SCIENCE, PILANI. Hyderabad campus.

End Semester Report

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Submitted in partial fulfilment of the requirements of
Course Name: STUDY IN ADVANCED TOPIC (BITS G513)Title: To know about the formulations that are in Clinical trial and prospect of Nano- formulations, in depth knowledge of Photosensitizers and therapeutic application by utilizing various light source.

Proposed Methodology: To Read the Literature and gather information about formulations in Clinic and Clinical Trials.

Date of submission: 30/04/2018.

Report Submitted by: Suvarna Kale.

ID: 2017H1460152H.

Dr.Swati Biswas.

Assistant Professor, Department of Pharmacy
Evaluator’s remarks: CERTIFICATE

This is to certify that the end semester report entitled To know about the formulations that are in Clinical trial and prospect of Nano- formulations, in depth knowledge of Photosensitizers and therapeutic application by utilizing various light source submitted by: Suvarna Kale ID: 2017H1460152H in partial fulfillment of the requirements of To Read the Literature and gather information about formulations in Clinic and Clinical Trials, the work done by her under my supervision.
Signature of the supervisor:
I would like to express our special thanks to Dr.Swati Biswas who gave me the opportunity to know about the formulations that are in Clinical trial and prospect of Nano- formulations, knowledge of Photosensitizers and therapeutic application by utilizing various light source. To Read the Literature and gather information about formulations in Clinic and Clinical Trials.

I would also like to thank my family and friends who helped during the course of the work.

Aim of study: To know about the formulations that are in Clinical trial and prospect of Nano- formulations, in depth knowledge of Photosensitizers and therapeutic application by utilizing various light source.

Photodynamic therapy is one of the most important tool which is used in oncology, which is one of the most important approach in used. It is one of the efficient, convenient, and inexpensive systems of light delivery are now available mostly.PDT is used in especially for treatment of non-melanoma skin cancer and Barrett’s esophagus
Photodynamic therapy (PDT) was very a useful tool in Oncology, but nowadays the approach is only mostly in the clinic. The understanding of PDT has advanced, and Results from well-controlled, Randomized phase III trials is also becoming available, , and improved photosensitizing drugs are in development. PDT has several potential advantages over the surgery and radiotherapy: it is comparatively non-invasive, it can be targeted accurately, repeated doses can be given without the total-dose limitations associated with radiotherapy, and the healing process results in little or no scarring. PDT can usually be use for an outpatient, is convenient for the patient, and has no side-effects.
Two Photosensitizing drugs, Porfirmer sodium and Temoporfin: now been approved mostly for Systemic administration, and Aminolevulinic acid and Methyl Aminolevulinate: been approved for Topical use. Here, we have review current use of PDT in oncology and look for its future potential as more selective photosensitizing drugs become available for use.

Photodynamic therapy (PDT) uses the combination of: Photosensitizing drug and light to cause selective damage to the target tissue or tumor. An adequate concentration of molecular oxygen is needed for tissue damage. If any one of these components is absent, there is no effect, and the overall effectiveness therefore requires good planning of both drug and light dosimetry.

The drugs are generally given systemically, but because the targeting process is mainly achieved through precise application of the light—usually from a laser source—the effect is local rather than systemic.
The local nature of the effect of PDT is be recognized from the outset because it contributes to both the limitations and the opportunities for PDT as a successful treatment in cancer.

WHAT IS CANCER????Body’s cells begin to divide without stopping and spread into surrounding tissues.

Old or Damaged cells survive when they should die, and new cells form when they are not needed. These extra cells can divide without stopping and may form growths called tumors.

In metastasis: cancer cells break away from where they first formed (primary cancer), travel through the blood or lymph system, and form new tumors (metastatic tumors) in other parts of the body. The metastatic tumor is the same type of cancer as the primary tumor

Photodynamic therapyPhotodynamic action: the Reaction of cells to: chemical reagent (photosensitizer) +light and oxygen.

Photodynamic therapy is that uses a drug, called photosensitizer or photosensitizing agent, and a particular type of light.

When photosensitizers are exposed to a specific wavelength of light, they produce a form oxygen that kills nearby cells.

Photosensitizer: What is ideal???A chemical that is required for photodynamic action is very useful for action.

A Photosensitizer transfers energy from the light to generate Reactive Oxygen Species (ROS).

The characteristic of a photosensitizer :
Strong absorption with a high extinction coefficient in the red/near infrared region of the electromagnetic spectrum (600–850 nm)—allows deeper tissue penetration. (Tissue is much more transparent at longer wavelengths (~700–850 nm).

Should not be harmful to the target tissue.

Rapid clearance from the body post-procedure.

High chemical stability.

Soluble in biological media, allowing intravenous administration. Otherwise, a hydrophilic delivery system must enable efficient and effective transportation of the photosensitizer to the target site via the bloodstream.

Low photo bleaching to prevent degradation of the photosensitizer so it can continue producing singlet oxygen.

Types of Photosensitizers: Eg from various articles with their absorption wavelength.

First generation: HpD and Photofrin (weak absorption at 630 nm)
At 630 nm, their effective tissue penetration of light is small, 2–3 mm, limiting treatment to surface tumors.

Although Photofrin® generate singlet oxygen with high quantum yield.

In spite of its safe applications in bladder, esophageal and lung cancers, Photofrin tends to be applied to head human part and thoracic part affected by cancer.

Second generation: 5-Aminolaevulinic acid, Verteporfin, Purlytin, Zinc phthalocyanine, Foscan, Lutex, Naphthalocyanines.

Most used second generation PDT sensitizers.

25 to 30 times more potent than HpD in tumor photo necrosis when irradiated at 648 nm. Phthalocyanine (Pc) are currently recognized as one of the best sensitizers used in PDT, have a long-wavelength band with a large extinction coefficient.

Third generation: Expanded metallo-porphyrins, Metallochlorins/ bacteriochlorins, Metallo-phthalocyanines, Metallo-naphthocyaninesulfobenzo-porphyrazines (M-NSBP), Metallo-Naphthalocyanines.

The NIR window in the range of 700–1000 nm is known as the optical tissue penetration window (700–1000 nm), in which biological tissues have the minimal light absorption, ideal for optical imaging and phototherapy.

So, from the requirements the photosensitizers are selected for the preparation of formulation and they must be selected on their properties and various formulation were developed:
Available formulations: Will be describing in detail:
Topical creams, Gel.

Nano formulations.

Steps in Photodynamic Therapy: There are 4 main steps:1371600193793
Mechanism of Photodynamic Therapy
Photosensitizing agent is injected into the bloodstream. The agent is taken by cells all over the body but stays in cancer cells for more time than it does in normal cells. Approximately 24 to 72 hours after injection , when most of the agent has left normal cells but remains in cancer cells, the tumor is exposed to light.

The photosensitizer absorbs the light in the tumor and produces an active form of oxygen that destroys nearby cancer cells.

The main pathways by which the combination of a PS, light and O2 results in photosensitized cell death are :
Type I reaction:PSs that are present in the ground non-excited state absorb visible light shifting first to an electronically excited singlet state (S1) and then, via mechanism of intersystem crossing, to the excited triplet state (T1), long-lived excited state.

The excited state PS converts molecular oxygen by electron transfer to superoxide and hydroxyl radicals, reactive oxygen species (ROS) can cause cell death and damage.

Type II reaction:Singlet oxygen is formed by energy transfer from the triplet PS to ground state triplet oxygen.

Fig. Mechanism of Photodynamic Therapy.PDT-mediated tumor destruction includes the cellular mechanisms with photo damage of mitochondria, lysosomes, nuclei, and cell membranes causing cell destruction.

This photo damage activates the apoptotic, necrotic and autophagic signals, leading to cell death.

In addition to directly killing cancer cells, PDT appears to shrink or destroy tumors in many of the other ways:
The photosensitizer damage blood vessels in the tumor, therefore preventing the cancer from receiving necessary nutrient.8509005715
EXTRACORPOREAL PHOTOPHERESISPDT is usually done as an outpatient treatment for PDT.

Extracorporeal photopheresis (ECP): Here a machine is used to collect the patient’s blood cells, treat them outside the body with a Photosensitizing agent, expose to light, and then return them to the patient body.

Extracorporeal photopheresis (ECP) is performed in 3 stages:
Leukapheresis: Collection of white blood cells, the collected WBCs are mixed with heparin, saline, and particular Photosensitizers, which intercalates with the DNA of the lymphocytes and makes the cells more susceptible to apoptosis when exposed to UVA radiation
Photo activation: Exposure to light.

Reinfusion: Treated cell product back to the patient.

Topical Solution, 20% (LEVULAN KERASTICK) + blue light illumination using the BLU-U® Blue Light Photodynamic Therapy Illuminator (LEVULAN KERASTICK and BLU-U PDT) is indicated for the treatment thick actinic keratosis of the face or scalp.

What are the limitations of PDT? Difficulty in administering photosensitizers.

The light needed to activate most Photosensitizers can’t pass through more than about one-third of an inch of tissue. For this reason, PDT is usually used to treat tumors on or just under the skin or on the lining of internal organs or body cavities.

PDT is also less useful in treating large tumors.

PDT is a local treatment and generally cannot be used to treat cancer that has spread (metastasized).

Complications or Side effects?Porfirmer sodium makes the skin and eyes sensitive to light 6 weeks after treatment.

PDT can cause burns, swelling, pain, and scarring in nearby healthy tissue.

Coughing, trouble swallowing, stomach pain, painful breathing, or shortness of breath these side effects are usually temporary.

Why Nanostructured Drug Delivery Systems????Improve the transcytosis of a Photosensitizer across barriers.

Effective in treating large tumors.

Treat cancer that has spread (metastasized).

Improve the photo stability of drugs and control their targeted delivery

The simultaneous co-delivery of two or more drugs.

Nanomaterials can significantly enhance the solubility of PS drugs in water, through hydrophilic properties and thus increase their cellular uptake.

Incorporation of Photosensitizers in Nanostructured Drug Delivery Systems by:
Polymeric nanoparticles (PNPs)
Solid lipid nanoparticles (SLNs)
Nanostructured lipid carriers (NLCs)
Gold nanoparticles (AuNPs),
Liquid crystals,
Dendrimers Types of Nanomaterials:Organic nanomaterials :
Liposomes and Polymeric nanoparticles, have achieved ease and controlled delivery of PS drugs by using biodegradable/biocompatible materials.

Inorganic nanomaterialsGold nanoparticles, Silica nanoparticles

Polymeric nanoparticles/micelles:Hydrophobic Ps drugs can be efficiently entrapped into nanoparticles by interaction between PS and hydrophobic polymers.

Biodegradable polymers: poly (lactide-co- glycolide) (PLGA) have been used as matrix materials for PS encapsulation.

ALA-loaded amorphous PLGA nanoparticles were internalized by squamous cell carcinoma cells and mediate photo cytotoxicity, which was more useful than free ALA of the same concentration.

Preparation of ALA-loaded PLGA NPsDouble emulsion solvent evaporation technique is used here:
Applications: Skin precancer and cancer such as actinic keratosis, Basal cell carcinoma, Bowen’s disease.

LiposomesPhospholipids Bilayer with Aqueous core.

Structural Flexibility and their ability to incorporate a variety of Hydrophilic and Hydrophobic PSs.

Hydrophilic drugs in their aqueous core and hydrophobic agents within their lipid bilayers renders them excellent delivery vehicles.

Eg. Aminolevulinic acid (ALA) prodrugs for PDT were encapsulated in Dipalmitoyl- phosphatidylcholine–based liposomes.

Gold nanoparticles (AuNPs):Heparin-coated gold nanoparticles (AuNPs) as glutathione (GSH) responsive PS drug carriers were useful delivery for advanced PDT.

Heparin was used for increasing gold nanoparticles water- solubility, biocompatibility, and colloidal stability.

Here Pheophorbide (PHA) was used as a PS drug. The hybrid gold Nanoparticles were formulated by incorporation of PhA-conjugated heparin with gold using gold- thiol interaction.

Carbon nanomaterials 🙁 fullerene, carbon nanotube, and graphene).

Carbon nanomaterials with unique structures have a great potential as PDT agents by attaching PS drugs on the functionalized carbon nanomaterials via either covalent or non-covalent manner.

Bio- compatibility and water-solubility of the carbon nanomaterials are also achieved by conjugation with various functional polymers.

Fullerene cages such as C60 have found their use in PDT because they can act as efficient PS drugs participating in the cascade of energy transfer that triggers the generation of ROS due to their abundant pi-bond electrons.

Carbon nanotubes can also act as either photosensitizers themselves or carriers for
Exogenous photosensitizers.Single walled carbon nanotubes (SWNTs) covalently functionalized with polyethylenimine (SWNT–PEI) and non-covalently functionalized with polyvinylpyrrolidone (SWNT–PVP) were discovered for PDT agents.

They has shown the photo cytotoxic effect against cancer cells under visible light illumination.

SWNT–PEI showed stronger photo cytotoxic effect compared to SWNT–PVP in vitro and in vivo.

Silica nanoparticlesORMOSIL (Organically modified silica) nanoparticles can be loaded with either hydrophilic or hydrophobic drugs, protecting them against extracellular barriers.

The ORMOSIL nanoparticles was synthesized by polycondensation of the iodo benzyl- pyro-silane, a precursor for ORMOSIL incorporating photosensitizer iodo benzyl pyropheophorbide.

Size of the prepared nanoparticles was ultralow (~20nm).

HydrogelsHydrogels are systems comprised of polymeric materials that are capable of absorbing water and Present a three-dimensional mesh structure.

These systems are widely used for the controlled release of hydrophilic drugs, mainly Due to the ease of dispersing the drug in the matrix. Additionally, they are biocompatible and have physical properties that are similar with living tissues.

DendrimersMostly used in PDT to load drug.

Dendrimers are highly branched polymers and have a very precisely defined diameter, usually about 1–10 nm. Their main advantage is the predictability and control of size and number of functional groups available for modifications. This provides greater certainty in predicting the amount of incorporated drug. Therefore, it enables reproducible pharmacokinetics, which makes dendrimers an interesting drug delivery system for PDT.

There are three ways to conjugate PS in dendrimers: 1. PS is trapped in the voids of a dendrimer;
PS is covalently bound to the dendrimers; 3. PS is used as a scaffold to form a dendrimer
ConclusionsNanomaterials combined with PS drugs increase the water solubility of hydrophobic PS drugs.

They also improve the target-specificity of PS drugs via passive targeting to tumor tissues.

Surface modification of PS-loaded Nano-particles with active targeting ligands further enhances the selective accumulation of PS drugs into tumors.

CLINICAL TRIALS: NANOTECHNOLOGY-BASED DRUG DELIVERY SYSTEMS FOR PHOTODYNAMIC THERAPY OF CANCER.Radachlorin” (Bremachlorin) a composition of 3 chlorophyll a derivatives in an aqueous solution.

465523311766Clinical phase I were performed.

Successfully passed Clinical Trials:”Radachlorin”® achieved marketing authorization In Russia in 2009 and a conditional approval in South Korea in 2008.

It is a candidate for phase III clinical trials In the EC and may be commercialized as
A prospective second-generation photosensitizer.

Metvix possesses a great advantage over Levulan in that it allows for deeper penetration into malignant lesions and has a large tumor selectivity, both of which may improve efficacy in cutaneous cancers.

149508967780700As noted previously, Metvix also results in reduced pain during treatment; Levulan and Metvix are now used routinely in dermatological oncology which represents a medical speciality where PDT is currently widely used.

Above are the other Photosensitizers used in PDT.

Case Study: We prove the efficacy of DL-PDT: Clinical Studies
They proved Sunlight can activate photodynamic therapy (PDT), and this is a proven way to reduce pain caused by the conventional PDT treatment.

Light sources included a Low fluence rate red LED panel, compact fluorescent bulbs, halogen bulbs and direct sunlight, as compared to traditional PDT delivery with conventional and fractionated high fluence rate red LED, Carbon dioxide (CO2) lasers, Argon lasers, Nd:YAG (Neodymium: Yttrium-Aluminum-Garnet) laser light delivery.

ABSTRACT:The incidence of actinic keratosis (AK) continues to increase in world. Currently available options for the treatment of AK include topical 5-fluorouracil (5-FU) Creams and daylight-mediated photodynamic therapy (DLPDT).

They use split-face pilot study was used to compared DLPDT using 16% methyl Aminolevulinate (MAL) cream versus 5-FU cream in patients with AK on the face/scal.

The objective of this comparative study was to evaluate the efficacy, safety, and patient satisfaction of DL-PDT using 16% methyl Aminolevulinate (MAL) cream versus topical treatment using 5-FU cream in patients with AK on the face and scalp.

An actinic keratosis (AK), also known as a solar keratosis, is a crusty, scaly growth caused by damage from exposure to ultraviolet (UV) radiation.

The lesion complete response rate at 3 months after treatment with DL-PDT and 5-FU was 80% and 93%, respectively.
The lesion partial response (decrease in lesion severity assessed visually) was 20% and 7%, respectively.

DL-PDT with 16% MAL cream is selected for a single session, with the possibility of a second session mostly after 3 months, necessary by the treating physician.

Safety assessment revealed a lower of adverse events (AEs) with DL-PDT (erythema, scales, and scabs) compared with 5-FU (erythema, crusts, pustules, and pruritus).
1188876129528Table 1. Various Formulation choices for PDT:
CONCLUSIONS:In addition, the single-day DL-PDT procedure (application of 16% MAL and exposure to sunlight), this treatment option more convenient compared with the 21-day home application of 5-FU for both the treating physician and patient.

Conclusively, DL-PDT is a favorable therapeutic alternative compared with 5-FU with good efficacy and a better safety profile in terms of incidence and duration of AEs.

These advantages allow patients to effectively treat their AK without compromising their social life.

From the overall SAT literature search I get to know about various photosensitizers and there types, various formulations and Clinical trials of various formulation.

In-depth knowledge of the nanoparticles based drug delivery systems for photodynamic therapy of cancer, How to prevent cancer cell growth to help society.

Information about Clinical grading of actinic keratosis Fig.2 (Olsen grading):

1032249-32870Above and Below Table2 & 3: Clinically Available Photosensitizers and under Trials:
720762303306Dyes as Photosensitizers:References:Photodynamic therapy of cancer: Basic principles and applications by Ángeles Juarranz, Pedro Jaén, Francisco Sanz-Rodríguez, Jesús Cuevas, Salvador González.

Photodynamic therapy for cancer by Dennis E.J.G.J. Dolmans, Dai Fukumura and Rakesh
K. Jain.

The present and future role of photodynamic therapy in cancer treatment by Stanley B Brown, Elizabeth A Brown, and Ian Walke Hopper C. Photodynamic therapy: a clinical reality in the treatment of cancer Lancet Oncol 2000; 1: 212–19.

Dougherty TJ, Gomer CJ, Henderson BW, et al. Photodynamic therapy. J Natl Cancer Inst
1998; 90: 889–905
Nanotechnology-Based Drug Delivery Systems for Photodynamic Therapy of Cancer: A Review by Giovana Maria Fioramonti Calixto, Jéssica Bernegossi, Laura Marise de Freitas Carla Raquel Fontana and Marlus Chorilli.

Targeted and effective photodynamic therapy for cancer using functionalized nanomaterials by Eun Ji Hong, Dae Gun Choi, and Min Suk Shim.

Bechet D, Couleaud P, Frochot C, Viriot ML, Guillemin F, Barberi Heyob M: Nanoparticles as vehicles for delivery of photodynamic therapy agents, Trends Biotechnol 2008;26:612–21.

Paszko E, Ehrhardt C, Senge MO, Kelleher DP, Reynolds JV : Nanodrug applications in photodynamic therapy. Photodiagn Photodynamic Ther 2011; 8:14–29.

Aisling E. O’Connor1, William M. Gallagher1 and Annette Byrne: Porphyrins and Nonporphyrin Photosensitizers in Oncology: Preclinical and Clinical Advances in Photodynamic Therapy, Received 28 August 2008, accepted 16 April 2009, DOI: 10.1111/j.1751-1097.2009.00585.

Elena V. Kochneva, Elena V. Filonenko, Elena G. Vakulovskaya, Elena G. Scherbakova, Oleg V. Seliverstov, Nikolay A. Markichev, Andrei V. Reshetnickov,” Photosensitizer Radachlorin®: Skin cancer PDT phase II clinical trials”, December 2010 Volume 7, Issue 4, Pages 258–267.

Gaston Nestor Galimberti: Daylight Photodynamic Therapy Versus5-Fluorouracil for the Treatment of Actinic Keratosis: A Case Series, Received: November 23, 2017 / published