Peptide and monoclonal antibody mediated targeting of nanoconjugates in cancer chemotherapy

Cancer is one of the most common causes of the death. Currently used anticancer drugs have shown to be effective against various cancers. However, these anticancer drugs can not differentiate between tumor cells and normal cells. These agents kill both types of cells resulting in severe side effects. Poor physico-chemical properties of anticancer drugs and development of chemo-resistance in cancer cells aggravate the problems. Over the past decade, nanotechnology-based formulations have been explored to overcome the limitations of anticancer drugs. These nanomedicines have shown promises to deliver drugs effectively to the cancer cells. In this research work, efforts have been made to improve the specificity of the drug loaded nanocarriers towards tumor cells. Cancer cells over express some receptors than normal cells. Therefore, nanocarriers attached with a ligand, having high affinity to particular receptor, could be targeted to cancer cells. In this context, two peptides (bombesin and cyclic RGDfK) and a monoclonal antibody, trastuzumab, were used as targeting ligand. Polymeric nanoparticles were used as drug carriers. Polymers such as poly(lactic-co-glycolic acid) (PLGA), D-α-tocopheryl polyethylene glycol succinate (TPGS), dendrimers and poly(glutamic acid) (PGA) were used for the preparation of nanoparticles. The selection of the polymers depended on the physicochemical properties of drug, desired particle size range, target tissue and the functional group available on the surface for conjugation with targeting ligand. Bombesin conjugated PLGA nanoparticles showed the potential to improve the delivery of a hydrophobic anticancer drug, docetaxel, in gastrin releasing peptide receptors over expressing breast and prostate cancer cells. Trastuzumab conjugated dendrimers demonstrated high specificity towards human epidermal growth factor 2 receptors over expressing breast cancer cells. cRGDfK conjugated TPGS nanomicelles showed significant cytotoxicity and anti-angiogenic activity of encapsulated docetaxel to integrin receptors over expressing prostate cancer cells. As integrin receptors have also been over expressed in other cancers such as ovarian, brain, lung and breast cancers, cRGDfK conjugated nanoparticles were investigated for the targeting of drugs to ovarian and brain cancers. cRGDfK conjugated PLGA nanoparticles were investigated for the delivery of hydrophilic gemcitabine hydrochloride to ovarian cancer. In a separate study, cRGDfK was conjugated to PGA nanoparticles for selective targeting of hydrophobic camptothecin to integrin over expressing brain tumor cells. In summary, this thesis presents a research done with regards to preparation of anticancer drugs loaded different nanoparticles, bioconjugation of targeting ligand on the surface of nanoparticles and evaluation of anticancer activities of these ligand mediated targeted drug delivery systems in cancer cells. The study revealed that the nanoparticle-based targeted formulations better control over the growth of cancer than plain drugs

Monoclonal antibody-conjugated dendritic nanostructures for siRNA delivery

Small interfering RNA (siRNA) is a promising tool for gene therapy-based disease treatments. However, delivery of siRNA to the target cells requires a specific and reliable carrier system. Herein we describe a targeted carrier system that can deliver siRNA to cancer cells overexpressing the human epidermal growth factor 2 (HER2) receptor. Trastuzumab-conjugated poly(amido)amine dendrimers can be synthesized using the protocols described here

Position Statement of the Max Planck Institute for Innovation and Competition of 25 May 2022 on the Commission's Proposal of 23 February 2022 for a Regulation on Harmonised Rules on Fair Access to and Use of Data (Data Act)

On 23 February 2022, the European Commission issued a Proposal for a Regulation on harmonised rules on fair access to and use of data (Data Act). The overarching objective of the Proposal is to ‘ensure fairness in the digital environment, stimulate a competitive data market, open opportunities for data-driven innovation and make data available for all’. The Institute hereby presents its Position Statement that features a comprehensive analysis of whether and to what extent the proposed rules might reach the envisaged objectives. It comments on all parts of the Proposal, including the new IoT data access and use right. Finally, the Institute offers a set of recommendations as to how the proposed provisions should be amended in the legislative process to align them better with the objectives of the Data Act

Artificial Intelligence and Intellectual Property Law - Position Statement of the Max Planck Institute for Innovation and Competition of 9 April 2021 on the Current Debate

This Position Statement presents a broad overview of issues arising at the intersection of AI and IP law based on the work of the Max Planck Institute for Innovation and Competition research group on Regulation of the Digital Economy. While the analysis is approached mainly from a perspective de lege lata, it also identifies questions which require further reflection de lege ferenda supported by in-depth interdisciplinary research. The scope is confined to substantive European IP law, in particular, as regards copyright, patents, designs, databases and trade secrets. Specific AI-related issues are mapped out around the core questions of IP law, namely, the eligibility for protection under the respective IP regimes, allocation of rights and the scope of protection. The structure of the analysis reflects three key components of AI: inputs required for the development of AI systems, AI as a process and the output of AI applications. Overall, it is emphasised that, while recent legal and policy discussions have mostly focused on AI-aided and AI-generated output, a more holistic view that accounts for the role of IP law across the AI innovation cycle is indispensable

Colloidal stability and physicochemical characterization of bombesin conjugated biodegradable nanoparticles

The aim of this investigation was to explore the potential of bombesin (BBN) peptide conjugated biodegradable polymeric nanoparticles as cancer targeting system. Poly (lactic-co-glycolic) acid nanoparticles were prepared using different concentration of surfactants. Nanoparticles, prepared with 0.25% sodium cholate (PNP), showed the smallest size (86.15 nm) and good zeta potential value (-34.2 mV). Bombesin was covalently conjugated to the nanoparticle surface by amide bonding. The surface conjugation was confirmed by change in surface potential and Fourier transform infrared analysis. Slight change in pH and buffer medium did not show significant effect on conjugation efficiency. Colloidal stability of nanoparticles was evaluated with respect to time, salt induced aggregation, storage medium and release of BBN from nanoparticle surface. The stability factor was determined by change in optical density and particle size with time. Nanoparticles were found to be more stable in phosphate buffer saline and serum when compared to that in normal saline and distilled water. Bombesin conjugated nanoparticles( BPNP) showed more stability in both PBS and serum than PNP which may be due to steric stabilization of nanoparticles by the peptide. Similarly, in aggregation resistance studies, BPNP were stable up to 0.7 M concentration of sodium sulphate. Bombesin was released only 12.76% in 24 h under acceleration conditions, showing the stability of amide bond formed between nanoparticles and peptide. Conclusively, the bombesin peptide conjugated PLGA nanoparticle could be a promising drug delivery system for targeting of anticancer drugs

Formulation and dosage of therapeutic nanosuspension for active targeting of docetaxel (WO 2014210485A1)

Non-specificity and drug resistance are two major limitations of all chemotherapeutic agents. Ligandconjugated nanomedicine is the most versatile approach for targeted cancer therapy. Attaching a targeting ligand to the nanoparticle surface increases drug concentration at the desired sites, decreases the dose needed and lessens side effects. The subject of this patent evaluation describes the preparation of a therapeutic nanosuspension of an anticancer drug, docetaxel (DTX). The nanoparticle matrix comprised a polylactic acid-polyethylene glycol block copolymer (PLA-PEG). The nanoparticles were actively directed towards prostate-specific membrane antigen (PSMA) over-expressing cancer cells using a targeting ligand S,S-2-{3-[1-carboxy-5-amino-pentyl-]ureido}-pantanedioic acid (GL2). The dose-limiting toxicity and maximum tolerated dose were determined for GL2-conjugated and DTX-loaded polymeric nanosuspensions. The efficacy of nanosuspensions was evaluated in people with various cancer types. The investigators claim the method of preparation of therapeutic nanosuspension, optimized composition of the formulation and dosage regimen for the clinical studies to effectively treat gastroesophageal and breast cancers

Fabrication of surfactant-stabilized nanosuspension of naringenin to surpass its poor physiochemical properties and low oral bioavailability

Background: Nanosuspension is a biphasic system consisting of native drug particles dispersed in an aqueous surfactant or polymeric solution with a particle size between 10 to 1000 nm. In contrast to other drug delivery systems, nanosuspension offer the unique advantage of increasing solubility of the native drug resulting into faster drug absorption and hence achieving faster maximum plasma concentration. Hypothesis/Purpose: The present study aims to evaluate surfactants/polymer stabilized nanosuspensions of naringenin (NN), a phytomedicine, to surpass its poor physiochemical properties and low oral bioavailability. Study design: Optimization and characterization (DLS, SEM, PXRD and DSC) of nanosuspensions followed by in-vitro drug dissolution studies and pharmacokinetic study in male Sprague-Dawley rats were performed. Methods: Nanosuspensions were prepared by precipitation-ultrasonication method with varying concentrations of different surfactants and polymer such as sodium cholate (SC), sodium lauryl sulphate (SLS), poly ethylene glycol 4000 (PEG), polysorbate 80 (Tween (R) 80), poloxomer-188 and D-alpha-Tocopherol polyethylene glycol 1000 succinate (TPGS or Vitamin E-TPGS). Results: Nanosuspension prepared with 0.5% w/v D-alpha-Tocopherol polyethylene glycol 1000 succinate (TPNS) and 7.5 mg NN, showed the smallest size of 118.1 +/- 2.7 nm. TPNS showed increase in drug dissolution in simulated gastric fluid pH 1.2 (SGF) and phosphate buffer pH 6.8 (PB). TPNS demonstrated an improved pharmacokinetic profile compared to pure NN resulting 2.14 and 3.76 folds increase in C-max and AUC, respectively. In addition, TPNS were stable over a period of six months. Conclusion: The developed formulation strategy of nanosuspension could be exploited to improve the solubility and bio-availability of poorly soluble NN and other phytomedicines

Bombesin conjugated solid lipid nanoparticles for improved delivery of epigallocatechin gallate for breast cancer treatment

Epigallocatechin-gallate (EGCG) is a potent anti-cancer therapeutic which effectively controls the growth of cancerous cells through a variety of different pathways. However, its molecular structure is susceptible to modifications due to cellular enzymes affecting its stability, bioavailability and hence, overall efficiency. In this study, we have initially encapsulated EGCG in the matrix of solid lipid nanoparticles to provide a stable drug carrier. To confer additional specificity towards gastrin releasing peptide receptors (GRPR) overexpressed in breast cancer, EGCG loaded nanoparticles were conjugated with a GRPR-specific peptide. In-vitro cytotoxicity studies showed that the peptide-conjugated formulations possessed greater cytotoxicity to cancer cell lines compared to the non-conjugated formulations. Further, in-vivo studies performed on C57/BL6 mice showed greater survivability and reduction in tumour volume in mice treated with peptide-conjugated formulation as compared to the mice treated with non-conjugated formulation or with plain EGCG. These results warrant the potential of the system designed in this study as a novel and effective drug delivery system in breast cancer therapy

Modulating the site-specific oral delivery of sorafenib using sugar-grafted nanoparticles for hepatocellular carcinoma treatment

Globally, one in six deaths is reported due to cancer suggesting the critical need for development of advanced treatment regimens. In this study, solid lipid nanoparticles (SLN) were prepared and appended with polyethylene glycol (PEGylated) galactose and a multikinase inhibitor sorafenib (SRFB) was used as chemotherapeutic drug, for treating hepatocellular carcinoma (HCC). The nanoparticles were evaluated for in-vitro and in-vivo performances to showcase the targeting efficiency and therapeutic benefits of the sorafenib loaded ligand conjugated nanoparticles (GAL-SSLN). When compared with SRFB or Sorafenib loaded SLN, GAL-SSLN showed superior cytotoxicity and apoptosis in HepG2 (human hepatocellular carcinoma cells). In addition, in-vivo pharmacokinetics and real time biodistribution studies in BALB/c mice showed that the surface conjugation of nanoparticles with galactose resulted in better pharmacokinetic performance and targeted delivery of the nanoparticles to liver. Results indicated that GAL-SSLN showed promising attributes in terms of targeting sorafenib to liver and therapeutic efficacy