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\def\citeauthor{~Sathish~Banala,
              ~Madhuri~Reddy~M,
              ~Archana~B,
              ~Marem~Laxmiprasanna,
              ~Abulgsim~Dudain~Ali~Babiker,
              ~Nimmalapudi~Aashritha,
              ~Ollepu~Keerthana}
\def\citetitle{Development and Characterization of Quercetin Loaded Polycaprolactone Nanoparticles for Tumors}
\def\copyrightstmt{This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial- ShareAlike 4.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as the author is credited and the new creations are licensed under the identical terms.}
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\def\RunningAuthor{Sathish Banala et al.}
\firstPage{22}
\articleType{Original Article}
\receivedDate{20 Nov 2021}
\acceptedDate{01 Dec 2021}
\revisedDate{30 Nov 2021}
\journalVolume{2}
\journalIssue{1}
\journalDoi{fjphs.v2i1.166}
\copyrightYear{2022}
\eISSN{2583-116X}
\journalDoi{fjphs.v2i1.166}
\def\authorCount{7}
\def\affCount{3}

\def\journalTitle{Future Journal of Pharmaceuticals and Health Sciences}

\title{Development and Characterization of Quercetin Loaded Polycaprolactone Nanoparticles for Tumors}
\author{Sathish~Banala\textsuperscript{*}\textsuperscript{1}\textsuperscript{\href{https://orcid.org/0000-0002-5583-8551}{\XeTeXLinkBox{\includegraphics[height=7pt]{orcid-logo-pharmascope.pdf}}}},  
            Madhuri~Reddy~M\textsuperscript{1}\textsuperscript{\href{https://orcid.org/0000-0001-5636-4653}{\XeTeXLinkBox{\includegraphics[height=7pt]{orcid-logo-pharmascope.pdf}}}},  
            Archana~B\textsuperscript{2}\textsuperscript{\href{https://orcid.org/0000-0002-1144-3849}{\XeTeXLinkBox{\includegraphics[height=7pt]{orcid-logo-pharmascope.pdf}}}},  
            Marem~Laxmiprasanna\textsuperscript{3}\textsuperscript{\href{https://orcid.org/0000-0003-4960-6567}{\XeTeXLinkBox{\includegraphics[height=7pt]{orcid-logo-pharmascope.pdf}}}},  
            Abulgsim~Dudain~Ali~Babiker\textsuperscript{3}\textsuperscript{\href{https://orcid.org/0000-0003-4297-9862}{\XeTeXLinkBox{\includegraphics[height=7pt]{orcid-logo-pharmascope.pdf}}}},  
            Nimmalapudi~Aashritha\textsuperscript{3}\textsuperscript{\href{https://orcid.org/0000-0002-8243-2020}{\XeTeXLinkBox{\includegraphics[height=7pt]{orcid-logo-pharmascope.pdf}}}}, 
            Ollepu~Keerthana\textsuperscript{3}\textsuperscript{\href{https://orcid.org/0000-0002-9629-4108}{\XeTeXLinkBox{\includegraphics[height=7pt]{orcid-logo-pharmascope.pdf}}}}~\\[5pt]{\textsuperscript{1}Department of Pharmaceutics, St. Mary's Group of Institution, Deshmukhi (Village), Pochampally (Mandal), Yadadri Bhuvanagiri (Dist), Telangana-508284, India}~\\{\textsuperscript{2}Department of Pharmacology, St. Mary's Group of Institution, Deshmukhi (Village), Pochampally (Mandal), Yadadri Bhuvanagiri (Dist), Telangana-508284, India}~\\{\textsuperscript{3}St. Mary's Group of Institution, Deshmukhi (Village), Pochampally (Mandal), Yadadri Bhuvanagiri (Dist), Telangana-508284, India}}

\begin{abstract}
Cancer is one of the dreadful diseases in the world, with a poor prognosis. Numerous assessments showed both tissue and cell distribution profiles of anticancer drugs might be reliant their defense in submicronic nanoparticles. The explanation behind this way is to wage increase antitumor efficacy while lowering systemic unwanted effects. These nanoparticles are well known to show theranostic activity which further increases the therapeutic index. In this study, we are developing antioxidant quercetin for the anti-tumor effect. The quercetin nanoparticles are prepared using the nanoprecipitation method with polycaprolactone as a polymer in which the nanoparticles are recovered. These nanoparticles are further optimized for the drug loading, characterized by the \-morphology using SEM and drug-polymer interactions by FT-IR, DSC. This lipophilic drug has shown a maximum entrapment efficiency of 81\% and the SEM images showed nanoparticles of different shapes. There showed no interactions indicating the stability of quercetin-loaded polycaprolactone nanoparticles.
\end{abstract}\def\keywordstitle{Keywords}

\begin{keywords}Cancer,\newline Nanoparticles,\newline Theranostic,\newline Tumor Cells,\newline Quercetin Dihydrate
\end{keywords}
\twocolumn[ \maketitle {\printKwdAbsBox}]
\makeatletter{\raggedright{\Large$^\ast$}Corresponding Author\par Name:\ Sathish~Banala~\\ Phone:\ +91 9848951382~\\  Email:\ sathibanala@gmail.com
        \par}\vspace*{-13pt}\hrulefill\par\ifx\@eISSN\@empty\else{\fontsize{12}{14}\selectfont eISSN: \@eISSN\hfill pISSN: \@pISSN}\par\fi% 
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        \makeatother
        
    
\section{Introduction}
Cancer is responsible for one in eight deaths worldwide. It encompasses more than 100 distinct diseases with diverse risk factors and epidemiology which originate from most of the cell types and organs of the human body and which are characterized by relatively unrestrained proliferation of cells that can invade beyond normal tissue boundaries and metastasize to distant organs \unskip~\cite{1291466:23863486}. It is not only confined to humans and animals; other living organisms can also get cancer. Cancer cells can break away from this original mass of cells, travel through the blood and lymph systems, and lodge in other organs where they can again repeat the uncontrolled growth cycle. Nanoparticles applied as drug delivery systems are sub-micron sized particles (3-200 nm), devices, or systems that can be made using a variety of materials including polymers (polymeric nanoparticles, micelles, or dendrimers), lipids (liposomes), viruses (viral nanoparticles), an organometallic compound or carbon nanotubes \unskip~\cite{1291466:23863510}. Quercetin (Q) is a flavonoid and, to be more specific, a flavonol. It is the aglycone form of several other flavonoid glycosides, such as rutin and quercitrin, found in citrus fruit, buckwheat, and onions. quercetin forms the glycosides quercitrin and rutin together with rhamnose and rutinose respectively. Quercetin is a powerful antioxidant. It is also believed to be a natural anti-cancer and anti-inflammatory agent. Quercetin has been promoted as being effective against a wide variety of diseases. The aim of the present study is to design a novel formulation of nanoparticles for the treatment of cancer \unskip~\cite{1291466:23863521}. This study involves designing nanoparticles using PCL as a polymer for sustained release action, to optimize the formulation of nanoparticles, Characterization of Q-loaded nanoparticles. 
    
\section{Material and Methods }
Quercetin dihydrate \& polycaprolactone sample sigma Aldrich, Polyvinyl alcohol, Gelatin, Acetone, Tween 80, span 80 was found to be Himedia. Dichloromethane, poloxamer-188, ethanol was found to be Hayman. All abundant chemical as well as chemical agent utilized in this study are of analytical grade.
    
\section{METHODOLOGY}
\textbf{Preparation of PCL Nanoparticles}

In this, the nanoparticles are prepared by a solvent evaporation method. Initially, a weighed quantity of poloxamer-188 is added to double distilled water with magnetic stirring. The solution was maintained at 50-60\ensuremath{^{0}} C and the PCL was dissolved in acetone with mild sonication. Then the organic solution was added to the aqueous solution slowly using a micro pipette to disperse the organic solution. Immediately on the addition of PCL to the aqueous solution, it forms a bluish tinge which indicates the formation of nanoparticles. This solution is then stirred for about 2 hrs at the same temperature. Then the nanoparticles are recovered by centrifugation at low pressure above 10,000 rpm. The formed sediment is then lyophilized to form\- nanoparticles \unskip~\cite{1291466:23863522}.

\textbf{Preparation of Quercetin-Loaded PCL Nanoparticles}

The preparation of the quercetin-loaded PCL nanoparticles follows the same method as that of empty nanoparticles along with the addition of drug into organic solution with PCL. 

The formed quercetin nanoparticles are then recovered by centrifugation at low pressure and 10,000 rpm \unskip~\cite{1291466:23863524}. The different formulations of Q loaded PCL [Table~\ref{tw-3b5f85472b79}].


\begin{table*}[!htbp]
\caption{\boldmath {Formulations of Quercetin- PCL Nanoparticle} }
\label{tw-3b5f85472b79}
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\begin{tabulary}{\linewidth}{p{\dimexpr.12799999999999999\linewidth-2\tabcolsep}p{\dimexpr.10200000000000001\linewidth-2\tabcolsep}p{\dimexpr.1399\linewidth-2\tabcolsep}p{\dimexpr.104\linewidth-2\tabcolsep}p{\dimexpr.11009999999999998\linewidth-2\tabcolsep}p{\dimexpr.10100000000000001\linewidth-2\tabcolsep}p{\dimexpr.11299999999999997\linewidth-2\tabcolsep}p{\dimexpr.10200000000000001\linewidth-2\tabcolsep}p{\dimexpr.10000000000000002\linewidth-2\tabcolsep}}
\tbltoprule \rowcolor{kwdboxcolor}Formula- \mbox{}\protect\newline tion Code & Method of preparation of NPs & Stirring rpm/Temp (\ensuremath{^{o}}C)/ Stirring time(hrs) & Stabilizer & Stabilizer \mbox{}\protect\newline (\%) & Volume of Stabilizer   \mbox{}\protect\newline (ml) & Quercetin  \mbox{}\protect\newline (mg) & Poly caprolactone  (mg) & Centri- \mbox{}\protect\newline fugation (rpm)\\
\tblmidrule 
N1 &
  Emulsion method &
   &
  Tween- 80 &
   &
   &
   &
   &
  \\
N2 &
   &
   &
  Gelatin &
   &
   &
   &
   &
  10000\\
N3 &
   &
   &
  Polyvinyl alcohol &
   &
   &
  2.5 &
   &
  \\
N4 &
  \multicolumn{1}{p{\dimexpr(.10200000000000001\linewidth-2\tabcolsep)}}{\multirow{2}{\linewidth}{Nano precipitation method}} &
  1000/ RT/ 2 &
   &
  0.2 &
  25 &
   &
  50 &
  \\
N5 &
   &
   &
  \multicolumn{1}{p{\dimexpr(.104\linewidth-2\tabcolsep)}}{\multirow{2}{\linewidth}{Poloxamer-188}} &
   &
   &
   &
   &
  \\
N6 &
   &
   &
   &
   &
   &
  5 &
   &
  18000\\
N7 &
   &
   &
   &
   &
   &
  7.5 &
   &
  \\
\tblbottomrule 
\end{tabulary}\par 
\end{table*}
\textbf{Drug - Excipient Interaction }

\textbf{Fourier Transform Infrared Spectral (FT-IR) Analysis}

FT-IR spectra determine the positions and relative sizes of all the absorptions, or peaks, in the IR region. Samples were analyzed by pressed pellet technique using KBr. The spectra of the drug, polymer, empty nanoparticles and drug-loaded nanoparticles are recorded \unskip~\cite{1291466:23863588}.

\textbf{Differential Scanning Calorimetrical Analysis}

Differential Scanning Calorimetry is the most widely used technique of all the thermal analysis methods. DSC measures the change in the difference of heat flow rate to the material (sample) and reference material while they are subjected to a controlled temperature program to obtain thermograms \unskip~\cite{1291466:23863612}.

\textbf{Scanning Electron Microscopy}

Scanning electron microscopy is an excellent tool for the physical observation of morphological features of nanoparticles. It is helpful to examine Nanoparticle's shape and surface characteristics to correlate other determining characteristics such as surface area and bulk density \unskip~\cite{1291466:23864175}.

\textbf{Evaluation of Quercetin Loaded PCL Nanoparticles}

\textbf{Particle Size}

To confirm the formation of nanoparticles the nanosuspension formed after the fluoridation of organic phase and soul stirring is after that collected plus analyzed by Malvern Zeta Sizer. The nanoparticles after lyophilization are also analyzed for particle size analysis \unskip~\cite{1291466:23864178}.

\textbf{Polydispersity index}

Polydispersity index is done for both nanosuspension both before and after lyophilization \unskip~\cite{1291466:23864179}. Polydispersity (non-uniform size distribution) was calculated by the following formula:\textbf{\space }

\textit{Polydispersity = (D\ensuremath{_{0.9}} {\textendash} D\-\ensuremath{_{0.1}}) / D\ensuremath{_{0.5}}}

Where D\ensuremath{_{0.9}}, D\ensuremath{_{0.5,}} and D\ensuremath{_{0.1}} are the particle diameters determined at the 90th, 50th and 10th percentile of undersized particles, respectively.

\textbf{Zeta Potential}

Zeta potential may be an indicator for comparing the stableness the dispersed colloidal solution system. The higher the absolute value of zeta potential, the bigger the electrostatic repulsion between each nanoparticle in solution \unskip~\cite{1291466:23864193}.

\textbf{Drug Loading and Encapsulation Efficiency}

1 mg of nanoparticles was accurately weighed in 2ml Expender tubes and then vortexed with 200 \ensuremath{\mu}l of dichloromethane for 5 min. 

Then add 1800 \ensuremath{\mu}l of ethanol for precipitating PCL (as it is insoluble) and vortexed again for 10 min. Then the absorbance of the samples is measured using a UV-Vis spectrophotometer at 370 nm. 

The absorbance obtained are then used for calculating the amount of Quercetin present in the nanoparticles \unskip~\cite{1291466:23864195}.

$\style{font-size:8px}\%\style{font-size:8px}\;\style{font-size:8px}D\style{font-size:8px}r\style{font-size:8px}u\style{font-size:8px}g\style{font-size:8px}\;\style{font-size:8px}l\style{font-size:8px}o\style{font-size:8px}a\style{font-size:8px}d\style{font-size:8px}i\style{font-size:8px}n\style{font-size:8px}g\style{font-size:8px}=\frac{\style{font-size:8px}W\style{font-size:8px}e\style{font-size:8px}i\style{font-size:8px}g\style{font-size:8px}h\style{font-size:8px}t\style{font-size:8px}\;\style{font-size:8px}o\style{font-size:8px}f\style{font-size:8px}\;\style{font-size:8px}Q\style{font-size:8px}u\style{font-size:8px}e\style{font-size:8px}r\style{font-size:8px}c\style{font-size:8px}e\style{font-size:8px}t\style{font-size:8px}i\style{font-size:8px}n\style{font-size:8px}\;\style{font-size:8px}i\style{font-size:8px}n\style{font-size:8px}\;\style{font-size:8px}N\style{font-size:8px}a\style{font-size:8px}n\style{font-size:8px}o\style{font-size:8px}p\style{font-size:8px}a\style{font-size:8px}r\style{font-size:8px}t\style{font-size:8px}i\style{font-size:8px}c\style{font-size:8px}l\style{font-size:8px}e\style{font-size:8px}s}{\style{font-size:8px}W\style{font-size:8px}e\style{font-size:8px}i\style{font-size:8px}g\style{font-size:8px}h\style{font-size:8px}t\style{font-size:8px}\;\style{font-size:8px}o\style{font-size:8px}f\style{font-size:8px}\;\style{font-size:8px}N\style{font-size:8px}a\style{font-size:8px}n\style{font-size:8px}o\style{font-size:8px}p\style{font-size:8px}a\style{font-size:8px}r\style{font-size:8px}t\style{font-size:8px}i\style{font-size:8px}c\style{font-size:8px}l\style{font-size:8px}e\style{font-size:8px}s}\style{font-size:8px}\ast\style{font-size:8px}{100} $

$\style{font-family:'Times New Roman'}{\style{font-size:8px}{\%\;Entrapment\;efficiency=\frac{\%\;Drug\;loading}{\%\;Theoritical\;loading}\ast100}} $

\textit{\textbf{In-vitro}} \textbf{ Release Studies}

In this, accurately weighed quantities of nanoparticles are taken into a pretreated dialysis membrane. A small quantity of buffer is added into the dialysis bag along with nanoparticles and suspended in PBS at 37\ensuremath{\pm}1\ensuremath{^{o}}C. 

Then aliquots of samples are collected at regular intervals and the same volume has to be replaced by the PBS to maintain sink conditions \unskip~\cite{1291466:23864198}. 

Then the absorbance of the collected aliquots are measured at 370 nm using a UV- Vis spectrophotometer.
    
\section{Results and Discussion}
\textbf{Surface Morphology}

These nanoparticles will be then examined for surface morphology employing a Scanning electron microscope and located that they tend to be spheric, rodlike with heterogeneous morphology [Figure~\ref{f-8517348ace23}  and Figure~\ref{f-c11b76c2b5a1}].


\bgroup
\fixFloatSize{images/0331afcf-e6ad-4a29-8f5e-8822ae121994-upicture1.png}
\begin{figure}[!htbp]
\centering \makeatletter\IfFileExists{images/0331afcf-e6ad-4a29-8f5e-8822ae121994-upicture1.png}{\includegraphics{images/0331afcf-e6ad-4a29-8f5e-8822ae121994-upicture1.png}}{}
\makeatother 
\caption{\boldmath {Surface Morphology of Empty PCL Nanoparticles}}
\label{f-8517348ace23}
\end{figure}
\egroup

\bgroup
\fixFloatSize{images/eb70e04c-4eb0-4362-90b7-185e396a0528-upicture2.png}
\begin{figure}[!htbp]
\centering \makeatletter\IfFileExists{images/eb70e04c-4eb0-4362-90b7-185e396a0528-upicture2.png}{\includegraphics{images/eb70e04c-4eb0-4362-90b7-185e396a0528-upicture2.png}}{}
\makeatother 
\caption{\boldmath {Surface Morphology of Q Loaded PCL Nanoparticle}}
\label{f-c11b76c2b5a1}
\end{figure}
\egroup
\textbf{Drug Excipient Interaction and Polymorphism Characterization}

\textbf{FT-IR Spectra}

The optimized formulation N6 is then characterized by FT-IR spectra obtained could confirm the chemical stability of quercetin in the nanoparticles. FT-IR spectra of quercetin, PCL, empty PCL nanoparticles, and quercetin-loaded PCL nanoparticles. Quercetin shows characteristic aromatic bending and stretching around 1100 and 1600 cm\ensuremath{^{-1}}, -OH phenolic bending around 1200 and 1400 cm\ensuremath{^{-1}}. FTIR spectrum of PCL shows prominent peaks at 1730 and 3440 cm\ensuremath{^{\ensuremath{-}1}}, which corresponds to the {\textendash}CO (stretching) and {\textendash}OH (bending) groups. The peaks at 2868 and 2947 cm\ensuremath{^{\ensuremath{-}1}} are related to the C{\textendash}H bond of saturated carbons. The FTIR analysis of empty PCL nanoparticles shows similar characteristic peaks to that of plain PCL [Figure~\ref{f-1cdfb8d7b307}, Figure~\ref{f-a970cbaa916d}, Figure~\ref{f-8746b458fa75}  and Figure~\ref{f-5235d846e5ef}].


\bgroup
\fixFloatSize{images/6abe7797-df0f-4ed2-b918-408a38842d0c-upicture3.png}
\begin{figure}[!htbp]
\centering \makeatletter\IfFileExists{images/6abe7797-df0f-4ed2-b918-408a38842d0c-upicture3.png}{\includegraphics{images/6abe7797-df0f-4ed2-b918-408a38842d0c-upicture3.png}}{}
\makeatother 
\caption{\boldmath {FT-IR Spectra of Quercetin Dihydrate}}
\label{f-1cdfb8d7b307}
\end{figure}
\egroup

\bgroup
\fixFloatSize{images/aec4ea93-97c5-44a2-bf96-be508c9025a8-upicture4.png}
\begin{figure}[!htbp]
\centering \makeatletter\IfFileExists{images/aec4ea93-97c5-44a2-bf96-be508c9025a8-upicture4.png}{\includegraphics{images/aec4ea93-97c5-44a2-bf96-be508c9025a8-upicture4.png}}{}
\makeatother 
\caption{\boldmath {FT-IR Spectra of Polycaprolactone}}
\label{f-a970cbaa916d}
\end{figure}
\egroup

\bgroup
\fixFloatSize{images/8b8e9207-c185-4aec-bf34-303cce1ce499-upicture5.png}
\begin{figure}[!htbp]
\centering \makeatletter\IfFileExists{images/8b8e9207-c185-4aec-bf34-303cce1ce499-upicture5.png}{\includegraphics{images/8b8e9207-c185-4aec-bf34-303cce1ce499-upicture5.png}}{}
\makeatother 
\caption{\boldmath {FT-IR Spectra of Empty Polycaprolactone Nanoparticles}}
\label{f-8746b458fa75}
\end{figure}
\egroup

\bgroup
\fixFloatSize{images/02bbb35d-c295-4273-933c-3a4cbc2bb969-upicture6.png}
\begin{figure}[!htbp]
\centering \makeatletter\IfFileExists{images/02bbb35d-c295-4273-933c-3a4cbc2bb969-upicture6.png}{\includegraphics{images/02bbb35d-c295-4273-933c-3a4cbc2bb969-upicture6.png}}{}
\makeatother 
\caption{\boldmath {FT-IR Spectra of Q Loaded Polycaprolactone Nanoparticles}}
\label{f-5235d846e5ef}
\end{figure}
\egroup
\textbf{Differential Scanning Calorimetry}

DSC analysis was performed on plain PCL, quercetin, empty nanoparticles, and Q-loaded nanoparticles (N6) and the respective thermograms. The melting temperature for PCL was observed at 55.11\ensuremath{^{o}}C. The melting temperature of quercetin was observed at 317.73\ensuremath{^{o}}C and it shows a broad endothermic peak for dehydration from 107.13\ensuremath{^{o}}C to 139.79\ensuremath{^{o}}C. These PCL nanoparticles did not contain any peaks associated with the crystals of the drug, suggesting that the drug was amorphous in the polycaprolactone matrix [Figure~\ref{f-2c0a0e76fce3}, Figure~\ref{f-d7e77de126a5}  \& Figure~\ref{f-1653fb0d0b44}].


\bgroup
\fixFloatSize{images/ed5c425e-1cee-44b4-8fd7-fc6c7f75b9ae-upicture7.png}
\begin{figure}[!htbp]
\centering \makeatletter\IfFileExists{images/ed5c425e-1cee-44b4-8fd7-fc6c7f75b9ae-upicture7.png}{\includegraphics{images/ed5c425e-1cee-44b4-8fd7-fc6c7f75b9ae-upicture7.png}}{}
\makeatother 
\caption{\boldmath {DSC Report of Quercetin}}
\label{f-2c0a0e76fce3}
\end{figure}
\egroup

\bgroup
\fixFloatSize{images/10eb874d-f61f-4c07-90a2-f7820a24ebdc-upicture8.png}
\begin{figure}[!htbp]
\centering \makeatletter\IfFileExists{images/10eb874d-f61f-4c07-90a2-f7820a24ebdc-upicture8.png}{\includegraphics{images/10eb874d-f61f-4c07-90a2-f7820a24ebdc-upicture8.png}}{}
\makeatother 
\caption{\boldmath {DSC Report of PCL}}
\label{f-d7e77de126a5}
\end{figure}
\egroup

\bgroup
\fixFloatSize{images/26ce9f6f-f116-4561-9828-3ab2b56b59c8-upicture9.png}
\begin{figure}[!htbp]
\centering \makeatletter\IfFileExists{images/26ce9f6f-f116-4561-9828-3ab2b56b59c8-upicture9.png}{\includegraphics{images/26ce9f6f-f116-4561-9828-3ab2b56b59c8-upicture9.png}}{}
\makeatother 
\caption{\boldmath {DSC Report of Q Loaded Nanoparticles}}
\label{f-1653fb0d0b44}
\end{figure}
\egroup
\textbf{Optimization of the Method of Preparation for Q-loaded PCL Nanoparticles}

The formulation N1 is prepared by using the emulsion method in which emulsion is formed and stabilized by using surfactants. The preparation procedure includes the organic solution which contains polycaprolactone, span-80, and quercetin. This organic solution is then added into an aqueous solution containing Tween-80 as a stabilizer. The next formulation N2 is prepared by the nanoprecipitation method with different stabilizers. In this method organic solution containing polycaprolactone, quercetin is added to the aqueous phase with stabilizers. The formed nanoparticles in both formulations are then centrifuged at 10,000 rpm at 4\ensuremath{^{0}} C and then lyophilized. In this, the nanoparticles in the N1 formulation have failed to recover because of the surfactants which formed slurry but in the N2 formulation, the nanoparticles are recovered. So, the nanoprecipitation method is best suited for the formation of quercetin nanoparticles using PCL as a polymer. Therefore, further optimization of stabilizers in the nanoprecipitation method was done.

\textbf{Optimization of Stabilizers in Nano Precipitation Method}

\textbf{Characterization of Nanosuspensions}

In this different stabilizer's gelatin, polyvinyl alco-


\begin{table*}[!htbp]
\caption{\boldmath {Evaluation of Nanoparticle Formulations} }
\label{tw-6c7683e99e3e}
\def\arraystretch{1.1}
\ignorespaces 
\centering 
\begin{tabulary}{\linewidth}{p{\dimexpr.32989999999999995\linewidth-2\tabcolsep}p{\dimexpr.3593000000000001\linewidth-2\tabcolsep}p{\dimexpr.3108\linewidth-2\tabcolsep}}
\tbltoprule \rowcolor{kwdboxcolor}\cAlignHack Formulation Code & \cAlignHack Polydispersity Index & \cAlignHack \% Drug Loading\\
\tblmidrule 
\cAlignHack N1 &
  \cAlignHack 0.64 &
  \cAlignHack ---\\
\cAlignHack N2 &
  \cAlignHack 0.15 &
  \cAlignHack ---\\
\cAlignHack N3 &
  \cAlignHack 0.69 &
  \cAlignHack ---\\
\cAlignHack N4 &
  \cAlignHack 1 &
  \cAlignHack 68\%\\
\cAlignHack N5 &
  \cAlignHack 1 &
  \cAlignHack 75.6\%\\
\cAlignHack N6 &
  \cAlignHack 1 &
  \cAlignHack 84\%\\
\cAlignHack N7 &
  \cAlignHack 1 &
  \cAlignHack 80.3\%\\
\tblbottomrule 
\end{tabulary}\par 
\end{table*}

\begin{table*}[!htbp]
\caption{\boldmath {In-vitro Drug Release of Quercetin from Nanoparticles} }
\label{tw-69ef81c4ba53}
\def\arraystretch{1.1}
\ignorespaces 
\centering 
\begin{tabulary}{\linewidth}{p{\dimexpr.0986\linewidth-2\tabcolsep}p{\dimexpr.1066\linewidth-2\tabcolsep}p{\dimexpr.1178\linewidth-2\tabcolsep}p{\dimexpr.11309999999999999\linewidth-2\tabcolsep}p{\dimexpr.15149999999999999\linewidth-2\tabcolsep}p{\dimexpr.1391\linewidth-2\tabcolsep}p{\dimexpr.1302\linewidth-2\tabcolsep}p{\dimexpr.1431\linewidth-2\tabcolsep}}
\tbltoprule \rowcolor{kwdboxcolor}Time \mbox{}\protect\newline (hrs) & Abs & Conc \mbox{}\protect\newline (\ensuremath{\mu}g/ml) & Vol of SF (ml) & Conc. of SF(\ensuremath{\mu}g) & Conc. in TV (\ensuremath{\mu}g) & Cumulative Concentration (\ensuremath{\mu}g) & \% Quercetin Release\\
\tblmidrule 
0 &
  0 &
  0 &
  0 &
  0 &
  0 &
  0 &
  0\\
0.25 &
  0 &
  0 &
  0 &
  0 &
  0 &
  0 &
  0\\
0.5 &
  0 &
  0 &
  0 &
  0 &
  0 &
  0 &
  0\\
1 &
  0.0061 &
  0.123232 &
  2 &
  0.246465 &
  4.929292929 &
  4.929293 &
  1.040264415\\
1.5 &
  0.0016 &
  0.032323 &
  2 &
  0.064646 &
  1.292929293 &
  1.539394 &
  0.324869461\\
2 &
  0.0036 &
  0.072727 &
  2 &
  0.145455 &
  2.909090909 &
  3.220202 &
  0.679582573\\
4 &
  0.0132 &
  0.266667 &
  2 &
  0.533333 &
  10.66666667 &
  11.12323 &
  2.347416339\\
7 &
  0.0105 &
  0.212121 &
  2 &
  0.424242 &
  8.484848485 &
  9.474747 &
  1.999524633\\
10 &
  0.0158 &
  0.319192 &
  2 &
  0.638384 &
  12.76767677 &
  14.18182 &
  2.992891882\\
19 &
  0.0276 &
  0.557576 &
  2 &
  1.115152 &
  22.3030303 &
  24.35556 &
  5.13992942\\
24 &
  0.0374 &
  0.755556 &
  2 &
  1.511111 &
  30.22222222 &
  33.3899 &
  7.046512396\\
30 &
  0.0818 &
  1.652525 &
  4 &
  6.610101 &
  66.1010101 &
  70.7798 &
  14.93717378\\
42 &
  0.1372 &
  2.771717 &
  4 &
  11.08687 &
  110.8686869 &
  122.1576 &
  25.77979862\\
54 &
  0.1638 &
  3.309091 &
  4 &
  13.23636 &
  132.3636364 &
  154.7394 &
  32.65577587\\
66 &
  0.1676 &
  3.385859 &
  4 &
  13.54343 &
  135.4343434 &
  171.0465 &
  36.09717519\\
90 &
  0.2263 &
  4.571717 &
  4 &
  18.28687 &
  182.8686869 &
  232.0242 &
  48.96575761\\
114 &
  0.2022 &
  4.084848 &
  4 &
  16.33939 &
  163.3939394 &
  230.8364 &
  48.71507094\\
174 &
  0.1874 &
  3.785859 &
  4 &
  15.14343 &
  151.4343434 &
  235.2162 &
  49.63937145\\
234 &
  0.1774 &
  3.583838 &
  4 &
  14.33535 &
  143.3535354 &
  242.2788 &
  51.12984866\\
294 &
  0.1662 &
  3.357576 &
  4 &
  13.4303 &
  134.3030303 &
  247.5636 &
  52.24514854\\
\tblbottomrule 
\end{tabulary}\par 
\end{table*}

\bgroup
\fixFloatSize{images/556378d9-5f25-4aeb-b8af-5990c079f20d-upicture10.png}
\begin{figure}[!htbp]
\centering \makeatletter\IfFileExists{images/556378d9-5f25-4aeb-b8af-5990c079f20d-upicture10.png}{\includegraphics[width=\linewidth]{images/556378d9-5f25-4aeb-b8af-5990c079f20d-upicture10.png}}{}
\makeatother 
\caption{\boldmath {In vitro Release Profile}}
\label{f-08e6c806f9ce}
\end{figure}
\egroup

\bgroup
\fixFloatSize{images/f5b4d370-8e87-45db-9708-62054cb4e9ad-upicture11.png}
\begin{figure}[!htbp]
\centering \makeatletter\IfFileExists{images/f5b4d370-8e87-45db-9708-62054cb4e9ad-upicture11.png}{\includegraphics[width=\linewidth]{images/f5b4d370-8e87-45db-9708-62054cb4e9ad-upicture11.png}}{}
\makeatother 
\caption{\boldmath {Initial Burst Release of Quercetin}}
\label{f-a255231a779a}
\end{figure}
\egroup
hol, poloxamer-188 of similar concentration are used in the nanoprecipitation method. The particle size analysis of the nanoparticle suspension using gelatin, polyvinyl alcohol, poloxamer-188 i.e., n3, n4, n5 respectively. The zeta potentials of the formulations are also measured. From reports the particle sizes and zeta potentials of gelatin, PVA stabilizers are better compared to that of poloxamer-188. For these suspensions, the polydispersity indexes are also measured to determine the uniformity of nanoparticles [Figure~\ref{f-c11b76c2b5a1}]. The polydispersity index of poloxamer-188 was found to be lesser than the other two indicating higher uniformity of particles.

\textbf{Optimization of Centrifugation rpm for Recovery of Product}

The nanosuspensions are then centrifuged at 10,000 rpm and 18,000 rpm for N4 and N5 formulations respectively. The formulations are then evaluated for particle size and zeta potentials. It has shown that 18,000 rpm for centrifugation produced nanoparticles of much uniform size because of the higher rpm that collects the smaller-sized nanoparticles. This also further has enhanced the \% yield of nanoparticles. The formed nanoparticles are then centrifuged and lyophilized at -54\ensuremath{^{o}}C and 1 pas pressure for 3 days for the removal of an aqueous solution. The dried nanoparticles are recovered and observed. The nanoparticles formed by using PVA, gelatin stabilizers have formed film-like structures failing to recover the nanoparticles. The nanoparticles of poloxamer-188 are powdery and are recovered properly. So, the poloxamer-188 stabilizer was selected for formulating the quercetin nanoparticles by the nanoprecipitation method. The formed nanoparticles also easily got redispersed in water.

\textbf{Optimization of Drug Loading}

In N5 formulation initially 2.5 mg of Quercetin was loaded into PCL nanoparticles (1:20). Then the nanoparticles are then evaluated for entrapment efficiency. The formulations N6, N7 are then loaded with a higher \% of Quercetin. The formulation N6 was loaded with 5mg (2:50) of Quercetin into the PCL nanoparticles and evaluated. The formulation N7 was also loaded with a higher amount of Quercetin (3:50) and then evaluated [Table~\ref{tw-6c7683e99e3e}]. The entrapment efficiency of the N6 formulation was found to be 84\% and so it is then used for further studies. The N6 formulation was then evaluated for drug excipient interaction and polymorphism characterization.

\textit{\textbf{In vitro}} \textbf{ Release Studies}

The quercetin release profiles were measured in phosphate buffer saline(PBS) of pH 7.4 at 37\ensuremath{^{o}}C [Table~\ref{tw-69ef81c4ba53}]. The formulation (N6) initially showed burst release for 24 hrs and then a constant release was observed. Initial burst release of quercetin from nanoparticles may be attributed due to the heterogeneous quercetin distribution [Figure~\ref{f-08e6c806f9ce}, Figure~\ref{f-a255231a779a}]. Quercetin that is either loosely associated with the surface or embedded in the surface layer are responsible for the burst release.
    
\section{CONCLUSION}
In this study, we have prepared the Quercetin nanoparticles for sustained release to show anti-tumor effects are designed and optimized. The nanoparticles prepared by the nanoprecipitation method showed product recovery. The stabilizers gelatin, PVA, poloxamer-188 used during the formulation is then optimized. The nanoparticles formed using poloxamer- 188 as a stabilizer are found well lyophilized. These nanoparticles are then evaluated for the drug loading efficiency and a higher drug loading formulation (N6) was found. This optimized formulation is then characterized and reported.
\section*{Acknowledgement}I would like to thank Principal sir (Dr. Kamal Hassan), St. Mary's Group of Institutions, Deshmukhi (Village), Pochampally (Mandal), Yadadri Bhuvanagiri(Dist), Telangana-508284, India.

\textbf{Future Perspectives}

To surface modify the optimized formulation of nanoparticles for the more therapeutic activity of quercetin nanoparticles. To load this optimized nanoparticle into a suitable scaffold to have more therapeutic activity in benign tumors. To study the release from this scaffold. To perform cell line and \textit{invivo} studies for this optimized formulation. The quercetin can also be loaded into a suitable polymer that causes the release of nanoparticles at the tumor site.

\textbf{Conflict of Interest} \textbf{\space }

The authors attest that they have no conflict of interest in this study. 

\textbf{Funding Support} \textbf{\space }

The authors declare that there is no financial support for the current study.
    

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{\fontsize{9.12}{10.12}\selectfont\textcopyright\ \makeatletter\@copyrightYear\makeatother\ Pharma Springs Publication.}

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