A Snapshot of photoresponsive liposomes in cancer chemotherapy and immunotherapy: opportunities and challenges

© 2023 The Authors. Published by American Chemical Society. This is an open access article under the Creative Commons Attribution-NonCommercial-NoDerivatives CC BY-NC-ND licence, https://creativecommons.org/licenses/by-nc-nd/4.0To provide precise medical regimens, photonics technologies have been involved in the field of nanomedicine. Phototriggered liposomes have been cast as promising nanosystems that achieve controlled release of payloads in several pathological conditions such as cancer, autoimmune, and infectious diseases. In contrast to the conventional liposomes, this photoresponsive element greatly improves therapeutic efficacy and reduces the adverse effects of gene/drug therapy during treatment. Recently, cancer immunotherpay has been one of the hot topics in the field of oncology due to the great success and therapeutic benefits that were well-recognized by the patients. However, several side effects have been encountered due to the unmonitored augmentation of the immune system. This Review highlights the most recent advancements in the development of photoresponsive liposome nanosystems in the field of oncology, with a specific emphasis on challenges and opportunities in the field of cancer immunotherapy.Peer reviewe

The Next Generation of Platinum Drugs: Targeted Pt(II) Agents, Nanoparticle Delivery, and Pt(IV) Prodrugs

The platinum drugs, cisplatin, carboplatin, and oxaliplatin, prevail in the treatment of cancer, but new platinum agents have been very slow to enter the clinic. Recently, however, there has been a surge of activity, based on a great deal of mechanistic information, aimed at developing nonclassical platinum complexes that operate via mechanisms of action distinct from those of the approved drugs. The use of nanodelivery devices has also grown, and many different strategies have been explored to incorporate platinum warheads into nanomedicine constructs. In this Review, we discuss these efforts to create the next generation of platinum anticancer drugs. The introduction provides the reader with a brief overview of the use, development, and mechanism of action of the approved platinum drugs to provide the context in which more recent research has flourished. We then describe approaches that explore nonclassical platinum(II) complexes with trans geometry or with a monofunctional coordination mode, polynuclear platinum(II) compounds, platinum(IV) prodrugs, dual-threat agents, and photoactivatable platinum(IV) complexes. Nanoparticles designed to deliver platinum(IV) complexes will also be discussed, including carbon nanotubes, carbon nanoparticles, gold nanoparticles, quantum dots, upconversion nanoparticles, and polymeric micelles. Additional nanoformulations, including supramolecular self-assembled structures, proteins, peptides, metal–organic frameworks, and coordination polymers, will then be described. Finally, the significant clinical progress made by nanoparticle formulations of platinum(II) agents will be reviewed. We anticipate that such a synthesis of disparate research efforts will not only help to generate new drug development ideas and strategies, but also will reflect our optimism that the next generation of approved platinum cancer drugs is about to arrive.National Cancer Institute (U.S.) (CA034992

Function of Polymers in Encapsulation Process

An interdisciplinary book that brings together, at an international level, a high-quality collection of reviews and original research articles dealing with the importance of natural or synthetic polymers in encapsulation processes and their applications. A deep understanding and relevant theoretical calculations for exploring the functions of the materials (involved in the formulations) have also been presented along with fundamental investigations. This book has explored the latest research on the function of polymers in encapsulation technology including fundamental theory and experiments together with reviews and articles. Moreover, the present book offers easy-to-achieve approaches that have been developed so far and could create a platform for industrial material production

Novel drug delivery systems for in-vitro cancer treatment

University of Technology Sydney. Faculty of Engineering and Information Technology.Breast and lung cancers collectively pose a significant global health burden, ranking among the top causes of cancer-related deaths worldwide. Triple-negative breast cancer (TNBC) stands out as an aggressive subtype of breast cancer, with limited treatment options and poor prognosis. Similarly, lung cancer is also characterized by its highly invasive and metastatic nature, leading to a poor prognosis. Standard treatment options for TNBC and lung cancer, including chemotherapy and radiation therapy, have limitations, such as significant side effects and the development of drug resistance. Hence, a treatment strategy that is both effective and safe would greatly benefit numerous cancer patients. Emerging treatment options such as plant-based and nucleic acid-based compounds show promise as safer alternatives. However, their clinical utility is hindered by challenges such as poor pharmacokinetic properties and delivery issues. Therefore, in this thesis, we have developed different nanoparticle drug delivery systems to safely deliver plant-based (berberine) and nucleic acid-based compounds (siRNA and NFκB decoy oligonucleotides (ODNs) to their target site, thereby enhancing their in-vitro therapeutic efficacy against both breast and lung cancer. The first research chapter focuses on developing targeted polymer hybrid nanoparticles to deliver siRNA, aiming to silence the X Box peotein-1 (XBP1) gene, a key driver of TNBC progression. Successful knockdown of the XBP1 gene with these nanoparticles significantly promoted cellular apoptosis, particularly under hypoxic conditions. The second research chapter investigates the potential of berberine-loaded liquid crystalline nanoparticles for in-vitro lung cancer treatment. Berberine, a natural compound with anti-cancer properties, faces challenges related to low bioavailability. Encapsulating berberine within nanoparticles improves its therapeutic effectiveness at lower doses against lung cancer cells. In the third research chapter, we explore the potential of polysaccharide-based nanoparticles to deliver NFκB decoy ODNs for inhibiting inflammation-mediated lung cancer progression. NFκB overexpression contributes to tumor aggressiveness by creating a pro-tumorigenic environment. The developed nanoparticles demonstrate high encapsulation efficiency and effectively inhibit inflammation-mediated cancer cell progression at lower doses, indicating safe and effective treatment method for lung cancer. In conclusion, by developing different nanoparticle delivery systems, this thesis offers a promising path toward more effective and safer treatments for these malignancies

Cancer Nanomedicine

This special issue brings together cutting edge research and insightful commentary on the currentl state of the Cancer Nanomedicine field

Advanced nanotechnologies for overcoming antimicrobial resistance

Multidrug-resistant pathogens are prevalent in chronic wounds. There is an urgent need to develop novel antimicrobials and formulation strategies to overcome antibiotic resistance and provide a safe alternative to traditional antibiotics. Chapter 2 aims to create a novel nanocarrier for two cationic antibiotics, tetracycline hydrochloride and lincomycin hydrochloride, overcoming antibiotic resistance. In this study, the use of surface-functionalised polyacrylic copolymer nanogels as carriers for cationic antibiotics is investigated. These nanogels can encapsulate small cationic antimicrobial molecules and act as a drug delivery system. They were further functionalised with a biocompatible cationic polyelectrolyte, bPEI, to increase their affinity towards the negatively charged bacterial cell walls. These bPEI-coated nanocarrier-encapsulated antibiotics were assessed against a range of wound isolated pathogens, which had been shown through antimicrobial susceptibility testing (AST) to be resistant to tetracycline and lincomycin. The data reveals that bPEI-coated nanogels with encapsulated tetracycline or lincomycin displayed increased antimicrobial performance against selected wound-derived bacteria, including strains resistant to the free antibiotic in solution.Next, after experimentation into the use of Carbopol nanogels against antibiotic-resistant wound-derived pathogens, in planktonic form, the work in chapter 3 investigated their use against biofilm-formed pathogens. Biofilms are prevalent in chronic wounds and once formed, are very hard to remove, which is associated with poor outcomes and high mortality rates. Biofilms are comprised of surface-attached bacteria embedded in an extracellular polymeric substance (EPS) matrix, which confers increased antibiotic resistance and host immune evasion. Therefore, disruption of this matrix is essential to tackle the biofilm-embedded bacteria. Novel nanotechnology is applied to do this, based on protease-functionalised nanogel carriers of antibiotics. Such active antibiotic nanocarriers, surface coated with the protease Alcalase, "digest" their way through the biofilm EPS matrix, reach the buried bacteria, and deliver a high dose of antibiotic directly on their cell walls, which overwhelms their defences. This thesis's work demonstrates that they are effective against six wound biofilm-forming bacteria, Staphylococcus aureus, Pseudomonas aeruginosa, Staphylococcus epidermidis, Klebsiella pneumoniae, Escherichia coli, and Enterococcus faecalis. Additionally, it is shown that co-treatments of ciprofloxacin and Alcalase-coated Carbopol nanogels led to a 3-log reduction in viable biofilm- forming cells when compared to ciprofloxacin treatments alone. Encapsulating an equivalent concentration of ciprofloxacin into the Alcalase-coated nanogel particles boosted their antibacterial effect much further, reducing the bacterial cell viability to below detectable amounts after 6 hours of treatment.Chapter 4 combines the work of chapter 2 (NPs against antibiotic-resistant pathogens) and chapter 3 (NPs against biofilm-forming pathogens). This concept is demonstrated by encapsulating Penicillin G and Oxacillin into shellac nanoparticles, subsequently coated Alcalase. It is shown for the first time that these active nanocarriers can destroy biofilms of S. aureus resistant to Penicillin G and are significantly more effective in killing the bacterial cells within compared to an equivalent concentration of free antibiotic. The approach of concentrating the antibiotic by encapsulating it into a nanocarrier allows a localised antibiotic delivery to the anionic cell wall, facilitated by coating the NPs with a cationic protease. This approach allowed the antibiotic to restore its effectiveness against S. aureus, characterised as resistant to the same antibiotic and cause rapid bacterial biofilm degradation. This approach could be potentially used to revive old antibiotics which have already limited clinical use due to developed resistance.Chapter 5 continued investigating the antimicrobial properties of antibiotic-loaded shellac NPs, with a cationic protease surface functionalisation, however this time on a pathogen fungal species, Candida albicans. These Amphotericin B (AmpB)‐loaded shellac NPs are fabricated by pH‐ induced nucleation of aqueous solutions of shellac and AmpB in the presence of Poloxamer 407 (P407) as a steric stabiliser (in the same fashion as penicillin G and oxacillin in chapter 4. The AmpB‐loaded shellac NPs are surface coated with the cationic protease Alcalase. The AmpB‐loaded shellac NPs show a remarkable boost of their antifungal action compared to free AmpB when applied to C. albicans in both planktonic and biofilm forms. The surface functionalisation with a cationic protease allows the NPs to adhere to the fungal cell walls, delivering AmpB directly to their membranes. Additionally, the hydrolysing activity of the protease coating degrades the biofilm matrix, thus increasing the effectiveness of the encapsulated AmpB compared to free AmpB at the same concentration.Additionally, these protease‐coated nanocarrier-based antibiotics showed no detectable cytotoxic effect against human keratinocytes. It is envisaged these antibiotic-loaded NPs. Subsequently, surface functionalised with the cationic protease could be potentially used to treat antibiotic-resistant biofilm infections in the clinic, for example, in recalcitrant chronic wounds. Chapter 6 outlines future work which could be performed using these NP formulations

Design of advanced materials and nano delivery approaches for enhancing activity against Methicillin resistant Staphylococcus aureus.

Doctoral Degree. University of KwaZulu-Natal, Durban.Infectious diseases, including bacterial infections, continue to be a significant cause of morbidity and mortality globally, antimicrobial resistance has further made them fatal. Limitations of conventional dosage forms have been found to be one of the contributing factors to antimicrobial resistance. Novel nano delivery systems are showing potential to combat antimicrobial resistance. The search for novel materials for efficient delivery of antibiotics is an active research area. The aim of the study was to design and synthesize advanced materials and explore nano-based strategies for preparations of novel drug delivery systems to treat SA and MRSA infections. In this study two novel materials; a linear polymer dendrimer hybrid star polymer (3-mPEA) comprising of a generation one poly (ester-amine) dendrimer (G1-PEA) and copolymer of methoxy poly (ethylene glycol)-b-poly(ε-caprolactone) (mPEG-b-PCL) and oleic acid based quaternary lipid (QL) were synthesized and characterized and Poloxamer 188 (P188) material available in the market were employed to formulate three nano drug delivery systems for efficient and targeted delivery of antibiotics. The synthesized materials and the drug delivery system were found to be biosafe after exhibiting cell viability above 75% in all the cell lines tested on using MTT assay. The formulated nano based systems were evaluated for sizes, polydispersity indices (PDI), zeta potential (ZP), surface morphology, drug release, in vitro and in vivo antibacterial activity. Nanovesicles were formulated from 3-mPEA and they had sizes, PDI, ZP and entrapment efficiency of 52.48 ± 2.6 nm, 0.103 ± 0.047, -7.3 ± 1.3 mV and 76.49 ± 2.4%. respectively. QL lipid was employed to formulate vancomycin (VCM) loaded liposomes with Oleic acid based ‘On’ and ‘Off’” pH responsive switches for infection site and intracellular bacteria targeting. They were found to have the size of 98.88 ± 01.92 at pH 7.4. and exhibited surface charge switching from negative at pH 7.4 to positive charge accompanied by faster drug release at pH 6.0. Fusidic acid nanosuspension (FA-NS) with size, PDI and ZP of 265 ± 2.25 nm, 0.158 ± 0.026 and -16.9 ± 0.794 mV respectively was formulated from P188. The drug release profile from both the nanovesicles and liposomes was found to have sustained release. In vitro antibacterial activity for the nanovesicles, FA-NS and liposomes showed 8, 6 and 4-fold better activity at pH 7.4, while the liposome being a pH responsive antibacterial system at pH 6 showed 8- and 16- fold better activity against both Methicillin susceptible (MSSA) and resistant Staphylococcus aureus (MRSA) respectively when compared with the bare drugs. An in vivo BALB/c mice, skin infection model revealed that treatment with VCM-loaded nanovesicles, liposomes and FA-Ns significantly reduced the MRSA burden compared to bare drugs and untreated groups. There was a 20, 6.33 and 76-fold reduction in the MRSA load in mice skin treated with nanovesicles, liposomes and FA-NS respectively compared to those treated with bare VCM and fusidic acid. In summary, synthesized material showed to be biosafe and potential for the development of nano-based drug delivery systems of antibiotics against bacterial infections. The data from this study has resulted in one book chapter and 3 first authored and 3 co-authored research publications

Chemical surface modification of porous silicon nanoparticles for cancer therapy

Anticancer drugs inhibit the cancer growth by killing the rapidly dividing cancer cells. However, anticancer drugs also kill the dividing healthy cells and cause severe damage to healthy tissues. More specific delivery of the cancer drugs to the cancer tissue can increase the drug delivery efficiency and reduce the drug s side effects. Nanocarriers can increase the solubility of poorly-water soluble anticancer drugs and be modified for targeted drug delivery and theranostic applications. For efficient drug delivery, the drug loading capacity has been one of the key issues for the development of nanoparticle (NP)-based drug delivery systems. The biocompatible and biodegradable porous silicon (PSi) nanomaterial presents high drug loading capacity and tunable surface chemistry which renders it an ideal candidate as a drug delivery carrier. Chemical surface modification, which is one of the approaches to improve the nanomaterials properties, can lead to a stable nanosystem for further drug delivery applications. The main aim of this dissertation was to employ chemical approaches and surface modified PSi nanoparticles (NPs) to improve the drug delivery efficiency for potential cancer therapy applications. Incorporating targeting moieties to the surfaces of the nanocarriers, such as targeting peptides, can increase the nanocarrier s accumulation into the cancer tissue after the intravenous administration. In this thesis, surface modification of amine-terminated PSi NPs was achieved with targeting peptides (RGDS and iRGD) via strain-promoted azide-alkyne cycloaddition click reaction. The functionalization of the PSi NPs with the targeting peptides did not comprise the drug loading capacity, but enhanced the cellular uptake and the drug delivery efficacy of the PSi NPs in vitro. In addition to the targeting NP surface modifications, a multifunctional nanosystem was prepared with simultaneous fluorescence- and radio-labeling, and iRGD surface modification of the carboxylic acid-terminated PSi NPs. Both labelings were accessible for the in vivo biodistribution evaluation in mice by single-photon emission computed tomography and X-ray computed tomography, and ex vivo by immunofluorescence staining, respectively. The iRGD modification enhanced the tumor uptake of the PSi NPs after the intravenous administration. In order to reduce the plasma protein adsorption onto the PSi NPs, five bioactive molecules (peptides and hydrophilic anti-fouling polymers) were used to modify the surface of alkyne-terminated PSi NPs using copper-catalized click chemistry. Dextran 40 kDa modified PSi NPs presented enhanced cellular uptake and the least protein adsorption of all the tested NPs. Furthermore, the chemical conjugation of drug molecules was studied. The targeting peptides were successfully conjugated to antisense interleukin-6 via copper-catalyzed [3+2] azide-alkyne cycloaddition for targeted angiogenic anti-inflammation in cancer. Finally, anticancer drug methotrexate (MTX) was chemically conjugated to the cationic PSi NPs and demonstrated to increase the cellular uptake of MTX with up to 96 h sustained drug release. A hydrophobic anti-angiogenic drug, sorafenib, was also loaded to the MTX-conjugated PSi NPs, and the dissolution rate of this drug was considerably increased. In conclusion, in this thesis different chemical approaches were used to biofunctionalize PSi NPs and to prepare drug-conjugates formulations for potential anti-cancer applications.Huokoisten Pii nanopartikkelien pinnan kemiallinen muokkaus syöpäterapiassa Syöpälääkkeet estävät syövän kasvua tappamalla nopeasti jakaantuvia syöpäsoluja. Lääkkeet kuitenkin tappavat myös terveitä nopeasti jakaantuvia soluja ja aiheuttavat vakavia vaurioita terveille kudoksille. Tarkempi syöpälääkkeen kuljetus syöpäkudokseen voi lisätä lääkkeen tehoa ja vähentää lääkkeen sivuvaikutuksia. Nanopartikkelit lääkkeen kuljettajina voivat parantaa huonosti veteen liukenevien syöpälääkkeiden liukoisuutta ja nanopartikkeleita voidaan muokata kohdentamaan lääkkeen kuljetusta syöpäkudokseen tai teranostisia tarkoituksia varten. Lääkeaineen kuljetuksessa nanopartikkelin kyky sitoa lääkeainetta on yksi oleellisista rajoittavista tekijöistä nanopartikkeleihin perustuvissa lääkeaineen kuljetus metodeissa. Huokoiset Pii nanopartikkelit (PSi) soveltuvat hyvin yhteen biologisten järjestelmien kanssa ja ovat biohajoavia. Myös niiden korkea lääkkeen sitomiskyky ja kemiallisesti muokattavat pinta ominaisuudet tekevät niistä ihanteellisia lääkkeen kuljetusta varten. Kemiallisten pinta ominaisuuksien muokkaus on yksi lähestymistapa jolla nanomateriaalien ominaisuuksia voidaan parantaa, kehitettäessä stabiilia lääkkeiden nanokuljetusjärjestelmää. Tämän väitöskirjan päätavoite on kehittää kemiallisesti muokkaamalla PSi nanopartikkeleiden pinta ominaisuuksia kuljettamaan lääkeaineita syöpäkudokseen. Liittämällä kohdentavia molekyylejä nanopartikkelien pintaan kuten ohjaus-peptideitä, voidaan lisätä nanopartikkelien kerääntymistä syöpäkudokseen. Tässä väitöskirjassa huokoisia amino-terminoituja Pii nanopartikkeleita modifioitiin RGD ja iRGD ohjauspeptideillä, tämä tehtiin käyttäen ketju promotoitua kupari katalysoitua azidi-alkyyni sykloadditioreaktiota. Peptideillä funktionalisointi ei haitannut nanopartikkelien lääkkeen sitomiskykyä, mutta lisäsi nanopartikkelien kulkeutumista soluihin ja paransi lääkkeen kuljetus kykyä in vitro olosuhteissa. Karboksyyli-terminoituja PSi nanopartikkeleita muokattiin monikäyttöisiksi lisäämällä niihin iRGD ohjauspeptidi, fluoresoiva- ja radioaktiivinenleima. Radioaktiivisen ja fluoresoivan leiman avulla voitiin määrittää partikkelien biodistribuutio in vivo joko röntgen emissio topografialla tai fotoni emissio topografialla. Radioaktiivisen ja fluoresoivan leiman avulla nanopartikkelit voitiin myös havaita ex-in vivo kudos ja soluleikkeistä. In vivo peptidi iRGD nosti nanopartikkelien kertymistä kasvaimeen. Alkyyni-terminoitujen PSi nanopartikkelien pinta ominaisuuksia muokattiin käyttäen kupari katalysoitua click reaktiota. Käytettiin viittä erilaista bioaktiivista molekyyliä jotta voitaisiin vaikuttaa plasman proteiinien adsorptioon ja partikkelien solun sisään ottoon. Voitiin havaita että Dextran 40 kDa modifioidut PSi nanopartikkelit adsorboivat vähiten proteiineja ja niiden sisään otto soluihin oli myös tehokkainta. Väitöskirjassa tutkittiin myös lääkeaineiden suoraa konjugoimista PSi nanopartikkeleihin ja ohjauspeptideihin. Antisense nukleotidia interleukiini 6 vastaan liitettiin onnistuneesti kupari katalysoidussa azidi-alkyyni sykloadditioreaktiossa useisiin ohjauspeptideihin. Syöpälääke Methotrexate (MTX) konjugoitiin kationisiin PSi nanopartikkeleihin. MTX lääkkeen soluun otto havaittiin tehokkaammaksi kun se on sidottu PSi nanopartikkeleihin ja lääkkeen myös havaittiin vapautuvan 96 tunnin ajan. Anti-angiogeenistä lääkettä Sorafenibia myös sidottiin PSi-MTX nanopartikkeleihin ja sen liukoisuus parani merkittävästi. Väitöskirjassa siis biofunktionalisoitiin PSi nanopartikkeleita ja liitettiin niihin lääkeaineita syöpäterapioita varten onnistuneesti

Drug Delivery Technology Development in Canada

Canada continues to have a rich history of ground-breaking research in drug delivery within academic institutions, pharmaceutical industry and the biotechnology community

Current Insights on Lipid-Based Nanosystems

Lipid-based nanosystems, including solid lipid nanoparticles (SLNs) and nanostructured lipid carriers (NLCs), cationic lipid nanoparticles, nanoemulsions, and liposomes, have been extensively studied to improve drug delivery through different administration routes. The main advantages of these systems are their ability to protect, transport, and control the release of lipophilic and hydrophilic molecules (either small-molecular-weight molecules or macromolecules); the use of generally recognized as safe (GRAS) excipients that minimize the toxicity of the formulations; and the possibility to modulate pharmacokinetics and enable the site-specific delivery of encapsulated payloads. In addition, the versatility of lipid-based nanosystems has further been demonstrated for the delivery of vaccines, the protection of active cosmetic ingredients, and the improvement of moisturizing properties of cosmetic formulations.Lipid-based nanosystems are well established and there are already different commercially approved formulations for various human disorders. This success has paved the way for the diversification of the pipeline of development, to address unmet medical needs for several indications, such as cancer, neurological disorders, and autoimmune, genetic, and infectious diseases.This Special Issue aims to update readers on the latest research on lipid-based nanosystems, both at the preclinical and clinical levels. A series of 15 articles (six reviews and nine studies) is presented, with authors from 12 different countries, showing the globality of the investigations that are being carried out in this area