Current developments in drug delivery with thermosensitive liposomes.

Thermosensitive liposomes (TSLs) have been an important research area in the field of tumor targeted chemotherapy. Since the first TSLs appeared that using 1,2-dipalmitoyl-sn-glyce-ro-3-phosphocholine (DPPC) as the primary liposomal lipid, many studies have been done using this type of liposome from basic and practical aspects. While TSLs composed of DPPC enhance the cargo release near the phase transition temperature, it has been shown that many factors affect their temperature sensitivity. Thus numerous attempts have been undertaken to develop new TSLs for improving their thermal response performance. The main objective of this review is to introduce the development and recent update of innovative TSLs formulations, including combination of radiofrequency ablation (RFA), high-intensity focused ultrasound (HIFU), magnetic resonance imaging (MRI) and alternating magnetic field (AMF). In addition, various factors affecting the design of TSLs, such as lipid composition, surfactant, size and serum components are also discussed.

Inorganic kernel - Supported asymmetric hybrid vesicles for targeting delivery of STAT3-decoy oligonucleotides to overcome anti-HER2 therapeutic resistance of BT474R.

As a recombinant humanized monoclonal antibody that targets the extracellular region of HER2 tyrosine kinase receptor, trastuzumab (TRAZ) has demonstrated comparable clinical efficacy and improved survival in patients with HER2-positive breast cancer. Nevertheless, the therapeutic potential of TRAZ is often limited due to its frequent resistance to anti-HER2 therapy. Therefore, we investigate the reversal effect of STAT3-specific decoy oligonucleotides (STAT3-decoy ODNs) on TRAZ resistance, which contain the consensus sequence within the targeted gene promoter of STAT3. Considering the shortcomings of poor cellular permeability and rapid degradation in vivo limit the further clinical applications of ODNs, we report here an asymmetric hybrid lipid/polymer vesicles with calcium phosphate as the solid kernel (CaP@HA). Through hyaluronan-mediated CD44 targeting, the constructed vesicles can specifically carry STAT3-decoy ODNs into TRAZ-resistant breast cancer cells and then regulate TRAZ-induced apoptosis. In comparison with the native ones, ODNs packaged with CaP@HA showed significantly increased serum stability, cellular transfection, synergistic cytotoxicity and apoptosis in vitro. The improved TRAZ sensitization is attributed to the blockade of STAT3 signaling as well as the expression of downstream target genes associated with TRAZ resistance. With the synergistic action of STAT3-decoy ODNs loaded CaP@HA, TRAZ inhibited the growth of its resistant breast cancer xenograft dramatically and induced significant tumor cell apoptosis in vivo. These results suggested that CaP@HA mediated targeted delivery of STAT3-decoy ODNs might be a promising new strategy to overcome anti-HER2 resistance in breast cancer therapy.

Inorganic Kernel-Reconstituted Lipoprotein Biomimetic Nanovehicles Enable Efficient Targeting "Trojan Horse" Delivery of STAT3-Decoy Oligonucleotide for Overcoming TRAIL Resistance.

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) can selectively induce apoptosis in a variety of tumor cells, but not most normal cells. Nevertheless, its therapeutic potential is limited due to the frequent occurrence of resistance in tumor cells, especially hepatocellular carcinoma cell lines. Therefore, we investigated the reversal effect of STAT3-decoy oligonucleotides (ODNs) on TRAIL resistance. Methods. Considering that the drawback of poor cellular permeability and rapid degradation in vivo limited ODNs' further clinical applications, we developed a biomimetic calcium phosphate-reconstituted low density lipoprotein nanovehicle (CaP@LDL) that would serve as a "Trojan horse" to carry STAT3-decoy ODNs into tumor cells and then regulate TRAIL-induced apoptosis. Results. In comparison with native ODNs, the reconstituted CaP@LDL packaged ODNs showed significantly increased serum stability, cellular transfection, in vitro synergistic cytotoxicity and apoptosis in hepatoma cells, while there was no cytotoxicity to normal cells. The improved TRAIL sensitization is attributed to blocking of STAT3 signaling and consequent expression of the downstream target antiapoptotic gene. Following systemic administration, CaP@LDL displayed LDL-mimicking pharmacokinetic behavior such as attenuated blood clearance as well as enhanced accumulation in tumor and hepatorenal sites. With the synergistic combination of decoyODN/CaP@LDL, TRAIL dramatically inhibited hepatic tumor growth in a xenograft model and induced significant tumor apoptosis in vivo. Conclusion. These results suggested that CaP@LDL-mediated STAT3-decoy ODN delivery might be a promising new strategy for reversing TRAIL resistance in hepatocellular carcinoma therapy.

Cleavable PEGylation: a strategy for overcoming the "PEG dilemma" in efficient drug delivery.

To prolong the circulation time of drug, PEGylation has been widely used via the enhanced permeability and retention (EPR) effect, thereby providing new hope for better treatment. However, PEGylation also brings the "PEG dilemma", which is difficult for the cellular absorption of drugs and subsequent endosomal escape. As a result, the activity of drugs is inevitably lost after PEG modification. To achieve successful drug delivery for effective treatment, the crucial issue associated with the use of PEG-lipids, that is, "PEG dilemma" must be addressed. In this paper, we introduced the development and application of nanocarriers with cleavable PEGylation, and discussed various strategies for overcoming the PEG dilemma. Compared to the traditional ones, the vehicle systems with different environmental-sensitive PEG-lipids were discussed, which cleavage can be achieved in response to the intracellular as well as the tumor microenvironment. This smart cleavable PEGylation provides us an efficient strategy to overcome "PEG dilemma", thereby may be a good candidate for the cancer treatment in future.

Polymeric lipid vesicles with pH-responsive turning on-off membrane for programed delivery of insulin in GI tract.

A kind of polymeric lipid vesicles (PLVs) with pH-responsive turning on-off membrane for programed delivery of insulin in gastrointestinal (GI) tract was developed, which was self-assembled from the grafted amphipathic polymer of N-tocopheryl-N'-succinyl-ɛ-poly-l-lysine (TP/SC-g-PLL). By controlling the grafting ratio of hydrophobic alkane and ionizable carboxyl branches, the permeability of membrane was adjustable and thus allowing insulin release in a GI-pH dependent manner. The effects of grafting degree of substitution (DS) on the pH-responsive behavior of the formed vesicles were confirmed by critical aggregation concentration determination, morphology and size characterization. Their transepithelial permeability across the GI tract was proved by both confocal visualization in vitro model of Caco-2 cellular monolayer and in vivo hypoglycemic study in diabetic rats. Accordingly, the work described here indicated that the self-assembled PLVs could be a promising candidate for improving the GI delivery of hydrophilic biomacromolecule agents.

[Comparing MSCT with MRI in preoperative staging of laryngeal carcinoma].

OBJECTIVE: To investigate the value of MRI and MSCT in TNM staging of laryngocarcinoma. METHOD: Thirty-seven patients with laryngocarcinoma were underwent by contrast enhanced scan and multiplanar reconstruction. Thirty-five patients with laryngocarcinoma were underwent contrast enhanced multislice spiral CT, which of them were done by MPR. There are 28 cases which were scan by MRI and MSCT in the two former and we contrasted the accuracy rating in laryngeal manifestation of abnormality. In the former two groups, we observed them the variability in the aspect of lymphaden metastasis and TNM staging. RESULT: In all 28 cases, the MRI had better accuracy rating in displaying the parts of preepiglottic space, larynx side interspace, lingual root, neck tissue, vocal cord. In the TNM staging, there was no difference in stage one in accuracy rating, as the stag stepping up, the accuracy rating of MRI had became better. The last result was that the two methods had difference in staging. In the two methods, MSCT had better sensitivity, specificity and accuracy rating. CONCLUSION: MRI and MSCT had good accuracy rating in TNM staging, MRI has better accuracy rating in some of laryngeal, but as the lymphaden metastasis, the MSCT was better. There were variability in staging, and the MRI was better.