A pinboard by
Yue Song

PhD student, Texas A&M University


Construction of polymeric nanoparticles by crystallization-driven assembly as nanocarriers

A polymer is a large molecule comprised of many repeating units. Polymers range from man-made plastics or fibers, such as Styrofoam™ and nylon, to natural biopolymers, such as DNA and proteins. Advanced polymer chemistry allows the synthesis of block copolymers, which connect two or more polymer segments together with a chemical bond, affording materials with different properties, such as solubility, than those of the individual blocks. For instance, by connecting the hydrophobic, water-insoluble polystyrene and hydrophilic, water-soluble poly(acrylic acid) together into an amphiphilic block copolymer, a combination of hydrophilic and hydrophobic characteristics causes supramolecular assembly to occur in water, yielding polymeric micelles with tunable size and shape.
Polymeric micelles are widely used nanomedicine, and are excellent components to efficiently deliver nanomedicine and optimize the efficacy of cancer/disease therapy. Through packaging hydrophobic drugs/easily precipitated insoluble antimicrobials inside the core, polymeric micelles usually protect the agents from attacking by human immune system, and therefore achieve an optimal carrying capacity and increased therapeutic effects. Polymeric nanoparticles are capable of carrying multiple small components, including drugs, antimicrobials, fluorescent dyes, etc.
Fully degradable, natural product-derived polymers are of special interests nowadays, as they enhance the appeal of polymeric materials by reducing environmental/biological hazards, reducing dependency on petroleum-based plastics, and improving biocompatibility. Carbohydrates are particularly convenient raw materials, as they are inexpensive, abundant in Nature (more than 150 billion tons of polysaccharides are produced naturally per year), and present considerable structural and stereochemical diversity.
Specifically, poly(glucose carbonate)s and poly(l-lactide) have been receiving attention due to their potential for degradation into carbon dioxide, glucose and lactic acid, respectively. By connecting together, these two polymers form amphiphilic block copolymers with crystalline characteristics that allow for interesting assembly behaviors. The presence of multifunctional chemical groups, as well as the amphiphilic core-shell structures facilitate the loading of small molecule agents, which hold promise in drug/antimicrobial delivery applications.


Targeted osteosarcoma chemotherapy using RGD peptide-installed doxorubicin-loaded biodegradable polymeric micelle.

Abstract: Osteosarcoma is the most common primary malignant bone tumor in the pediatric age group, and chemotherapy directed by targeted nanoparticulate drug delivery system represents a promising approach for osteosarcoma treatment recently. Here, we designed and developed a novel DOX-loaded targeted polymeric micelle self-assembled from RGD-terminated poly(ethylene glycol)-block-poly (trimethylene carbonate) (RGD-PEG-PTMC) amphiphilic biodegradable block copolymer, for high-efficiency targeted chemotherapy of osteosarcoma. Notably, the RGD-installed DOX-loaded biodegradable polymeric micelle (RGD-DOX-PM) with drug loading efficiency of 57%-73% displayed a narrow distribution (PDI=0.05-0.12) with average sizes ranging from 46 to 73nm depending on the DOX loading content. The release amount of DOX from RGD-DOX-PM achieved 63% within 60h under physiological condition. Interestingly, MTT assays in MG-63 and MNNG/HOS osteosarcoma cells exhibited that half-maximal inhibitory concentration (IC50) value of RGD-DOX-PM was much lower than its non-targeted counterpart (DOX-PM), implying RGD decorated nanoparticles had enhanced cell targeting ability and led to more effective anti-tumor effect. Furthermore, the targeting ability of RGD-DOX-PM was confirmed by in vitro flow cytometry and confocal laser scanning microscopy (CLSM) imaging assays, where the results showed more RGD-DOX-PM were taken up by MG-63 cells than that of DOX-PM. Therefore, this RGD decorated DOX-loaded polymeric micelle is promising for targeted chemotherapy of osteosarcoma.

Pub.: 09 Dec '16, Pinned: 30 Jun '17

Self-Crosslinkable and Intracellularly Decrosslinkable Biodegradable Micellar Nanoparticles: A Robust, Simple and Multifunctional Nanoplatform for High-Efficiency Targeted Cancer Chemotherapy

Abstract: Nanomedicines based on biodegradable micelles offer a most promising treatment for malignant tumors. Their clinical effectiveness, however, remains to be improved. Here, we report that self-crosslinkable and intracellularly decrosslinkable micellar nanoparticles (SCID-Ms) self-assembled from novel amphiphilic biodegradable poly(ethylene glycol)-b-poly(dithiolane trimethylene carbonate) block copolymer achieve high-efficiency targeted cancer chemotherapy in vivo. Interestingly, doxorubicin (DOX)-loaded SCID-Ms showed favorable features of superb stability, minimal drug leakage, long circulation time, triggered drug release inside the tumor cells, and an unprecedented maximum-tolerated dose (MTD) of over 100 mg DOX equiv./kg in mice, which was at least 10 times higher than free drug. The in vivo studies in malignant B16 melanoma-bearing C57BL/6 mice revealed that DOX-SCID-Ms at a dosage of 30 mg DOX equiv./kg could effectively suppress tumor growth and prolong mice survival time without causing obvious systemic toxicity. Moreover, DOX-SCID-Ms could be readily decorated with a targeting ligand like cRGD peptide. The biodistribution studies showed that cRGD20/DOX-SCID-Ms had a high tumor accumulation of 6.13% ID/g at 6 h post injection, which was ca. 3-fold higher than that for clinically used pegylated liposomal doxorubicin (DOX-LPs). Accordingly, cRGD20/DOX-SCID-Ms exhibited significantly better therapeutic efficacy and lower side effects than DOX-LPs in B16 melanoma-bearing mice. These self-regulating biodegradable micellar nanoparticles offer a robust, multifunctional and viable nanoplatform for targeted cancer chemotherapy.

Pub.: 28 May '16, Pinned: 30 Jun '17

Drug carrier system self-assembled from biomimetic polyphosphorycholine and biodegradable polypeptide based diblock copolymers

Abstract: Polymeric nanoscale drug carrier systems are of particular interest for tumor therapy, offering significant advantages of improved targeting and efficacy. Herein, a well-defined polymeric micelle as drug carrier system is demonstrated with the functions of polypeptide based biodegradability and zwitterionic polyphosphorylcholine based biocompatibility. The polymeric micelles was self-assembled from amphiphilic poly(γ-benzyl-l-glutamate)-block-poly(2-methacryloyloxyethyl phosphorylcholine) (PBLG-b-PMPC) diblock copolymers, with biodegradable PBLG as hydrophobic core and biomimetic PMPC as hydrophilic shell. Anticancer drugs, doxorubicin (DOX), could be encapsulated into the micelle core via the hydrophobic interaction with the polypeptide blocks, resulting in a 70 nm drug carrier with very narrow size distribution. In vitro cellular uptake and cytotoxicity studies demonstrated DOX-loaded PBLG-b-PMPC micelles were taken up by breast cancer cells via endocytosis, with slightly slower intracellular release and lower cytotoxicity compared with free DOX. However, in mice models of breast cancer, these drug-loaded micelles showed higher selectively accumulation in tumor due to the enhanced permeability and retention (EPR) effect than free drugs, leading to enhanced therapeutic efficacy, reduced systemic toxicity and increased apoptosis in tumor tissues. The in vivo results indicated this biomimetic polymeric micelle could be used as a promising strategy for systemic cancer treatment.

Pub.: 05 Aug '16, Pinned: 30 Jun '17

Synthesis of novel amphiphilic poly(N-isopropylacrylamide)-b-poly(aspartic acid) nanomicelles for potential targeted chemotherapy in ovarian cancer

Abstract: The purpose of this study was to merge amino terminated poly(N-isopropylacrylamide) (PNIPAm-NH2) with L-Aspartic acid-N-carboxyanhydride (L-Asp-NCA) using thermal ring-cleavage polymerization to synthesize a pH and thermo-responsive amphiphilic PNIPAm-b-PAsp copolymer for self-assembling nanomicelles. The stimuli-responsive nanomicelles are intended for targeted delivery of methotrexate (MTX) for potential application in ovarian cancer chemotherapy. Rheological profiles of various concentrations of the block copolymer were evaluated. The thermal ring-opening polymerization of L-Asp-NCA onto PNIPAm-NH2 yielded a copolymer with an inherent viscosity of 494.527mPas that was confirmed by advanced rheometry with a high mean molecular weight (MW = 2.217 × 106kDa) computed by the partially-proportional Mark-Houwink formula. Scanning electron microscopy (SEM) elucidated the copolymer topography and pore distribution. Vibrational Fourier Transform Infrared (FTIR), Nuclear Magnetic Resonance (NMR), Differential Scanning Calorimetry (DSC), and Thermal Gravimetric Analysis (TGA) confirmed the synthesis of the amphiphilic block copolymer. The PNIPAm-b-PAsp nanomicelles were 90 nm in size with a zeta potential value of −0.539 mV (PdI ≤0), a yield of 94% and a DEE value of >77%. The in vitro release profile of MTX displayed constant release of MTX over 72 h. The critical micelle concentration (CMC) was computed to be 0.09 mg/mL. Furthermore, the potential of the amphiphilic PNIPAm-b-PAsp copolymeric nanomicelles to target delivery of MTX for ovarian cancer cell destruction was evaluated following determination of cytotoxicity and internalization in an ovarian cancer cell line (NIH:OVAR-5). Overall, results demonstrated that the novel PNIPAm-b-PAsp copolymer synthesized was practical for nanomicelle formation and for the potential application as a stimuli-responsive nanocarrier system for the targeted delivery of MTX in ovarian cancer.

Pub.: 15 Apr '17, Pinned: 30 Jun '17