3D Printing in Development of Nanomedicines

Three-dimensional (3D) printing is gaining numerous advances in manufacturing approaches both at macro- and nanoscales. Three-dimensional printing is being explored for various biomedical applications and fabrication of nanomedicines using additive manufacturing techniques, and shows promising potential in fulfilling the need for patient-centric personalized treatment. Initial reports attributed this to availability of novel natural biomaterials and precisely engineered polymeric materials, which could be fabricated into exclusive 3D printed nanomaterials for various biomedical applications as nanomedicines. Nanomedicine is defined as the application of nanotechnology in designing nanomaterials for different medicinal applications, including diagnosis, treatment, monitoring, prevention, and control of diseases. Nanomedicine is also showing great impact in the design and development of precision medicine. In contrast to the “one-size-fits-all” criterion of the conventional medicine system, personalized or precision medicines consider the differences in various traits, including pharmacokinetics and genetics of different patients, which have shown improved results over conventional treatment. In the last few years, much literature has been published on the application of 3D printing for the fabrication of nanomedicine. This article deals with progress made in the development and design of tailor-made nanomedicine using 3D printing technology

General Reagent Free Route to pH Responsive Polyacryloyl Hydrazide Capped Metal Nanogels for Synergistic Anticancer Therapeutics

Herewith, we report a facile synthesis of pH responsive polyacryloyl hydrazide (PAH) capped silver (Ag) or gold (Au) nanogels for anticancer therapeutic applications. A cost-effective instant synthesis of PAH-Ag or PAH-Au nanoparticles (NPs) possessing controllable particle diameter and narrow size distribution was accomplished by adding AgNO₃ or AuCl to the aqueous solution of PAH under ambient conditions without using any additional reagent. PAH possessing carbonyl hydrazide pendant functionality served as both reducing and capping agent to produce and stabilize the NPs. The stability analysis by UV–vis, dynamic light scattering, and transmission electron microscopy techniques suggested that these NPs may be stored in a refrigerator for at least up to 2 weeks with negligible change in conformation. The average hydrodynamic size of PAH-Ag NPs synthesized using 0.2 mmol/L AgNO₃ changed from 122 to 226 nm on changing the pH of the medium from 5.4 to 7.4, which is a characteristic property of pH responsive nanogel. Camptothecin (CPT) with adequate loading efficiency (6.3%) was encapsulated in the PAH-Ag nanogels. Under pH 5.4 conditions, these nanogels released 78% of the originally loaded CPT over a period of 70 h. The antiproliferative potential of PAH-Ag-CPT nanogels (at [CPT] = 0.6 μg/mL) against MCF-7 breast adeno-carcinoma cells were ∼350% higher compared to that of the free CPT as evidenced by high cellular internalization of these nanogels. Induction of apoptosis in MCF-7 breast adeno-carcinoma cells by PAH-Ag-CPT nanogels was evidenced by accumulation of late apoptotic cell population. Drug along with the PAH-Ag NPs were also encapsulated in a pH responsive hydrogel through in situ gelation at room temperature using acrylic acid as the cross-linker. The resulting hydrogel released quantitative amounts of both drug and PAH-Ag NPs over a period of 16 h. The simplicity of synthesis and ease of drug loading with efficient release render these NPs a viable candidate for various biomedical applications, and moreover this synthetic procedure may be extended to other metal NPs

Polyacryloyl Hydrazide: An Efficient, Simple, and Cost Effective Precursor to a Range of Functional Materials through Hydrazide Based Click Reactions

Preparation and studies of ion exchangeable epoxy resins, stimuli responsive hydrogels, and polymer–dye conjugates have been accomplished through hydrazide based click reactions using polyacryloyl hydrazide (PAH) as the precursor. A convenient synthesis of PAH with quantitative functionality was achieved by treatment of polymethyl acrylate with hydrazine hydrate in the presence of tetra-<i>n</i>-butyl ammonium bromide. PAH was cured with bisphenol A diglycidyl ether (BADGE) at 60 °C to form transparent resins with superior mechanical properties (tensile strength = 2–40 MPa, Young’s modulus = 3.3–1043 MPa, and ultimate elongation = 9–75%) compared to the conventional resins prepared using triethylene tetramine. The resins exhibited higher ion exchange capacities (1.2–6.3 mmol/g) compared to the commercial AHA ammonium-type (Tokuyama Co., Japan) membranes. An azo dye with aldehyde functionality was covalently attached to PAH through hydrazone linkage, and the dye labeled PAH exhibited colorimetric sensing ability for base and acids up to micromolar concentration. The swelling of the PAH based hydrogel varied in the range 4–450% depending on the pH and temperature of the medium. The hydrogels gradually released 30% of the original encapsulated dye in a period of 200 h. PAH–hydroxy naphthaldehyde conjugate released 75% of the original loading in ∼11 days at 37 °C and pH 5.0 through cleavage of the CONHNC linkage. The study depicts the versatility of PAH as a precursor and inspires synthesis of a range of new materials based on PAH in the future

Recyclable Thermosets Based on Dynamic Amidation and Aza-Michael Addition Chemistry

Utilizing the dynamic amidation and aza-Michael addition chemistry, a set of high strength, recyclable, and self-healable covalent adaptable networks (CANs) are synthesized by reacting the precursor and commercial oligoamine cross-linkers under mild temperature (25–50 °C) and solvent-free conditions. The amide linkages present in these CANs are readily hydrolyzable under mild acidic (pH = 5.3) conditions, whereas the aza-Michael adducts with secondary amines are thermally reversible. Utilizing the above, these CANs are depolymerized under ambient conditions in mild acidic solution and recycled with retention of original mechanical properties. The crack on the material surface is self-healed at 50 °C. The precursor, a Knoevenagel condensation product of terephthalaldehyde and diethyl malonate, is easily synthesized in a large scale. Suitable model compounds are synthesized and studied to further understand the transformations involved in the polymerization–depolymerization of these networks. These networks exhibit adequate tensile properties (ultimate tensile strength ≤35 MPa and Young’s modulus ≤3 GPa), and the properties can be tuned further by suitably changing the oligoamine cross-linker. The simplicity of synthesis, cost effectiveness, adequate mechanical property, stability in aqueous and organic media, and recyclability along with self-healability render these CANs suitable for a range of applications

Ionization-Induced Reversible Aggregation of Self-Assembled Polycarbonyl Hydrazide Nanoparticles: A Potential Candidate for Turn-On Base Sensor and pH-Switchable Materials

Hierarchical assembly of nanostructures remains one of the desirable targets in nanoscience. Herewith, we report a hydrogen-bond-promoted polymeric nanoparticle (NP) system that reversibly aggregates into different microstructures upon variation of the concentration of the base in the medium. Polycarbonyl hydrazide, a polyaza-Michael adduct, formed uniform spherical NPs in solution owing to the presence of inherent CO---HNCO hydrogen-bond-based physical cross-links in the system. In the presence of the base, the CONH groups ionized to form the corresponding nitranions, and the resulting anion−π interaction between the ionic polymer NPs promoted the secondary aggregation to different shapes and sizes in the microdomain. The shape of the aggregated microparticles gradually changed from spherical to fiber through flakes upon a gradual increase in the base concentration in the medium. The modulus of these superstructures notably decreased compared to that of the original un-ionized NPs, suggesting the involvement of anion−π interaction and loss of hydrogen bonding in the system. Importantly, these dynamic shape changes in the submicron range were reversible, and the addition of a protic solvent or acid recovered the original shape and size. PBTH in sufficiently low concentration (40 μg/mL) is capable of detecting various organic and inorganic bases in the ppm level and pH values between 8.4 and 11.4 with 1.0 precision. The polymer is also a promising candidate for pH-switchable applications