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.
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
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
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
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
Abstract: Co-crystallization of polymers with different configurations/tacticities provides access to materials with enhanced performance. The stereocomplexation of isotactic poly(L-lactide) and poly(D-lactide) has led to improved properties compared with each homochiral material. Herein, we report the preparation of stereocomplex micelles from a mixture of poly(L-lactide)-b-poly(acrylic acid) and poly(D-lactide)-b-poly(acrylic acid) diblock copolymers in water via crystallization-driven self-assembly. During the formation of these stereocomplex micelles, an unexpected morphological transition results in the formation of dense crystalline spherical micelles rather than cylinders. Furthermore, mixture of cylinders with opposite homochirality in either THF/H2O mixtures or in pure water at 65 °C leads to disassembly into stereocomplexed spherical micelles. Similarly, a transition is also observed in a related PEO-b-PLLA/PEO-b-PDLA system, demonstrating wider applicability. This new mechanism for morphological reorganization, through competitive crystallization and stereocomplexation and without the requirement for an external stimulus, allows for new opportunities in controlled release and delivery applications.
Pub.: 18 Dec '14, Pinned: 30 Jun '17
Abstract: In current study, we report the synthesis and characterization of renewable fatty acid-based block copolymer. The block copolymer was synthesized via RAFT polymerization under microwave irradiations. Firstly, the homopolymer of N,N-dimethylacrylamide (DMA) was prepared and used as a macro-CTA to copolymerize with modified stearic acid monomer (SAM). The characterization of copolymer p-DMA-b-SAM was done by 1H NMR, ATR-FTIR and GPC. The block copolymer was allowed to self-assemble and the entrapment of carbamazepine (CBZ) into hydrophobic core of polymeric micelles was investigated in aqueous media. A high drug entrapment efficiency (69%) was observed for block copolymer micelles. The spherical appearance of micelles in the size range of 20–70 nm was determined with transmission electron microscopy (TEM). An effort was also made to investigate the in vitro release profile of CBZ from micelles. A sustained drug release rate was observed, showing complete release of drug within 70 h.
Pub.: 14 Mar '17, Pinned: 30 Jun '17
Abstract: A carborane-containing triblock copolymer conjugated with a near infrared (NIR) fluorescence probe has been synthesized via reversible addition fragmentation chain transfer (RAFT), ring open polymerization (ROP), and conjugations of a cyanine NIR dye. Reactions were traced by means of 1H-NMR, GPC and FT-IR. The NIR amphiphilic copolymer with polycaprolactone and polycarborane as hydrophobic segments and poly(ethylene glycol)methyl ether methacrylate as the hydrophilic segment could self-assemble into micelles in aqueous solution, and was characterized by means of DLS and TEM. In the copolymer, carborane works as a boron neutron capture therapy (BNCT) agent while the aminocyanine (Cy) dye works as a NIR bioimaging agent, and the nanoparticles of the copolymers are a potential theranostic BNCT system for cancer therapy, which was supported by MTT experiments and in vitro fluorescence microscopy studies.
Pub.: 07 Jun '16, Pinned: 29 Jun '17
Abstract: Polylactide (PLA) is biocompatible and FDA-approved for clinical use and thus has been considered to be a choice of the materials valuable for extensive applications in biomedical fields. However, conventionally-designed PLA-based amphiphilic block copolymer nanoassemblies exhibit slow and uncontrolled release of encapsulated drugs because of the slow biodegradation of hydrophobic PLA in physiological conditions. In order to improve potentials for clinical use and commercialization of conventional PLA-based nanoassemblies, stimuli-responsive degradation (SRD) platform has been introduced into the design of PLA-based nanoassemblies for enhanced/controlled release of encapsulated drugs. This review summarizes recent strategies that allows for the development of PLA-based ABPs and their self-assembled nanostructures exhibiting SRD-induced enhanced drug release. The design, synthesis, and evaluation of the nanoassemblies as intracellular drug delivery nanocarriers for cancer therapy are focused. Further, the outlook is briefly discussed on the important aspects for the current and future development of more effective SRD PLA-based nanoassemblies toward tumor-targeting intracellular drug delivery.
Pub.: 12 May '17, Pinned: 29 Jun '17