Polymeric Micelles with Uniform Surface Properties and Tunable Size and Charge: Positive Charges Improve Tumor Accumulation

The influence of surface charge on biodistribution and tumor accumulation remains debatable because most research has been carried out by changing the surface functional groups of nanocarriers. In this work, to avoid the interference of different surface properties such as chemical composition and hydrophilicity, polymeric micelles with uniform PEG coatings and continuously tunable sizes or zeta potentials were developed via a facile route. Therefore, the influence of surface charge on the biological functions of micelles with the same size and surface properties could be well-explored. In this case, positive charge was found to enhance both tumor cellular uptake and tumor accumulation. Immunofluorescence staining indicated that the improved tumor accumulation was mainly due to the tumor vasculature targeting of positively charged micelles. It is predicted that efficient drug delivery systems for both tumor vasculature and cancer cell targeting can be realized based on positively charged micelles

Efficient Tumor Accumulation, Penetration and Tumor Growth Inhibition Achieved by Polymer Therapeutics: The Effect of Polymer Architectures

To obtain high tumor-specific accumulation, strong tumor penetration and low off-target uptake, we developed a series of polymer therapeutics with different architectures, including random, block, and brush-like structure, based on the classic N-(2-hydroxypropyl) methacrylamide polymers. The influence of polymer architecture on biological properties such as cellular uptake, blood clearance, and biodistribution have been investigated. Besides small micelles whose sizes were determined by polymer architectures, large aggregates formed by micelle aggregation could also be observed. Although they had different architectures, the drug release rate, endocytic pathways and cellular uptake level of various conjugates have been proved to be identical. The polymer architecture of various conjugates lay great impact on the blood clearance, biodistribution and tumor growth inhibition. We assumed that the differences in in vivo biological properties were coordinately caused by the different size of the small aggregates and the formation and stability of large aggregates for different conjugates. Even though the reason was still unclear, the results inspired us that only by diblock conjugates with improved cellular uptake can we realize tumor specific accumulation, deep penetration, and efficient tumor inhibition

Positively Charged Combinatory Drug Delivery Systems against Multi-Drug-Resistant Breast Cancer: Beyond the Drug Combination

The formation and development of cancer is usually accompanied by angiogenesis and is related to multiple pathways. The inhibition of one pathway by monotherapy might result in the occurrence of drug resistance, tumor relapse, or metastasis. Thus, a combinatory therapeutic system that targets several independent pathways simultaneously is preferred for the treatment. To this end, we prepared combinatory drug delivery systems consisting of cytotoxic drug SN38, pro-apoptotic KLAK peptide, and survivin siRNA with high drug loading capacity and reductive responsiveness for the treatment of multi-drug-resistant (MDR) cancer. With the help of positive charge and the synergistic effect of different drug, the combinatory systems inhibited the growth of doxorubicin-resistant breast cancer cells (MCF-7/ADR) efficiently. Interestingly, the systems without siRNA showed more superior <i>in vivo</i> anticancer efficacy than those with siRNA which exhibited enhanced <i>in vitro</i> cytotoxicity and pro-apoptotic ability. This phenomenon could be attributed to the preferential tumor accumulation, strong tumor penetration, and excellent tumor vasculature targeting ability of the combinatory micelles of SN38 and KLAK. As a result, a combinatory multitarget therapeutic system with positive charge induced tumor accumulation and vasculature targeting which can simultaneously inhibit the growth of both tumor cell and tumor vasculature was established. This work also enlightened us to the fact that the design of combinatory drug delivery systems is not just a matter of simple drug combination. Besides the cytotoxicity and pro-apoptotic ability, tumor accumulation, tumor penetration, or vascular targeting may also influence the eventual antitumor effect of the combinatory system

Integrins-FAK-Rho GTPases Pathway in Endothelial Cells Sense and Response to Surface Wettability of Plasma Nanocoatings

Vascular endothelial cell (EC) adhesion and migration are essential processes in re-endothelialization of implanted biomaterials, which are affected by surface properties of implanted materials such as surface wettability. Our previous study demonstrated that, as model substrates, EC adhesion/migration showed an opposite behavior on the hydrophobic and hydrophilic surfaces of plasma SiO_<i>x</i>:H nanocoatings. Extending our previous works, the expression and distribution of crucial proteins in integrins-FAK-Rho GTPases signaling pathways were examined, respectively. The results showed that a hydrophilic surface could enhance the expression of focal adhesion protein associated with cell adhesion; however, the hydrophobic surface could improve the expression of Rho GTPases associated with cell migration and phosphorylation level of FAK, revealing the potential reason of surface wettability mediating different cells’ adhesion/migration behaviors. These findings reveal the relationship and molecular mechanism of endothelial cell adhesion/migration, which was expected to guide the surface modification of implants for accelerating endothelialization

CD44-Targeted Facile Enzymatic Activatable Chitosan Nanoparticles for Efficient Antitumor Therapy and Reversal of Multidrug Resistance

Nanoparticles are attractive platforms for the delivery of various anticancer therapeutics. Nevertheless, their applications are still limited by the relatively low drug loading capacity and the occurrence of multidrug resistance (MDR) against chemotherapeutics. In this study, we report that the integration of d-α-tocopherol succinate (VES) residue with both chitosan and paclitaxel (PTX) led to significant improvement of drug loading capacity and drug loading efficiency through the enhancement of drug/carrier interaction. After the incorporation of hyaluronic acid containing PEG side chains (HA-PEG), higher serum stability and more efficient cellular uptake were obtained. Due to HA coating, VES residues and the enzymatic responsive drug release property, such facile nanoparticles actively targeted cancer cells that overexpress CD44 receptor and efficiently reversed the MDR of treated cells, but caused no significant toxicity to mouse fibroblast (NIH-3T3). More importantly, with HA-PEG coating, longer blood circulation and more effective tumor accumulation were achieved for prodrug nanoparticles. Finally, superior anticancer activity and excellent safety profile was demonstrated by HA-PEG coated enzymatically activatable prodrug nanoparticles compared to commercially available Taxol formulation

Polymer–Doxorubicin Conjugate Micelles Based on Poly(ethylene glycol) and Poly(<i>N</i>‑(2-hydroxypropyl) methacrylamide): Effect of Negative Charge and Molecular Weight on Biodistribution and Blood Clearance

Well-defined water-soluble block copolymers poly­(ethylene glycol)-<i>b</i>-poly­(<i>N</i>-(2-hydroxypropyl) methacrylamide-<i>co</i>-<i>N</i>-methacryloylglycylglycine) (PEG-<i>b</i>-P­(HPMA-<i>co</i>-MAGG)) and their doxorubicin (Dox) conjugates with different composition and molecular weight were synthesized. These Dox conjugates can form micelles in buffer solution. The physicochemical properties, in vivo biodistribution, blood clearance, and especially the tumor accumulation of copolymers and micelles were studied. Severe liver accumulation can be observed for PEG-<i>b</i>-PMAGG copolymers. This was quite different from their Dox conjugate for which decreased RES uptake and elevated kidney accumulation could be observed. When decrease the negative charge to an appropriate amount such as 8–10 mol %, both RES uptake and kidney accumulation could be suppressed. Obvious tumor accumulation could be achieved especially when the molecular weight were increased from ∼40 to ∼80 KDa. These results provided us with a guideline for the design of nanoscaled drug delivery system as well as a potential option for treating kidney-related cancers

Tumor Specific and Renal Excretable Star-like Triblock Polymer–Doxorubicin Conjugates for Safe and Efficient Anticancer Therapy

Efficient tumor accumulation and body clearance are two paralleled requirements for ideal nanomedicines. However, it is hard for both to be met simultaneously. The inefficient clearance often restrains the application of drug delivery systems (DDSs), especially for high-dosage administration. In this study, the star-like and block structures are combined to enhance the tumor specific targeting of the parent structures and obtain additional renal excretion property. The influences of polymer architectures and chemical compositions on the physicochemical and biological properties, particularly the simultaneous achievement of tumor accumulation and renal clearance, have been investigated. Among the tested conjugates, an eight-arm triblock star polymer based on poly­(ethylene glycol) (PEG) and poly­(<i>N</i>-(2-hydroxyl) methacrylamide) (PHPMA) is found to simultaneously fulfill the requirements of superior tumor accumulation and efficient renal clearance due to the appropriate micelle size and reversible aggregation process. On the basis of this conjugate, 60 mg/kg of Dox equivalent (much higher than the maximum tolerated dose (MTD) of Dox) can be administered to efficiently suppress tumor growth without causing any obvious toxicity. This work provides a new approach to design polymer–drug conjugates for tumor specific application, which can simultaneously address the efficacy and safety concerns