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Purpose: Nanoparticle size is important in drug delivery. Clearance of nanoparticles by cells of the reticuloendothelial system has been reported to increase with increase in particle size. Further, nanoparticles should be small enough to avoid lung or spleen filtering effects. Endocytosis and accumulation in tumor tissue by the enhanced permeability and retention effect are also processes that are influenced by particle size. We present the results of studies designed to optimize cross-linked biodegradable stealth polymeric nanoparticles fabricated by dispersion polymerization. Methods: Nanoparticles were fabricated using different amounts of macromonomer, initiators, crosslinking agent and stabilizer in a dioxane/DMSO/water solvent system. Confirmation of nanoparticle formation was by scanning electron microscopy (SEM). Particle size was measured by dynamic light scattering (DLS). D-optimal mixture statistical experimental design was used for the experimental runs, followed by model generation (Scheffe polynomial) and optimization with the aid of a computer software. Model verification was done by comparing particle size data of some suggested solutions to the predicted particle sizes. Results and conclusion: Data showed that average particle sizes follow the same trend as predicted by the model. Negative terms in the model corresponding to the cross-linking agent and stabilizer indicate the important factors for minimizing particle size. [ABSTRACT FROM AUTHOR]

Three methods were investigated for their suitability for the activation of poly(ethylene glycol) 2000 mono-methyl ether en route to conjugation with dendrimers, using 4-nitrophenylchloroformate as the activator. The use of acetonitrile as a solvent gave the best results. Poly(ethylene glycol) (PEG) grafted polyamidoamine (PAMAM) dendrimers were synthesized and characterized; the use of acetonitrile as a solvent gave the best result. A series of PEG conjugated PAMAM dendrimers with varying degrees of substitution of the dendrimer surface functional group by PEG were prepared. The encapsulation efficiency and the in vitro release characteristics of these PEG conjugated PAMAM dendrimers were studied. The percentage coverage of PAMAM dendrimer surface with PEG had little effect on the encapsulation efficiency but affected the release of methotrexate. JR spectra showed that many of the encapsulated methotrexate molecules were located within the cavity of the dendrimer. [ABSTRACT FROM AUTHOR]

Nanoparticles offer several advantages in drug delivery. The progress in the development of nanoparticles for biomedical applications has moved from the first generation nanoparticles to the fifth generation nanoparticles and the transitions reflect their increasing versatility in biomedical applications. Polymeric nanoparticles are prepared mainly by two methods: dispersion of preformed polymers and in situ polymerization of monomers and macromonomers. Polymerization induced self-assembly (PISA) for the fabrication of nanoparticles is believed to be a better strategy than nanoparticle fabrication from preformed polymers (ease of tethering targeting ligands to the corona of the nanoparticles and unlike PISA, creation of nanostructures via self-assembly of block copolymers is performed in low concentrations. Dispersion polymerization involves one-pot synthesis of nanoparticles. RDRP processes such as atom transfer radical polymerization, reversible addition-fragmentation chain transfer polymerization and nitroxide mediated polymerization have revolutionized polymer synthesis by providing polymer chemists with powerful tools that enable control over architecture, composition and chain length distributions. The technique for the fabrication of nanoparticles by dispersion polymerization (PISA) at ambient temperature was described with examples from our laboratory involving organic redox initiated polymerization using the FDA approved biodegradable polymers. Computer optimization is useful in understanding the factors that ensure optimized properties of drug-loaded nanoparticles., Competing Interests: CONFLICTS OF INTEREST The author declares no conflict of interest.

The HER2 receptor tyrosine kinase is a member of the epidermal growth factor receptor family which includes EGFR, HER3 and HER4. They are known to play critical roles in both normal development and cancer. A subset of breast cancers is associated with the HER2 gene, which is amplified and/or overexpressed in 20-25% of invasive breast cancers and is correlated with tumor resistance to chemotherapy, Metastatic Breast Cancer (MBC) and poor patient survival. The advent of receptor tyrosine kinase inhibitors has improved the prognosis of HER2-postive breast cancers; however, HER2+MBC invariably progresses (acquired resistance or de novo resistance). The monoclonal antibody-based drugs (large molecule TKIs) target the extracellular binding domain of HER2; while the small molecule TKIs act intracellularly to inhibit proliferation and survival signals. We reviewed the modes of action of the TKIs with a view to showing which of the TKIs could be combined in nanoparticles to benefit from the power of nanotechnology (reduced toxicity, improved solubility of hydrophobic drugs, long circulation half-lives, circumventing efflux pumps and preventing capture by the reticuloendothelial system (mononuclear phagocyte system). Nanotherapeutics also mediate the synchronization of the pharmacokinetics and biodistribution of multiple drugs incorporated in the nanoparticles. Novel TKIs that are currently under investigation with or without nanoparticle delivery are mentioned, and nano-based strategies to improve their delivery are suggested. Immunotherapies currently in clinical practice, clinical trials or at the preclinical stage are discussed. However, immunotherapy only works well in relatively small subsets of patients. Combining nanomedicine with immunotherapy can boost therapeutic outcomes, by turning "cold" non-immunoresponsive tumors and metastases into "hot" immunoresponsive lesions.

Objective: The objective of this work is to synthesize and characterize PEGylated monoclonal antibody using the reactivity of oligosaccharide residues in the Fc region of trastuzumab and pertuzumab with a view to preserving their activities., Methods: The hydrazide-functionalized PEG monomethacrylate was synthesized and reacted with NaIO 4 -generated aldehyde groups on glycans in the Fc-domain of trastuzumab and pertuzumab. The conjugates were purified by HPLC. SAMSA-fluorescein substitution method and MALDI MS spectroscopy were used to determine the number of PEG per antibody. Preliminary biological studies involved antiproliferative studies and binding (flow cytometry) following treatments with SKBR3 (HER2-overexpressing) cells and the control., Results: 1 H NMR and 13 C NMR confirmed the formation of hydrazide-functionalized PEG monomethacrylate. MALDI mass-spectrometry showed that there are two PEGs per each antibody and it appears more reliable than the degree of SAMSA-fluorescein substitution method. HER-2 binding assay showed that PEGylated monoclonal antibody bound less efficiently to SKBR3 (high HER-2 expressing) cells than unmodified trastuzumab and pertuzumab. In vitro growth inhibitory effects of unmodified monoclonal antibodies increased with increase in concentration; while the in vitro growth inhibitory effects of PEGylated monoclonal antibodies also increased (but less than the pure antibody) with concentration and it appeared to be more active than unmodified mAbs at higher concentration., Conclusion: The results indicate that PEG can be site-specifically attached via the oxidized glycans in the Fc domain of monoclonal antibodies but the process needs further optimization in terms of PEG size and biological testing at each stage of development., Competing Interests: CONFLICTS OF INTEREST The authors confirm that the content of this research article has no conflict of interest.

Background: Development of pH-responsive nanoparticles capable of rapid degradation in the acidic environments in the endosomes and lysosomes of tumor tissues but relatively more stable in the physiological pH (pH 7.4) is desirable., Objective: To show that the number of methoxy groups on the benzene ring of benzaldehyde bisacrylate acetal crosslinkers should affect the rate of hydrolysis of the crosslinkers and in vitro availability of the drug loaded into the nanoparticles., Method: Three pH-sensitive acetal crosslinkers were synthesized and characterized by 1H NMR, 13C NMR, FT-IR and high resolution mass spectroscopy (HR-MS). The nanoparticles were fabricated by free-radical dispersion polymerization method. Hydrolysis studies were carried out on the crosslinkers and nanoparticles; drug release studies were done on docetaxel-loaded nanoparticles at pH 5.0 and pH 7.4. The statisitical experimental design was randomized complete block design followed by analyses of variance with F-test of significance. Pairwise comparison test was used to locate specific differences among parameters of the crosslinkers and the nanopaticles., Results: Scanning electron micrographs showed the formation of spherical particles. Particle size analysis showed that the nanoparticles are within nanosize range with negative zeta potential. Data showed that the rate of hydrolysis and drug release were faster at pH 5.0 compared to pH 7.4. Hydrolysis and drug release studies were dependent on the structure of the acetals: Di(2-methacryloyloxyethoxy)- [2,4,6-trimethoxyphenyl] methane crosslinker showed the fastest rate of hydrolysis, followed by di(2- methacryloyloxyethoxy)-[2,4-dimethoxyphe-nyl] methane and di(2-methacryloyloxyethoxy)-[4-methoxyphenyl] methane., Conclusion: The pH-responsive nanoparticles are suitable for the delivery of bioactive agents, especially anticancer drugs., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

Quality by design (QbD) in the pharmaceutical industry involves designing and developing drug formulations and manufacturing processes which ensure predefined drug product specifications. QbD helps to understand how process and formulation variables affect product characteristics and subsequent optimization of these variables vis-à-vis final specifications. Statistical design of experiments (DoE) identifies important parameters in a pharmaceutical dosage form design followed by optimizing the parameters with respect to certain specifications. DoE establishes in mathematical form the relationships between critical process parameters together with critical material attributes and critical quality attributes. We focused on the fabrication of biodegradable nanoparticles by dispersion polymerization. Aided by a statistical software, d-optimal mixture design was used to vary the components (crosslinker, initiator, stabilizer, and macromonomers) to obtain twenty nanoparticle formulations (PLLA-based nanoparticles) and thirty formulations (poly-ɛ-caprolactone-based nanoparticles). Scheffe polynomial models were generated to predict particle size (nm), zeta potential, and yield (%) as functions of the composition of the formulations. Simultaneous optimizations were carried out on the response variables. Solutions were returned from simultaneous optimization of the response variables for component combinations to (1) minimize nanoparticle size; (2) maximize the surface negative zeta potential; and (3) maximize percent yield to make the nanoparticle fabrication an economic proposition.