antitumor effect of combined capecitabine (CAP) and osimertinib (OSI) therapy and quickly and efficiently reduce tumor volumes for preoperative chemotherapy, we designed a compound CAP colon-targeted microparticle (COPMP) prepared by coaxial electrospray. COPMP is a core-shell microparticle composed of a Eudragit S100 outer layer and a CAP/OSI-loaded PLGA core. In this study, we characterized its size distribution, drug loading (DL), encapsulation efficiency (EE), differential scanning calorimetry (DSC), Fourier transform infrared spectra (FTIR), in vitro release, formula ratio, cellular growth inhibition, and in vivo antitumor efficacy. COPMP is of spherical appearance with a size of 1.87 ± 0.23 µm. The DLs of CAP and OSI are 4.93% and 4.95%, respectively. The DSC showed that the phase state of CAP and OSI changed after encapsulation. The FTIR results indicated good compatibility between the drug and excipients. The release curve showed that CAP and OSI were released in a certain ratio. They were barely released prior to 2 h (pH 1.0), less than 50% was released between 3 and 5 h (pH 6.8), and sustained release of up to 80% occurred between 6 and 48 h (pH 7.4). CAP and OSI demonstrated a synergistic effect on HCT-116 cells. In a colon tumor model, the tumor inhibition rate after oral administration of COPMP reached 94% within one week. All the data suggested that COPMP promotes the sustained release of CAP and OSI in the colon, which provides a preoperative chemotherapy scheme for the treatment of colon cancer.

Sequential Release of Paclitaxel and Imatinib from Core-Shell Microparticles Prepared by Coaxial Electrospray for Vaginal Therapy of Cervical Cancer.

To optimize the anti-tumor efficacy of combination therapy with paclitaxel (PTX) and imatinib (IMN), we used coaxial electrospray to prepare sequential-release core-shell microparticles composed of a PTX-loaded sodium hyaluronate outer layer and an IMN-loaded PLGA core. The morphology, size distribution, drug loading, differential scanning calorimetry (DSC), Fourier transform infrared spectra (FTIR), in vitro release, PLGA degradation, cellular growth inhibition, in vivo vaginal retention, anti-tumor efficacy, and local irritation in a murine orthotopic cervicovaginal tumor model after vaginal administration were characterized. The results show that such core-shell microparticles were of spherical appearance, with an average size of 14.65 µm and a significant drug-loading ratio (2.36% for PTX, 19.5% for IMN, w/w), which might benefit cytotoxicity against cervical-cancer-related TC-1 cells. The DSC curves indicate changes in the phase state of PTX and IMN after encapsulation in microparticles. The FTIR spectra show that drug and excipients are compatible with each other. The release profiles show sequential characteristics in that PTX was almost completely released in 1 h and IMN was continuously released for 7 days. These core-shell microparticles showed synergistic inhibition in the growth of TC-1 cells. Such microparticles exhibited prolonged intravaginal residence, a >90% tumor inhibitory rate, and minimal mucosal irritation after intravaginal administration. All results suggest that such microparticles potentially provide a non-invasive local chemotherapeutic delivery system for the treatment of cervical cancer by the sequential release of PTX and IMN.

Synergistic Antitumor Effects on Drug-Resistant Breast Cancer of Paclitaxel/Lapatinib Composite Nanocrystals.

Drug resistance presents serious difficulties for cancer treatment. A combination of paclitaxel (PTX) and lapatinib (LAPA) shows potentials in multiple drug resistant cancers in the clinic, but it is almost impossible to deliver these two drugs to the tumor at the same time with the best proportion by simple co-administration of the respective current formualtions for their different pharmacokinetic profiles. Here composite nanocrystals of PTX and LAPA (cNC) were designed with a ratio of 2:1 (w/w), which was their intracellular ratio at the best synergistic efficacy on a drug-resistant cancer cell line (MCF-7/ADR). Such cNC were prepared using a bottom-up method to achieve a nearly spherical appearance and a narrow size distribution of 95.1 ± 2.1 nm. For nanocrystal stabilization, Polyethylene glycol (PEG) coating was introduced into the cNC via polydopamine (PDA) coating in order to get a PEGylated composite nanocrystal (cNC@PDA-PEG) with nanoscale size (170.5 ± 1.4 nm), considerable drug loading (PTX: 21.33 ± 1.48%, LAPA: 10.95 ± 1.24%) and good stability for at least 4 days in plasma-containing buffers. Differential scanning calorimeter (DSC) and XRD data both indicated the different crystalline states of the cNC as well as the cNC@PDA-PEG in comparison with bulk drugs. In vitro release data showed that PTX and LAPA were gradually and completely released from cNC@PDA-PEG in 3 days, while drug release from bulk drugs or cNC was only 30%. cNC@PDA-PEG also showed negligible hemolysis in vitro. Cellular uptake experiments in the MCF-7/ADR cell line showed that the nanocrystals entered the cells in a complete form through endocytosis and then released the drug in the cell. cNC@PDA-PEG inhibits the growth of this drug-resistant cell more effectively than the unmodified version (cNC). In summary, PEGylated PTX and LAPA composite nanocrystals showed the potential for treament of drug-resistant tumors by simultaneously delivering two drugs to tumor cells with the best proportion.

Correction to: CCR5 editing by Staphylococcus aureus Cas9 in human primary CD4+ T cells and hematopoietic stem/progenitor cells promotes HIV-1 resistance and CD4+ T cell enrichment in humanized mice.

Following publication of their article [1], the authors realized that they inadvertently omitted the contribution of Dr. Li Wu (Ohio State University) who commented on the manuscript at the early stage of the manuscript preparation and provided one plasmid related to this work.

CCR5 editing by Staphylococcus aureus Cas9 in human primary CD4+ T cells and hematopoietic stem/progenitor cells promotes HIV-1 resistance and CD4+ T cell enrichment in humanized mice.

BACKGROUND: The chemokine receptor CCR5, which belongs to the superfamily of G protein-coupled receptors, is the major co-receptor for HIV-1 entry. Individuals with a homozygous CCR5Δ32 mutation have a long lasting and increased resistance to HIV-1 infection. Therefore, CCR5 represents an optimal target for HIV-1/AIDS gene therapy. The CRISPR/Cas9 system has been developed as one of the most efficacious gene editing tools in mammalian cells and the small-sized version from Staphylococcus aureus (SaCas9) has an advantage of easier delivery compared to the most commonly used version from Streptococcus pyogenes Cas9 (SpCas9). RESULTS: Here, we demonstrated that CCR5 could be specifically and efficiently edited by CRISPR/SaCas9 together with two sgRNAs, which were identified through a screening of 13 sgRNAs. Disruption of CCR5 expression by lentiviral vector-mediated CRISPR/SaCas9 led to increased resistance against HIV-1 infection in human primary CD4+ T cells. Moreover, humanized mice engrafted with CCR5-disrupted CD4+ T cells showed selective survival and enrichment when challenged with CCR5 (R5)-tropic HIV-1 in comparison to mock-treated CD4+ T cells. We also observed CCR5 could be targeted by CRISPR/SaCas9 in human CD34+ hematopoietic stem/progenitor cells without obvious differentiation deficiencies. CONCLUSIONS: This work provides an alternative approach to disrupt human CCR5 by CRISPR/SaCas9 for a potential gene therapy strategy against HIV-1/AIDS.

Genome modification of CXCR4 by Staphylococcus aureus Cas9 renders cells resistance to HIV-1 infection.

BACKGROUND: The CRISPR/Cas9 system has been widely used for genome editing in mammalian cells. CXCR4 is a co-receptor for human immunodeficiency virus type 1 (HIV-1) entry, and loss of CXCR4 function can protect cells from CXCR4 (X4)-tropic HIV-1 infection, making CXCR4 an important target for HIV-1 gene therapy. However, the large size of the CRISPR/SpCas9 system presents an obstacle to its efficient delivery into primary CD4+ T cells. Recently, a small Staphylococcus aureus Cas9 (SaCas9) has been developed as a genome editing tool can address this question. Therefore, it provides a promising strategy for HIV-1 gene therapy if it is used to target CXCR4. RESULTS: Here, we employed a short version of Cas9 from Staphylococcus aureus (SaCas9) for targeting CXCR4. We demonstrated that transduction of lenti-virus expressing SaCas9 and selected single-guided RNAs of CXCR4 in human CD4+ T cell lines efficiently induced the editing of the CXCR4 gene, making these cell lines resistant to X4-tropic HIV-1 infection. Moreover, we efficiently transduced primary human CD4+ T cells using adeno-associated virus-delivered CRISPR/SaCas9 and disrupted CXCR4 expression. We also showed that CXCR4-edited primary CD4+ T cells proliferated normally and were resistant to HIV-1 infection. CONCLUSIONS: Our study provides a basis for possible application of CXCR4-targeted genome editing by CRISPR/SaCas9 in HIV-1 gene therapy.

Hepatitis B e antigen and its precursors promote the progress of hepatocellular carcinoma by interacting with NUMB and decreasing p53 activity.

UNLABELLED: Hepatitis B viral infection is one of the leading causes of hepatocellular carcinoma (HCC) worldwide. Although several viral factors have been identified that may increase the risk for HCC development, the molecular mechanisms leading to the transformation of normal hepatocytes into cancer cells remain elusive. In this study, we demonstrated that the intracellular hepatitis B e antigen (HBeAg) and its precore precursors, but not their homologous core protein, could associate with NUMB and thereby impair the stability and transcriptional activity of tumor suppressor p53. HBeAg and its precursors could disrupt p53-NUMB and HDM2-NUMB interactions and tricomplex p53-HDM2-NUMB formation, inhibit the acetylation and translocation of p53 from cytosol to the nucleus, promote HDM2-mediated ubiquitination and degradation of p53, and suppress p53-dependent apoptosis. A xenograft tumorigenicity assay showed that expression of HBeAg and its precursors promoted carcinogenesis in a mouse model. Immunohistochemical analysis of the bioptic liver samples of HCC patients revealed that HBeAg positivity was associated with reduced transcriptional activity of p53. Taken together, the results suggest a role of intracellular HBeAg and its precursors in HCC development. CONCLUSION: HBeAg and its precursors promote HDM2-mediated degradation and impair transcriptional activity of p53 by interacting with NUMB, consequently contributing to HCC development. (Hepatology 2016;64:390-404).

Co-administration of tLyp-1 with polymeric paclitaxel conjugates: Enhanced intratumoral accumulation and anti-tumor efficacy.

BACKGROUND: It has been previously demonstrated that conjugation of paclitaxel to a linear poly(l-γ-glutamylglutamine) backbone can enhance water solubility of paclitaxel. However, intratumoral penetration of the nanoscale poly(l-γ-glutamylglutamine)-paclitaxel conjugate (PGG-PTX) was still limited due to dysfunctional tumor blood vessels as well as high interstitial pressure in the tumor microenvironment. PURPOSE: The objective of the present research was to investigate the feasibility of co-administration of a tumor penetration enhancing peptide tLyp-1 for improving intratumoral accumulation and consequent anti-tumor efficacy of PGG-PTX. METHODS: The influence of co-administration of tLyP-1 with PGG-PTX on intratumoral accumulation (via HPLC-MS/MS) and anti-tumor efficacy (by monitoring the change in the tumor volume) was investigated using a breast cancer (4T1) tumor-bearing mouse model. In addition, the systemic toxicity of co-administration of tLyP-1 with PGG-PTX was assessed by monitoring the change in the animal body weight. RESULTS: It was observed that co-administration of tLyP-1 with PGG-PTX dramatically improved PGG-PTX accumulation in the tumors, resulting in improved inhibition efficiency against tumor growth. Moreover, co-administration of tLyP-1 with PGG-PTX did not change the systemic toxicity profile of PGG-PTX. CONCLUSION: Co-administration of tLyp-1 may be a promising strategy for improving the passive tumortargeting performance of polymeric drug conjugates.

A novel electrospun nanofiber system with PEGylated paclitaxel nanocrystals enhancing the transmucus permeability and in situ retention for an efficient cervicovaginal cancer therapy.

Overcoming the vaginal barrier to achieve sufficient drug penetration and retention is a huge obstacle for drug delivery in chemotherapeutics for cervical cancer. In this study, we investigate the feasibility of a novel composite nanocrystal/nanofiber system for improving the transmucus penetration and, thus, enhancing retention and drug delivery to the lesion of a cervicovaginal tumor. Herein, paclitaxel (PTX) was sequentially formulated in the form of nanocrystals, coated with polydopamine (PDA), and modified with PEG. The nanocrystals (NCs@PDA-PEG) were creatively fabricated to create a composite nanofibrous membrane (NCs@PDA-PEG NFs) by using an electrospinning technique. The morphology, size distribution, drug loading, encapsulation efficiency, X-ray powder diffraction (XRD), Fourier transform infrared (FTIR) spectra, in vitro release, in vivo vaginal retention, apoptosis index, anti-tumor efficacy in a murine cervicovaginal tumor model, and local irritation were characterized. The NCs@PDA-PEG were formulated in a cube-like shape with an average size of 385.6 ± 35.47 nm; they were dispersed in electrospun nanofibers, and the drug loading was 7.94 %. The XRD curves indicated that the phase state of PTX changed after the creation of the nanocrystals. The FTIR spectra showed that the drug and the excipients were compatible with each other. In vitro delivery showed that the dissolution of PTX in the electrospun nanofibers was significantly faster than that when using bulk PTX. Compared with the PTX NC NFs, the NC@PDA-PEG NFs exhibited prolonged vaginal residence, superior transmucus penetration, minimal mucosal irritation, and significant tumor inhibition efficacy after the intravaginal administration of the NFs in tumor-bearing mice. In conclusion, by acting as novel pharmaceutical repositories, NCs@PDA-PEG NFs can be promising candidates for non-invasive local treatment, leading to efficient tumor inhibition in cervicovaginal cancer.

Novel erythrocyte-shaped electrosprayed nanoparticles for co-delivery of paclitaxel and osimertinib: Preparation, characterization, and evaluation.

In this work, novel erythrocyte-shaped electrosprayed nanoparticles (EENPs) were designed and constructed by tri-axial electrospraying technique with PEG as the outer layer, PLGA as the middle drugs (paclitaxel [PTX] and osimertinib [OSI]) carrier layer and air as the inner layer. The prepared EENP were characterized and evaluated based on their spectral and morphological attributes. After the PTX/OSI ratio and process optimization, the EENP has inspiring features, including nanoscale size, erythrocyte morphology with a concave disk shape, and satisfactory drug loading (DL) and encapsulation efficiency (EE). In vitro drug release showed that PTX and OSI in the formulation were released in the same ratio, and the cumulative release percentage at 24 h was close to 80 %. Furthermore, the TGIR in the EENP formulation group exceeded 90 %, approximately 3.8-fold higher than that in the free drug group. In summary, we developed an erythrocyte three-core-shell nanoparticle for the co-delivery of PTX and OSI, providing a potential chemotherapeutic delivery system for the treatment of breast cancer.

Erratum: Author correction to 'Amino-functionalized poloxamer 407 with both mucoadhesive and thermosensitive properties: Preparation, characterization and application in vaginal drug delivery system' [Acta Pharm Sin B 7 (2017) 593-602].

[This corrects the article DOI: 10.1016/j.apsb.2017.03.002.].

Electrospun fibers with blank surface and inner drug gradient for improving sustained release.

New engineering methods and advanced strategies are highly desired for creating novel drug sustained release nanomaterials. In this study, a trilayer concentric spinneret was explored to implement several multifluid electrospinning processes. A trilayer core-shell nanofiber was successfully fabricated, which comprise a drug-free polymeric coating and an inner drug gradient distribution, and then compared with bilayer core-shell and monolithic medicated nanofibers. All the electrospun nanofibers similarly consisted of two components (guest drug acetaminophen and host polymer cellulose acetate) and presented a linear morphology. Due to the secondary interactions within nanofibers, loaded drug with amorphous state was detected, as demonstrated by SEM, DSC, XRD, and FTIR determinations. In vitro and in vivo gavage treatments to rats tests were carried out, the trilayer nanofiber with an elaborate structure design were demonstrated to provide better drug sustained release profile than the bilayer core-shell nanofibers in term of initial burst release, later tail-off release and long sustained release time period. The synergistic mechanism for improving the drug sustained release behaviors is disclosed. By breaking the traditional concepts about the implementation of multifluid electrospinning and the strategy of combining surface properties and inner structural characteristics, the present protocols open a new way for developing material processing methods and generating novel functional nanomaterials.

Correction: Ci et al. Enhanced Delivery of Imatinib into Vaginal Mucosa via a New Positively Charged Nanocrystal-Loaded in Situ Hydrogel Formulation for Treatment of Cervical Cancer. Pharmaceutics 2019, 11, 15.

In the original publication [...].

Sorafenib Nanomicelles Effectively Shrink Tumors by Vaginal Administration for Preoperative Chemotherapy of Cervical Cancer.

To investigate the potential of sorafenib (SF) in preoperative chemotherapy for cervical cancer to reduce tumor volume, sorafenib micelles (SF micelles) with good stability and high drug loading were designed. SF micelles were prepared by film hydration followed by the ultrasonic method. The results showed that the SF micelles were spherical with an average particle size of 67.18 ± 0.66 nm (PDI 0.17 ± 0.01), a considerable drug loading of 15.9 ± 0.46% (w/w%) and satisfactory stability in buffers containing plasma or not for at least 2 days. In vitro release showed that SF was gradually released from SF micelles and almost completely released on the third day. The results of in vitro cellular intake, cytotoxicity and proliferation of cervical cancer cell TC-1 showed that SF micelles were superior to sorafenib (Free SF). For intravaginal administration, SF micelles were dispersed in HPMC (SF micelles/HPMC), showed good viscosity sustained-release profiles in vitro and exhibited extended residence in intravaginal in vivo. Compared with SF micelles dispersed in N.S. (SF micelles/N.S.), SF micelles/HPMC significantly reduced tumor size with a tumor weight inhibition rate of 73%. The results suggested that SF micelles had good potential for preoperative tumor shrinkage and improving the quality life of patients.

Coaxial Electrospun PLLA Fibers Modified with Water-Soluble Materials for Oligodendrocyte Myelination.

Myelin sheaths are essential in maintaining the integrity of axons. Development of the platform for in vitro myelination would be especially useful for demyelinating disease modeling and drug screening. In this study, a fiber scaffold with a core-shell structure was prepared in one step by the coaxial electrospinning method. A high-molecular-weight polymer poly-L-lactic acid (PLLA) was used as the core, while the shell was a natural polymer material such as hyaluronic acid (HA), sodium alginate (SA), or chitosan (CS). The morphology, differential scanning calorimetry (DSC), Fourier transform infrared spectra (FTIR), contact angle, viability assay, and in vitro myelination by oligodendrocytes were characterized. The results showed that such fibers are bead-free and continuous, with an average size from 294 ± 53 to 390 ± 54 nm. The DSC and FTIR curves indicated no changes in the phase state of coaxial brackets. Hyaluronic acid/PLLA coaxial fibers had the minimum contact angle (53.1° ± 0.24°). Myelin sheaths were wrapped around a coaxial electrospun scaffold modified with water-soluble materials after a 14-day incubation. All results suggest that such a scaffold prepared by coaxial electrospinning potentially provides a novel platform for oligodendrocyte myelination.

Enhanced mucosal penetration and efficient inhibition efficacy against cervical cancer of PEGylated docetaxel nanocrystals by TAT modification.

To investigate the potential of cell penetrating peptide (CPP) modification on nanomedicine for improving mucosal penetration and effective therapy of cervical cancer, docetaxel nanocrystals modified with trans-activator of transcription (TAT) peptide were designed for treatment of cervical cancer via vaginal administration. Docetaxel nanocrystals were coated by polymerization of dopamine to form polydopamine (PDA) coating which facilitated TAT modification and PEGylation for less mucus entrapment to get PEGylated nanocrystals modified with TAT (NC@PDA-PEG-TAT). Enhanced cellular drug uptake and cytotoxicity of NC@PDA-PEG-TAT was observed in cervical cancer-related TC-1 cells than that of PEGylated nanocrystals (NC@PDA-PEG). Intravaginally administered NC@PDA-PEG-TAT dispersed in poloxamer 407-based thermosensitive gel exhibited prolonged in vivo intravaginal retention, deeper mucosal penetration and more potent inhibition on the growth of murine orthotopic cervical cancer than NC@PDA-PEG, PDA-coated nanocrystals or unmodified nanocrystals. All data suggested the significance of CPP-modification on nanocrystals in the local treatment of vaginal mucosa-related diseases by vaginal administration.

Genome editing of CCR5 by AsCpf1 renders CD4+T cells resistance to HIV-1 infection.

BACKGROUND: The chemokine receptor CCR5 is one of the co-receptor of HIV-1 infection. People with homozygous CCR5Δ32 deletion resist HIV-1 infection, which makes the CCR5 an important target for HIV-1 gene therapy. Although the CRISPR/Cas9 has ever been used for HIV-1 study, the newly developed CRISPR/AsCpf1 has never been utilized in HIV-1 co-receptor disruption. The CRISPR/Cpf1 system shows many advantages over CRISPR/Cas9, such as lower off-target, small size of nuclease, easy sgRNA design for multiplex gene editing, etc. Therefore, the CRISPR/Cpf1 mediated gene editing will confer a more specific and safe strategy in HIV-1 co-receptor disruption. RESULTS: Here, we demonstrated that CRISPR/AsCpf1 could ablate the main co-receptor of HIV-1 infection-CCR5 efficiently with two screened sgRNAs via different delivery strategies (lentivirus, adenovirus). The edited cells resisted R5-tropic HIV-1 infection but not X4-tropic HIV-1 infection compared with the control group in different cell types of HIV-1 study (TZM.bl, SupT1-R5, Primary CD4+T cells). Meanwhile, the edited cells exhibited selective advantage over unedited cells while under the pressure of R5-tropic HIV-1. Furthermore, we clarified that the predicted off-target sites of selected sgRNAs were very limited, which is much less than regular using sgRNAs for CRISPR/Cas9, and no evident off-target was observed. We also showed that the disruption of CCR5 by CRISPR/AsCpf1 took no effects on cell proliferation and apoptosis. CONCLUSIONS: Our study provides a basis for a possible application of CCR5-targeting gene editing by CRISPR/AsCpf1 with high specific sgRNAs against HIV-1 infection.

The key role of straight fluid jet in predicting the drug dissolution from electrospun nanofibers.

In nanopharmaceutics, a robust manipulation of the preparation process and an accurate prediction of the final product size are very important for developing novel nano drug delivery systems. In the present study, for the first time, a process parameter, i.e. the length of the straight fluid jet, L, is correlated with an experimental parameter, i.e. fluid flow rate, F; a nanofiber property, i.e. diameter, D; and the corresponding drug-sustained release profile. Using a mixed solution consisting of 15% (w/v) polyacrylonitrile and 3% (w/v) ketoprofen in acetone and N,N-dimethylformamide (2:8, v:v) as a spinnable working fluid, a series of medicated nanofibers were prepared under variable F and were characterized. The analysis results disclosed the quantitative relationships among different types of parameters. The process parameter L exhibited a better linear relationship with the nanofibers' diameter (D) than the processing parameter F. These results give a hint that process parameters can be exploited as useful tools for accurately predicting and tailoring the resultant nanofibers' D, and in turn their functional performances. The strategy proposed here presents a new approach to investigate the electrohydrodynamic process and manipulate the functions of nanoproducts through process-property-performance relationships.

RGD-modified PEGylated paclitaxel nanocrystals with enhanced stability and tumor-targeting capability.

Nanocrystals has been constructed for insoluble drugs as a novel type of nanoscale drug delivery systems with high drug loading. How to prepare nanocrystals with good stability and tumor targeting capability is still challenging. This study was to modify paclitaxel nanocrystals with polyethylene glycol (PEG) for stabilization and RGD peptide for tumor targeting. Inspired by the structure of mussel's foot protein, polydopamine (PDA) was introduced to the drug delivery system for the modification of nanocrystals. Briefly, PDA was coated on the surface of nanocrystals to form a reaction platform for further PEGylation and RGD peptide conjugation. PEGylated nanocrystals with RGD peptide modification (NC@PDA-PEG-RGD) were prepared with near-spheroid shape, drug loading 45.12 ±â€¯1.81% and a hydrodynamic diameter 419.9 ±â€¯80.9 nm. The size of NC@PDA-PEG-RGD remained basically unchanged for at least 72 h in the presence of plasma while the size of unmodified nanocrystals (NC) increased and exceeded 1000 nm in 12 h. Cellular uptake and cellular growth inhibition experiments using the lung cancer cell line A549 demonstrated the superiority of NC@PDA-PEG-RGD over NC or PEGylated nanocrystals without RGD modification (NC@PDA-PEG). In A549 model tumor bearing-mice, NC@PDA-PEG-RGD showed significantly higher intratumor accumulation and slower tumor growth than NC@PDA-PEG or free paclitaxel. In summary, our study suggested the superiority of RGDmodified PEGylated paclitaxel nanocrystals as a lung cancer-targeted delivery system and the potential of PDA coating technique for targeting functionalization of nanocrystals.

Enhanced Delivery of Imatinib into Vaginal Mucosa via a New Positively Charged Nanocrystal-Loaded in Situ Hydrogel Formulation for Treatment of Cervical Cancer.

The present study was carried out to investigate the potential of cationic functionalization on imatinib nanocrystals to improve the mucoadhesiveness and, thus, delivery to the lesion of cervicovaginal tumors. Amino-group-functionalized imatinib nanocrystals (NC@PDA-NH2) were prepared with near-spheroid shape, nanoscale size distribution, positive zeta potential, and relatively high drug content with the aid of the polydopamine-coating technique. Efficient interaction between NC@PDA-NH2 and mucin was proven by mucin adsorption which was related to the positive zeta-potential value of NC@PDA-NH2 and the change in the size distribution on mixing of NC@PDA-NH2 and mucin. Cellular uptake, growth inhibition, and apoptosis induction in cervicovaginal cancer-related cells demonstrated the superiority of NC@PDA-NH2 over unmodified nanocrystals. For practical intravaginal administration, NC@PDA-NH2 was dispersed in Pluronic F127-based thermosensitive in situ hydrogel, which showed suitable gelation temperature and sustained-release profiles. In comparison with unmodified nanocrystals, NC@PDA-NH2 exhibited extended residence on ex vivo murine vaginal mucosa, prolonged in vivo intravaginal residence, and enhanced inhibition on the growth of murine orthotopic cervicovaginal model tumors indicated by smaller tumor size, longer median survival time, and more intratumor apoptosis with negligible mucosal toxicity. In conclusion, cationic functionalization endowed NC@PDA-NH2 significant mucoadhesiveness and, thus, good potential against cervicovaginal cancer via intravaginal administration.